Use of rnai inhibiting parp activity for the manufacture of a medicament for the treatment of cancer

TRICYCLI PARP HEMMER

USE OF RNAI INHIBITING PARP ACTIVITY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

... ²²²The present invention relates to the use of an agent that inhibits the ²activity of an enzyme that mediates repair of a DNA strand break in the ²manufacture of a medicament for the treatment of diseases caused by a defect ²in a gene that mediates homologous recombination.² ...

USE OF RNAI INHIBITING PARP ACTIVTIY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.

TRICYCLIC PARP INHIBITORS

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Pollen preferred promoters and methods of use

Compositions and methods for regulating expression of heterologous nucleotide sequences in a plant are provided. Compositions include nucleotide sequences encompasses a strong pollen preferred promoter which drives strong, specific expression of gene products in pollen. Also provided is a method for expressing a heterologous nucleotide sequence in a plant using a promoter sequence disclosed herein.

TRICYCLIC PARP INHIBITORS

ТРИЦИКЛИЧЕСКИЕ ИНГИБИТОРЫ ПАРП

Настоящее изобретение относится к применению ингибиторов поли(АДФ-рибозо)полимеразы формул I, II и III для лечения раковых опухолей, в клетках которых имеет место генетический дефект гена, опосредующего гомологичную рекомбинацию. При применении соединений формул I, II и III предварительно выбирают млекопитающее с генетическим дефектом гена, опосредующего гомологичную рекомбинацию, после чего соединения формул I, II, III используют для индуцирования апоптоза в клетках с дефектом гена, опосредующего гомологичную рекомбинацию ! ! ! Технический результат - разработка способа лечения рака у млекопитающих с генетическим дефектом гена, опосредующего гомологичную рекомбинацию. 3 н. и 20 з.п. ф-лы, 9 ил., 1 табл.

ПЕПТИДЫ, ПРИМЕНИМЫЕ ДЛЯ ЛЕЧЕНИЯ ЗЛОКАЧЕСТВЕННОЙ ОПУХОЛИ

ТРИЦИКЛИЧЕСКИЕ ИНГИБИТОРЫ ПАРП

... 1. Соединение для ингибирования активности поли(АДФ-рибозо)полимеразы (ПАРП), имеющее формулу I и его фармацевтически приемлемые соли. 2. Соединение для ингибирования активности ПАРП, имеющее формулу II и его фармацевтически приемлемые соли. 3. Соединение для ингибирования активности ПАРП, имеющее формулу III и его фармацевтически приемлемые соли. 4. Соединение по п.1, где соединение находится в форме фосфатной соли следующей формулы: 5. Применение терапевтического количества соединения формулы I и его фармацевтически приемлемой соли при производстве лекарственного средства 6. Применение терапевтического количества соединения формулы II и его фармацевтически приемлемой соли при производстве лекарственного средства 7. Применение терапевтического количества соединения формулы III и его фармацевтически приемлемой соли при производстве лекарственного средства 8. Применение терапевтического количества соединения формулы I и его фармацевтически приемлемой соли при производстве лекарственного ...

Use of rnai inhibiting parp activtiy for the manufacture of a medicament for the treatment of cancer

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.

Use of RNAi inhibiting PARP activtiy for the manufacture of a medicament for the treatment of cancer

Poly adp-ribose polymerase gene and its uses

Gene therapy prostate cancer: sensitization of cells to dna damaging drugs and radiation

Vault complexes for cytokine delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

USE OF RNAI INHIBITING PARP ACTIVTIY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination. © KIPO & WIPO 2007 ...

GENE THERAPY PROSTATE CANCER: SENSITIZATION OF CELLS TO DNA DAMAGING DRUGS AND RADIATION

The present invention is directed to a novel therapeutic method for treating prostate cancer. The method employs the tissue-specific PSA promoter/enhancer as well as the unique properties of the DNA binding domain (dbd) of poly (ADP-ribose) polymerase (PARP) as a potent inhibitor of DNA damage repair and as a molecular sensitizer to genotoxic stresses. The sustained presence of the PARP-DBD in prostate tumor tissue induces enhanced tumor cell killing in response to DNA damaging treatments. The invention may be used as a biotherapeutic approach in the treatment of prostate cancers, which fail local-regional therapy, without significant risk of normal tissue damage.

TANKYRASE2 MATERIALS AND METHODS

L'invention concerne de nouveaux polypeptides tankyrase nommés tankyrase2, des polynucléotides codant pour ces polypeptides, des constructions d'expression comprenant ces polynucléotides et des cellules hôtes transformées à l'aide des constructions d'expression. L'invention concerne également des méthodes permettant de produire ces polypeptides tankyrase2, des anticorps qui sont immunoréactifs avec ces polypeptides tankyrase2. L'invention concerne en outre des méthodes permettant d'identifier des partenaires de liaison spécifiques de tankyrase2, et notamment des méthodes permettant d'identifier des partenaires de liaison qui modulent l'activité biologique de tankyrase2. L'invention concerne enfin des méthodes permettant de moduler l'activité biologique de tankyrase2 in vitro et in vivo.

タンキラーゼ2物質および方法

... 本発明は、タンキラーゼ2と命名された新規なタンキラーゼポリペプチド、かかるポリペプチドをコードするポリヌクレオチド、かかるポリヌクレオチドを含む発現構築体、およびかかる発現構築体で形質転換された宿主細胞を提供する。さらに提供されるのは、タンキラーゼ2ポリペプチドを製造するための方法と、タンキラーゼ2ポリペプチドとの免疫反応性を有する抗体である。加えて、タンキラーゼ2の特異的結合パートナーを同定するための方法、より詳細にはタンキラーゼ2の生物学的活性を調節する結合パートナーを同定するための方法が提供される。in vitroおよびin vivoでタンキラーゼ2の生物学的活性を調節する方法も提供される。 ...

Use of rnai inhibiting parp activtiy for the manufacture of a medicament for the treatment of cancer

Tricyclic PARP inhibitors

POLYPEPTIDES AND USE THEREOF FOR TREATMENT OF TRAUMATIC OR DEGENERATIVE NEURONAL INJURY

The present invention relates to polypeptides transiently activating Ras homolog gene family member A (RhoA) GTPase, polynucleotides encoding said polypeptides and pharmaceutical compositions comprising said polypeptides or said polynucleotides. The present invention further relates to the use of said polypeptides, said polynucleotides or said pharmaceutical compositions for long-term treatment of damage of the peripheral or central nervous system.

Vault complexes for cytokine delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

Use

PROCEDURE FOR THE INCREASE OF THE RUGGEDNESS OF PLANTS AGAINST HYPOXIC CONDITIONS

POLY (ADP RIBOSE) POLYMERASE GENES

USE OF RNAI WITH INHIBIERENDER PARP ACTIVITY TO HERSTELLLUNG A DRUG FOR THE TREATMENT OF CANCER

Tankyrase2 materials and methods

PEPTIDES USEFUL FOR TREATING CANCER

Provided is a class of peptides which are useful for modulating the activity of poly (ADP-ribose) polymerase (PARP) and in particular for the treatment of cancer. The peptides include an active group and a cassette for delivering the active group to a cell. Also provided are peptides having an anionic group which is believed to act as a competitive inhibitor of proteases which cleave PARP.

VAULT COMPLEXES FOR CYTOKINE DELIVERY

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

POLY ADP-RIBOSE POLYMERASE GENE AND ITS USES

Compositions and methods for influencing the metabolic state of plant cells are provided. The compositions comprise poly ADP-ribose polymerase genes and portions thereof, particularly the maize poly ADP-ribos e polymerase gene as well as antisense nucleotide sequences for poly ADP-ribose polymerase genes. The nucleotide sequences find use in transforming plant cells to alter the metabolic state of the transformed plants and plant cells.

TRICYCLIC PARP INHIBITORS

METHODS FOR INCREASING THE RESISTANCE OF PLANTS TO HYPOXIC CONDITIONS

Methods are provided for increasing the resistance of plants to hypoxic or anoxic conditions. Such methods may be applied to increase the penetrance of plant roots in the growth medium or into soil. The methods according to the invention may include providing plants with a stress tolerance gene. Similar effects can be obtained by applying chemical compounds, including neonicotinoid compounds, to the plants.

POLLEN PREFERRED PROMOTERS AND METHODS OF USE

Compositions and methods for regulating expression of heterologous nucleotide sequences in a plant are provided. Compositions include nucleotide sequences encompasses a strong pollen preferred promoter which drives strong, specific expression of gene products in pollen. Also provided is a method for expressing a heterologous nucleotide sequence in a plant using a promoter sequence disclosed herein. 1. A method for selectively expressing gene products in plant male tissue , comprising (i) a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO:53, 54, 55 and 56;', '(ii) a nucleotide sequence comprising a fragment or variant of the nucleotide sequence of SEQ ID NO: 53, 54, 55 and 56, wherein the sequence initiates transcription in a plant cell;', '(iii) a polynucleotide which is complementary to the polynucleotide of (a) or (b),, 'a) transforming a plant using an isolated nucleic acid molecule comprising a polynucleotide selected from the group comprisingb) growing the plant under normal plant growing conditions, where the polynucleotide encodes a pollen preferred promoter which drives pollen specific expression.2. An expression cassette comprising the polynucleotide of operably linked to a heterologous polynucleotide of interest.3. A vector comprising the expression cassette of .4. A plant cell comprising the expression cassette of .5. The plant cell of claim 4 , wherein said expression cassette is stably integrated into the genome of the plant cell.6. The plant cell of claim 4 , wherein said plant cell is from a dicot.7. The plant cell of claim 6 , wherein said dicot is soybean.8. A plant comprising the expression cassette of .9. The plant of claim 8 , wherein said plant is a dicot.10. The plant of claim 9 , wherein said dicot is soybean.11. The plant of claim 8 , wherein said expression cassette is stably incorporated into the genome of the plant.12. A transgenic seed of the plant of claim 11 , wherein the seed comprises the expression cassette.13. ...

Therapeutic compounds

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Vault complexes for cytokine delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

Human poly(ADP-ribose) polymerase 2 materials and methods

Methods for increasing the resistance of plants to hypoxic conditions

Methods are provided for increasing the resistance of plants to hypoxic or anoxic conditions. Such methods may be applied to increase the penetrance of plant roots in the growth medium or into soil. The methods according to the invention may include providing plants with a stress tolerance gene. Similar effects can be obtained by applying chemical compounds, including neonicotinoid compounds, to the plants.

THERAPEUTIC COMPOUNDS

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

TANKYRASE2 MATERIALS AND METHODS

The invention provides novel tankyrase polypeptides designated tankyrase2, polynucleotides encoding the polypeptides, expression constructs comprising the polynucleotides, and host cells transformed with the expression constructs. Also provided are methods for producing the tankyrase2 polypeptides, antibodies that are immunoreactive with the tankyrase2 polypeptides. In addition, there are provided methods for identifying specific binding partners of tankyrase2, and more particularly methods for identifying binding partners that modulate biological activity of tankyrase2. Methods of modulating biological activity of tankyrase2 in vitro and in vivo are also provided.

TRICYCLIC PARP INHIBITORS

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Therapeutic compounds

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Peptides useful for treating cancer

Peptides useful for treating cancer

Provided is a class of peptides which are useful for modulating the activity of poly (ADP-ribose) polymerase (PARP) and in particular for the treatment of cancer. The peptides include an active group and a cassette for delivering the active group to a cell. Also provided are peptides having an anionic group which is believed to act as a competitive inhibitor of proteases which cleave PARP.

VAULT COMPLEXES FOR CYTOKINE DELIVERY

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

POLY ADP-RIBOSE POLYMERASE GENE AND ITS USES

Compositions and methods for influencing the metabolic state of plant cells are provided. The compositions comprise poly ADP-ribose polymerase genes and portions thereof, particularly the maize poly ADP-ribose polymerase gene as well as antisense nucleotide sequences for poly ADP-ribose polymerase genes. The nucleotide sequences find use in transforming plant cells to alter the metabolic state of the transformed plants and plant cells.

PFLANZEN GEGEN HYPOXISCHE BEDINGUNGEN

TCF7L2 VARIANT AND METHODS OF USE THEREOF IN DIAGNOSTIC AND DRUG SCREENING ASSAYS

Compositions and methods useful for the identification of therapeutic agents useful for the treatment of T2D are disclosed.

POLY ADP-RIBOSE POLYMERASE GENE AND ITS USES

Compositions and methods for influencing the metabolic state of plant cells are provided. The compositions comprise poly ADP-ribose polymerase genes and portions thereof, particularly the maize poly ADP-ribose polymerase gene as well as antisense nucleotide sequences for poly ADP-ribose polymerase genes. The nucleotide sequences find use in transforming plant cells to alter the metabolic state of the transformed plants and plant cells.

METHODS TO INCREASE THE RESISTANCE OF THE PLANTS TO CONDITIONS HIPOXICAS

Métodos para incrementar la resistencia de las plantas a condiciones hipoxicas o anoxicas. Estos métodos pueden aplicarse para incrementar la penetracion de las raíces de la planta en el medio de cultivo o la tierra. Los métodos de acuerdo con la invencion pueden incluir proporcionarle a las plantas un gen de tolerancia al estrés. Pueden obtenerse efectos similares aplicándole a las plantas compuestos químicos, incluyendo compuestos neonicotinoides.

METHODS FOR INCREASING THE RESISTANCE OF PLANTS TO HYPOXIC CONDITIONS

Vault Complexes for Cytokine Delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer. 152-. (canceled)53. A composition comprising a vault complex comprising a fusion protein comprising a cytokine and a vault targeting domain.54. The composition of claim 53 , wherein the cytokine comprises the amino acid sequence of SEQ ID NO:2 (human) or SEQ ID NO:1 (mouse).55. The composition of claim 53 , wherein the vault targeting domain comprises the amino acid sequence of SEQ ID NO:8 (human) or SEQ ID NO:9 (mouse).56. The composition of claim 53 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:13 (human) or SEQ ID NO:12 (mouse).57. The composition of claim 53 , further comprising a vault poly ADP-ribose polymerase (VPARP) claim 53 , a telomerase vault associated protein 1 (TEP1) claim 53 , or an untranslated RNA molecule (vRNA).58. The composition of claim 53 , wherein the fusion protein further comprises a fluorescent protein.59. An isolated nucleic acid encoding a chemokine fusion protein comprising a cytokine encoding sequence and a mINT encoding sequence.60. The isolated nucleic acid of claim 59 , wherein the mINT encoding sequence comprises the nucleic acid sequence of SEQ ID NO:7 (human) or SEQ ID NO:6 (mouse).61. The isolated nucleic acid of claim 59 , wherein (a) the cytokine encoding sequence consists of the nucleic acid sequence of SEQ ID NO:5 (human) and the mINT encoding sequence consists of the nucleic acid sequence of SEQ ID NO:7 (human) claim 59 , or (b) the cytokine encoding sequence consists of the nucleic acid sequence of SEQ ID NO:3 (mouse) and the mINT encoding sequence consists of the nucleic acid sequence of SEQ ID NO:6 (mouse).62. The isolated nucleic acid of claim 59 , wherein the cytokine ...

POLY(ADP-RIBOSE)POLYMERASE-GENE

Methods for increasing the resistance of plants to hypoxic conditions

COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.

USE OF RNAI INHIBITING PARP ACTIVITY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

NUCLEIC ACID MOLECULES ENCODING A POLY(ADP-RIBOSE) POLYMERASE

Disclosed are nucleic acid molecules encoding a protein having poly(ADP-ribose) polymerase (PARP) activity as well as the encoded protein. Furthermore, the invention describes expression vectors, host cells, antibodies, pharmaceutical compositions and methods for treating disorders associated with aberrant regulation of cellular behaviour. Finally, screening methods are described for compounds that act as agonist or antagonist of the protein having PARP activity.

METHOD FOR PREPARING INDUCED PLURIPOTENT STEM CELLS AND ITS APPLICATIONS

The present invention relates to a novel method for preparing induced pluripotent stem cells (iPSCs) by introducing three genes, Oct3/4, Sox2, and Parp1, into somatic cells. The present invention also relates to the iPSCs produced by the aforementioned method. Also provided is a method of rejuvenating cells by use of a PARylated protein or an enzyme with PARylation activity. Further provided is a method for inducing the secretion of interferon- inducible protein-10 (IP-10) comprising administering to a subject in need thereof an effective amount of iPSCs or iPSC-CM.

METHODS FOR INCREASING THE RESISTANCE OF PLANTS TO HYPOXIC CONDITIONS

HUMAN POLY(ADP-RIBOSE) POLYMERASE 2 MATERIALS AND METHODS

The invention provides a novel human poly(ADP-ribose) polymerase (hPARP2) polypeptides, polynucleotides encoding the polypeptides, expression constructs comprising the polynucleotides, and host cells transformed with the expression constructs. Also provided are methods for producing the hPARP2 polypeptides, antibodies that are immunoreactive with the hPARP2 polypeptides. In addition, there are provided methods for identifying specific binding partners of hPARP2, and more particularly methods for identifying binding partners that modulate biological activity of hPARP2. Methods of modulating biological activity of hPARP2 in vitro andin vivo are also provided.

METHODS FOR INCREASING THE RESISTANCE OF PLANTS TO HYPOXIC CONDITIONS

Methods are provided for increasing the resistance of plants to hypoxic or anoxic conditions. Such methods may be applied to increase the penetrance of plant roots in the growth medium or into soil. The methods according to the invention may include providing plants with a stress tolerance gene. Similar effects can be obtained by applying chemical compounds, including neonicotinoid compounds, to the plants.

METHODS FOR INCREASING THE RESISTANCE OF PLANTS TO HYPOXIC CONDITIONS

Methods are provided for increasing the resistance of plants to hypoxic or anoxic conditions. Such methods may be applied to increase the penetrance of plant roots in the growth medium or into soil. The methods according to the invention may include providing plants with a stress tolerance gene. Similar effects can be obtained by applying chemical compounds, including neonicotinoid compounds, to the plants. © KIPO & WIPO 2008 ...

Vault complexes for facilitating biomolecule delivery

The invention relates to compositions of vault complexes containing recombinant membrane lytic proteins, such as an adenovirus protein VI lytic domain, and methods of using the vault complexes to facilitate delivery and entry of a biomolecule into a cell or subject.

Method of lethally sensitizing human and animal cells

The present invention relates to a method, nucleic acid and amino acid sequences to sensitizing human or animal cells to be killed by chemical entities or irradiation. Particularly, the present invention describes nucleic acid and amino acid sequences pertaining to the group of PME factors, that are target to sensitizing the cells before treatment with killing elemenst.

PARP9 AND PARP14 AS KEY REGULATORS OF MACROPHAGE ACTIVATION

The invention relates to compositions and methods for inhibiting macrophage activation via modulating PARP9 and/or PARP14 expression or activity, such as small molecules, RNAi and antibodies. Modulating the expression and/or activity of PARP9 and/or PARP14 allows the inhibition of monocytes or macrophage M1 activation and inflammation. Inhibiting undesirable excessive or sustained inflammation found in humans, for the treatment, prevention and/or management of conditions where undesirable excessive or sustained inflammation is known or likely to contribute to the onset, development and/or progression the conditions.

TANKYRASE2 MATERIALS AND METHODS

The invention provides novel tankyrase polypeptides designated tankyrase2, polynucleotides encoding the polypeptides, expression constructs comprising the polynucleotides, and host cells transformed with the expression constructs. Also provided are methods for producing the tankyrase2 polypeptides, antibodies that are immunoreactive with the tankyrase2 polypeptides. In addition, there are provided methods for identifying specific binding partners of tankyrase2, and more particularly methods for identifying binding partners that modulate biological activity of tankyrase2. Methods of modulating biological activity of tankyrase2 in vitro and in vivo are also provided.

Methods for increasing the resistance of plants to hypoxic conditions

Nucleic acid molecules encoding a poly(adp-ribose) polymerase

PARP 및 탄키라제 동시 저해제에 대한 감수성 결정 방법

... 본 발명은 PARP(Poly ADP Ribose Polymerase) 및 탄키라제(tankyrase) 동시 저해제에 대한 감수성 결정 방법에 관한 것이다. 본 발명에 따르면, PARP 및 탄키라제 동시 저해제에 대한 감수성을 갖는 환자군을 분류함으로써 대장암 치료 효과를 극대화 할 수 있다.

METHOD FOR THE TREATMENT OF PULMONARY DISEASE AND METHOD OF PRODUCING PROTEINS OF USE THEREIN

Disclosed herein are methods of treating a subject with pulmonary disease including administering to the subject a therapeutically effective amount of a polypeptide including at least one arginine residue susceptible to ADP-ribosylation and nicotinamide adenine dinucleotide (NAD). In some embodiments, the polypeptide and/or NAD is administered via inhalation. Also disclosed is a pharmaceutical composition including at least one polypeptide (such as HNP-I) and NAD. The disclosure also provides in vitro methods of producing a polypeptide with altered activity, including contacting the polypeptide with NAD and an arginine- specific mono-ADP-ribosyltransferase (for example, ARTl) to produce a polypeptide including at least one ADP-ribosylated arginine residue, incubating the ADP-ribosylated polypeptide under conditions sufficient for conversion of at least one ADP-ribosylated arginine residue to ornithine, and isolating the ornithine- containing polypeptide. Methods of treating a subject with ...

Vault immunotherapy

The invention relates to compositions of vault complexes for use as adjuvants for stimulating a cellular immune response to an antigen, for example a tumor antigen, and methods of using the vault complexes in the treatment of diseases, such as cancer.

Use of rnai inhibiting parp activity for the manufacture of a medicament for the treatment of cancer

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.

Peptides useful for treating cancer

A cyclic peptide, capable of modulating the activity of poly (ADP-ribose) polymerase 1 (PARP-1), useful for the treatment of cancer, comprises the formula: Â Â Â Â [X1-X2-X3-X4-X3-X4-X3] Wherein X1 is a peptide moiety capable of inhibiting the cleavage of PARP-1, X2 may absent, or Val or Ser, X3 is selected from Trp-Trp or Ar1-Ar2, and X4 is selected from Arg-Arg or a dipeptide comprising two homocysteic acid residues or two guanidinophenylalanine residues, wherein Ar1 and Ar2 are amino acids comprises an aryl side chain comprising a napthyl, 1,2-dihydronapthyl or 1,2,3,4-tetrahydronapthyl group. The X1 group which inhibits PARP-1 cleavage may be, for example, -Pro-Arg-Gly-Pro-Arg-Pro-, or derivatives thereof with the Arg residues substituted by acidic residues, or -Gly-Asp-Glu-NMeAsp-MeGly-Val (where NMeAsp is N-methyl aspartic acid). The cyclic peptides may be administered together with an aerobic glycolysis inhibitor, such as 2-deoxyglucose.

Tankyrase homolog protein (thp), nucleic acids, and methods related to the same

Compounds, compositions, and methods for treatment of diseases involving acidic or hypoxic diseased tissues

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.

Compounds, compositions, and methods for treatment of diseases involving acidic or hypoxic diseased tissues

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.

THERAPEUTIC COMPOUNDS

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Therapeutic compounds

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Vault complexes for cytokine delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.

Poly ADP-ribose polymerase gene and its uses

Methods for increasing the resistance of plants to hypoxic conditions

TCF7L2 variant and methods of use thereof in diagnostic and drug screening assays

Compositions and methods useful for the identification of therapeutic agents useful for the treatment of T2D are disclosed.

Antisense modulation of parp expression

Human poly(adp-ribose) polymerase 2 materials and methods

Tricyclic PARP inhibitors

HUMAN POLY(ADP-RIBOSE) POLYMERASE 2 MATERIALS AND METHODS

L'invention concerne de nouveaux polypeptides poly(ADP-ribose) polymerase (hPARP2) humains, des polynucléotides qui codent ces polypeptides, des produits de recombinaison d'expression incluant ces mêmes polynucléotides ainsi que des cellules hôtes transformées par les produits de recombinaison d'expression. L'invention concerne également des procédés de production des polypeptides hPARP2, anticorps immunoréactifs vis-à-vis des polypeptides hPARP2. De plus, l'invention procure des procédés d'identification des partenaires de liaison spécifiques des hPARP2, et tout particulièrement, des procédés d'identification des partenaires de liaison qui modulent l'activité biologique des hPARP2. L'invention fournit encore des procédés de modulation de l'activité biologique des hPARP2 in vitro et in vivo.

Poly-(ADP) ribose polymerase enzyme and uses thereof

Poly(ADP)-ribose polymerase (PARP) becomes activated at sites of DNA damage and is thought to promote repair by modifying local chromatin proteins and transcription factors. Disclosed is an isoform of PARP, PARP-e, which lacks enzymatic function and which is encoded by a gene having a novel structure. Also disclosed are methods of modulating chromatin structure resulting in modulation of gene activation, gene repression and chromatin condensation and decondensation.

Human poly(ADP-ribose) polymerase 2 materials and methods

The invention provides a novel human poly(ADP-ribose) polymerase (hPARP2) polypeptides, polynucleotides encoding the polypeptides, expression constructs comprising the polynucleotides, and host cells transformed with the expression constructs. Also provided are methods for producing the hPARP2 polypeptides, antibodies that are immunoreactive with the hPARP2 polypeptides. In addition, there are provided methods for identifying specific binding partners of hPARP2, and more particularly methods for identifying binding partners that modulate biological activity of hPARP2. Methods of modulating biological activity of hPARP2 in vitro and in vivo are also provided.

Poly(adp-ribose)polymerase gene

Use of RNAi inhibiting PARP activtiy for the manufacture of a medicament for the treatment of cancer

ANTISENSE MODULATION OF PARP EXPRESSION

Antisense compounds, compositions and methods are provided for modulating the expression of human PARP. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding human PARP. Methods of using these compounds for modulation of human PARP expression and for treatment of diseases associated with expression of human PARP are provided.

タンキラーゼホモログタンパク質(THP)、核酸およびそれらに関連した方法

... 本発明は、ヒトタンキラーゼタンパク質(THP)のヒトポリペプチドホモログ、およびTHPを同定しコードするポリヌクレオチドを提供する。また、本発明は、発現ベクター、宿主細胞およびその製造方法を提供する。本発明はまた、ヒトの疾患、例えばヒトの癌および加齢関連疾患の治療に有用なTHPアゴニスト/アンタゴニストの同定方法を提供する。 ...

METHOD FOR THE TREATMENT OF PULMONARY DISEASE AND METHOD OF PRODUCING PROTEINS OF USE THEREIN

Disclosed herein are methods of treating a subject with pulmonary disease including administering to the subject a therapeutically effective amount of a polypeptide including at least one arginine residue susceptible to ADP-ribosylation and nicotinamide adenine dinucleotide (NAD). In some embodiments, the polypeptide and/or NAD is administered via inhalation. Also disclosed is a pharmaceutical composition including at least one polypeptide (such as HNP-I) and NAD. The disclosure also provides in vitro methods of producing a polypeptide with altered activity, including contacting the polypeptide with NAD and an arginine- specific mono-ADP-ribosyltransferase (for example, ARTl) to produce a polypeptide including at least one ADP-ribosylated arginine residue, incubating the ADP-ribosylated polypeptide under conditions sufficient for conversion of at least one ADP-ribosylated arginine residue to ornithine, and isolating the ornithine- containing polypeptide. Methods of treating a subject with ...

COMPOSITIONS AND METHODS FOR IDENTIFICATION OF PARP FUNCTION, INHIBITORS, AND ACTIVATORS

The invention provides nucleic acids encoding PARP fusion proteins, PARP fusion proteins, antibodies that bind to one or more of these PARP fusion proteins, and transgenic cells expressing one or more PARP fusion proteins. The invention also provides methods for identifying an agent as a specific PARP inhibitor or activator requiring contacting one or more PARP fusion proteins with a labeled nicotinamide adenine dinucleotide substrate and the agent and measuring the amount of labeled of ADP-ribose covalently attached to the one or more PARP fusion proteins. The invention also provides methods for identifying an agent that specifically binds to one or more PARP fusion proteins and methods for quantitating the level of one or more PARP proteins in a sample.

TANKYRASE HOMOLOG PROTEIN (THP), NUCLEIC ACIDS, AND METHODS RELATED TO THE SAME

L'invention concerne un polypeptide humain homologue de la protéine tankyrase humaine (PTH) et des polynucléotides identifiant et codant pour cette protéine tankyrase humaine. En outre, l'invention concerne des vecteurs d'expression, des cellules hôtes et des procédés de production associés. L'invention concerne également des procédés permettant d'identifier des agonistes/antagonistes de la PTH, utiles pour le traitement de maladies chez l'homme, telles que le cancer et les maladies liées à l'âge.

Method of lethally sensitizing human and animal cells

The present invention relates to a method, nucleic acid and amino acid sequences to sensitizing human or animal cells to be killed by chemical entities or irradiation. Particularly, the present invention describes nucleic acid and amino acid sequences pertaining to the group of PME factors, that are target to sensitizing the cells before treatment with killing elements.

Vault Complexes for Facilitating Biomolecule Delivery

The invention relates to compositions of vault complexes containing recombinant membrane lytic proteins, such as an adenovirus protein VI lytic domain, and methods of using the vault complexes to facilitate delivery and entry of a biomolecule into a cell or subject. 1. A vault-like particle comprising a modified MVP , wherein the modified MVP comprises a membrane lytic peptide sequence.2. The vault-like particle of claim 1 , wherein said membrane lytic peptide sequence is added to the N-terminus of the modified MVP.3. The vault-like particle of claim 1 , wherein said membrane lytic peptide sequence comprises the membrane lytic domain of adenovirus VI (pVI) (SEQ ID NO:1)4. The vault-like particle of claim 3 , wherein the membrane lytic domain comprises SEQ ID NO:3.5. The vault-like particle of claim 3 , wherein the membrane lytic domain comprises SEQ ID NO:4.6. The vault-like particle of claim 1 , further comprising an EGF domain.7. The vault-like particle of claim 6 , wherein the EGF domain is added to the C-terminus of the modified MVP.8. The vault-like particle of claim 1 , further comprising an antibody binding domain.9. The vault-like particle of claim 8 , wherein the antibody binding domain is a Z-domain.10. The vault-like particle of claim 10 , wherein the Z-domain is added to the C-terminus of the modified MVP.11. The vault-like particle of claim 1 , further comprising a vault poly ADP-ribose polymerase (VPARP) claim 1 , a telomerase vault associated protein 1 (TEP1) claim 1 , or an untranslated RNA molecule (vRNA).12. An isolated nucleic acid encoding a pVI-MVP fusion protein comprising an adenovirus protein VI membrane lytic domain and an MVP encoding sequence.13. The isolated nucleic acid of claim 12 , wherein the MVP encoding sequence comprises the nucleic acid sequence of SEQ ID NO:17.14. The isolated nucleic acid of claim 12 , wherein the protein VI membrane lytic domain encoding sequence comprises the nucleic acid sequence of SEQ ID NO:215. The ...

TARGETING PARP1 FOR TREATMENT OF TSC AND CANCERS

The present invention relates to methods of treating a condition associated with mTORC1 hyperactivation or TSC2-deficient cancer, the method comprising administering to a subject having the cancer a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor. In some embodiments, the condition associated with mTORC1 hyperactivation is tuberous sclerosis complex (TSC). In some embodiments, the condition associated with mTORC1 hyperactivation is lymphangioleiomyomatosis (LAM). In some embodiments, the condition associated with mTORC1 hyperactivation is TSC2-deficient cancer.

Vault Complexes for Cytokine Delivery

The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer. 1. A composition comprising a vault complex comprising a chemokine fusion protein comprising a chemokine (C—C motif) ligand 21 (CCL-21) consisting of the amino acid sequence of SEQ ID NO:2 (human) and a major vault protein interaction domain (mINT) consisting of the amino acid sequence of SEQ ID NO:8 (human).2. A composition comprising a vault complex comprising a fusion protein comprising a cytokine and a vault targeting domain.3. The composition of claim 2 , wherein the cytokine is a chemokine.4. The composition of claim 2 , wherein the cytokine is a cysteine-cysteine (CC) chemokine.5. The composition of claim 2 , wherein the cytokine is a CCL-21 chemokine.6. The composition of claim 2 , wherein the cytokine comprises the amino acid sequence of SEQ ID NO:2 (human).7. The composition of claim 2 , wherein the cytokine consists of the amino acid sequence of SEQ ID NO:2 (human).8. The composition of claim 2 , wherein the cytokine comprises the amino acid sequence of SEQ ID NO:1 (mouse).9. The composition of - claim 2 , wherein the vault targeting domain is a vault interaction domain from a vault poly ADP-ribose polymerase (VPARP).10. The composition of - claim 2 , wherein the vault targeting domain is a major vault protein interaction (mINT) domain.11. The composition of - claim 2 , wherein the vault targeting domain comprises the amino acid sequence of SEQ ID NO:8 (human).12. The composition of - claim 2 , wherein the vault targeting domain consists of the amino acid sequence of SEQ ID NO:8 (human).13. The composition of - claim 2 , wherein the vault targeting domain comprises the amino acid sequence of SEQ ID NO:9 (mouse).14. The composition of - ...

Use of RNAI Inhibiting PARP Activity for the Manufacture of a Medicament for the Treatment of Cancer

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination. 132-. (canceled)33. A method of treatment of cancer cells defective in homologous recombination (HR) in a human patient , the method comprising;administering to the patient a therapeutically effective amount of a compound which inhibits PARP-1.34. The method of wherein the PARP inhibitor is selected from the group consisting of benzimidazole-carboxamides claim 33 , quinazolin-4-[3H]-ones and isoquinolone derivatives.35. The method of wherein the PARP inhibitor is selected from the group consisting of 2-(4-hydroxyphenyl)benzimidazole-4-carboxamide claim 34 , 8-hydroxy-2-methylquinazolin-4-[3H]one claim 34 , 6(5H)phenanthridinone claim 34 , 3-aminobenzamide claim 34 , benzimidazole-4-carboxamides and tricyclic lactam indoles.36. The method of wherein the cancer cells have defect in a gene encoding a protein involved in HR.37. The method of wherein the human patient has one functional allele of said gene claim 36 , said functional allele being lost in the cancer cells.38. The method of wherein the gene encoding a protein involved in HR is selected from the group consisting of XRCC1 claim 33 , CTPS claim 33 , RPA claim 33 , RPA1 claim 33 , RPA2 claim 33 , RPA3 claim 33 , XPD claim 33 , ERCC1 claim 33 , XPF claim 33 , MMS19 claim 33 , RAD51 claim 33 , RAD51B claim 33 , RAD51C claim 33 , RAD51D claim 33 , DMC1 claim 33 , XRCC2 claim 33 , XRCC3 claim 33 , BRCA1 claim 33 , BRCA2 claim 33 , RAD52 claim 33 , RAD54 claim 33 , RAD50 claim 33 , MRE11 claim 33 , NBS1 claim 33 , WRN claim 33 , BLM claim 33 , Ku70 claim 33 , Ku80 claim 33 , ATM claim 33 , ATR claim 33 , chkl claim 33 , chk2 claim 33 , FANCA claim 33 , FANCB claim 33 , FANCC claim 33 , FANCD1 claim 33 , FANCD2 claim 33 , FANCE claim 33 , FANCF claim ...

TARGETING OF CHONDROITIN SULFATE GLYCANS

The present invention relates to functional binding fragments comprising the minimal binding fragments of VAR2CSA, to antibodies against such binding fragments of VAR2CSA, nucleic acids encoding such fragments of VAR2CSA as well as methods for their production. The invention further relates to conjugates and fusion proteins of VAR2CSA polypeptides including the minimal binding fragments and their use, in particular in the treatment of conditions associated with expression of chondroitin sulfate A (CSA), such as an inappropriate expression of chondroitin sulfate A (CSA). 117-. (canceled)18. A conjugate or fusion protein comprising a VAR2CSA polypeptide , and a therapeutic or diagnostic effector moiety , such as a cytotoxic moiety , fluorescent label , and/or a radio label.19. The conjugate according to claim 18 , wherein the VAR2CSA polypeptide is or comprises a protein fragment consisting of a sequential amino acid sequence ofa) ID1, andb) DBL2Xb, and optionally ID2a.20Pseudomonas. The conjugate according to claim 18 , wherein the cytotoxic moiety is selected from calicheamycin claim 18 , auristatin claim 18 , doxorubicin claim 18 , maytansinoid claim 18 , taxol claim 18 , ecteinascidin claim 18 , geldanamycin claim 18 , methotrexate and their derivatives claim 18 , cytotoxic proteins such as exotoxin A claim 18 , diphtheria toxin claim 18 , ricin toxin claim 18 , pokeweed antiviral protein claim 18 , saporin claim 18 , gelonin and functional variants claim 18 , fragments claim 18 , and combinations thereof.2122-. (canceled)23. The conjugate according to claim 18 , wherein the therapeutic or diagnostic effector moiety is an anti-inflammatory agent.24. The conjugate according to claim 18 , wherein the therapeutic or diagnostic effector moiety is CSPG4 claim 18 , CD44 claim 18 , or other proteoglycans exemplified but not limited to those in Table 1.25. A composition comprising the conjugate according to .2632-. (canceled)33. A method for the treatment of any ...

NOVEL POLY(ADP-RIBOSE) POLYMERASE GENES

The invention relates to poly(ADP-ribose)polymerase (PARP) homologs which have an amino acid sequence which has 4. A PARP homolog as claimed in claim 1 , selected from human PARP homologs claim 1 , which has the amino acid sequence shown in SEQ ID NO: 2 (human PARP2) or SEQ ID NO: 4 or 6 (human PARP3 type 1 or 2); or murine PARP homologs which have the amino acid sequence shown in SEQ ID NO:8 (mouse PARP long form) or SEQ ID No:10 (mouse PARP short form).5. A binding partner for having specificity for PARP homologs as claimed in claim 1 , selected froma) antibodies and fragments thereof,b) protein-like compounds which interact with a part sequence of the protein, andc) low molecular weight effectors which modulate the catalytic PARP activity or another biological function of a PARP molecule.6. A nucleic acid comprising{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a) a nucleotide sequence coding for at least one PARP homolog as claimed in , or the complementary nucleotide sequence thereof;'}b) a nucleotide sequence which hybridizes with a sequence as specified in a) under stringent conditions; orc) nucleotide sequences which are derived from the nucleotide sequences defined in a) and b) through the degeneracy of the genetic code.7. A nucleic acid as claimed in claim 6 , comprisinga) nucleotides +3 to +1715 shown in SEQ ID NO:1;b) nucleotides +242 to +1843 shown in SEQ ID NO:3;c) nucleotides +221 to +1843 shown in SEQ ID NO:5;d) nucleotides +112 to +1710 shown in SEQ ID NO:7; ore) nucleotides +1 to +1584 shown in SEQ ID NO:9.8. An expression cassette comprising claim 6 , under the genetic control of at least one regulatory nucleotide sequence claim 6 , at least one nucleotide sequence as claimed in .9. A recombinant vector comprising at least one expression cassette as claimed in .10. A recombinant microorganism comprising at least one recombinant vector as claimed in .11. A transgenic mammal comprising a vector as claimed in .12. A PARP-deficient mammal or PARP- ...

Compositions and Methods for the Modulation of DNA Damage Responses Using BAL1 and BBAP

The invention provides methods and compositions for enhancing the efficacy of cancer therapies through modulation of BAL1 and/or BBAP. Also provided are methods for predicting the efficacy of cancer therapies or treating cancer in a subject through modulation of BAL1 and/or BBAP. Further provided are methods for identifying compounds that are capable of modulating BAL1-BBAP complexes.

CELL-TARGETING MOLECULES COMPRISING PROTEASE-CLEAVAGE RESISTANT, SHIGA TOXIN A SUBUNIT EFFECTOR POLYPEPTIDES AND CARBOXY-TERMINAL MOIETIES

The present invention provides protease-cleavage resistant molecules comprising Shiga toxin effector polypeptides capable of exhibiting potent, Shiga toxin functions (e.g. subcellular routing and cytotoxicity). The present invention also provides protease-cleavage resistant, cell-targeting molecules for targeting specific cell types, e.g., infected or malignant cells. Certain molecules of the present invention are cytotoxic, and certain cell-targeting molecules of the present invention may be used for the targeted killing of specific cell types and the treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections. Certain cell-targeting molecules of the invention exhibit improved, in vivo tolerability as compared to related cell-targeting molecules comprising protease-cleavage sensitive, wild-type, Shiga toxin effector polypeptides. The cell-targeting molecules of the invention can deliver additional materials, such as, e.g., antigens, cytotoxic agents, and detection-promoting agents, into the interiors of target cells. 1. A cell-targeting molecule comprisingi) a heterologous, binding region capable of specifically binding an extracellular target biomolecule; [ amino acids 75 to 251 of SEQ ID NO: 1 or SEQ ID NO: 2; or', 'amino acids 1 to 251 of SEQ ID NO: 1 or SEQ ID NO: 2;', 'and, '(a) a Shiga toxin A1 fragment region having a carboxy terminus, wherein said Shiga toxin A1 fragment region comprises an amino acid sequence that is at least 95% identical to, '(b) a disrupted furin-cleavage motif at the carboxy terminus of the A1 fragment region comprising one or more mutations in a minimal furin-cleavage site relative to a wild-type Shiga toxin A Subunit, the one or more mutations comprising a substitution mutation of an arginine residue natively positioned at 248 or 251 of SEQ ID NO: 1 or SEQ ID NO: 2 with a non-positively charged amino acid residue;', 'wherein the Shiga toxin ...

LATERAL FLOW DEVICE AND METHOD OF USE

Lateral flow devices, methods and kits for performing lateral flow western blot assays are provided. 1. A lateral flow device comprising: 'wherein the wicking pad has a first end, a second end and two lateral edges;', 'a wicking pad composed of a porous material, the wicking pad having a region for applying a substrate comprising immobilized analytes; and'}a first reservoir comprising a stack of a plurality of reagent layers located on the first end of the wicking pad; anda second reservoir comprising an absorbent pad located on the second end of the wicking pad.2. The device of claim 1 , wherein each of the plurality of reagent layers comprises a reagent immobilized in an absorbent pad.3. The device of claim 2 , wherein each of the plurality of reagent layers has a different reagent therein.4. The device of claim 2 , wherein the reagent is selected from the group consisting of a primary antibody claim 2 , a secondary antibody claim 2 , a first wash solution claim 2 , and a second wash solution.5. The device of claim 1 , wherein the plurality of reagent layers claim 1 , starting at a reagent layer in contact with the wicking pad claim 1 , comprises a first reagent layer having a primary antibody claim 1 , a second reagent layer having a first wash solution claim 1 , a third reagent layer having a secondary antibody claim 1 , and a fourth reagent layer having a second wash solution.6. The device of claim 5 , wherein the fourth reagent layer is at least twice the thickness of the third reagent layer.7. The device of claim 5 , further comprising a fifth reagent layer comprising the second wash solution.8. The device of claim 5 , wherein the volume of the second wash solution is at least twice the volume of the secondary antibody.9. The device of claim 5 , wherein each of the plurality of reagent layers is formed of an absorbent pad and at least a portion of the first reagent layer is in intimate contact with the wicking pad.10. The device of claim 1 , wherein the ...

METHODS AND COMPOSITIONS FOR VAULT NANOPARTICLE IMMOBILIZATION OF THERAPEUTIC MOLECULES AND FOR VAULT TARGETING

Described herein are compositions and methods for the immobilization of passenger molecules in a dense matrix of ADP-ribose within the vault particle. The present disclosure also describes a method for altering the physicomechanical properties (e.g. density, compressive strength, electrostatic properties, etc.) of packaged vaults for enhanced stability and/or downstream functionality. In addition, the present disclosure also describes compositions and methods for altering amino acid sequence of the vault protein in the vault particle by amino acid mutation, amino acid insertion and/or amino acid deletion to package passenger molecules and/or to target vault particles to specific receptors or ligands. 118.-. (canceled)19. A composition comprising a vault particle , wherein the vault particle comprises multiple copies of a modified sequence of major vault protein (MVP) , wherein the modified sequence comprising a mutation , insertion , or deletion of at least one amino acid , whereinthe mutation, insertion, or deletion of the at least one amino acid is located in an unstructured region of a shoulder domain of the MVP;the mutation, insertion, or deletion of the at least one amino acid results in a change in local charge, hydrophobicity, polarity of the unstructured region, and/or affinity or avidity for a binding partner; andthe mutation, insertion, or deletion of the at least one amino acid results in expression of a receptor or ligand binding peptide.20. The composition of claim 19 , wherein modified shoulder domain is capable of specific binding to receptors or ligands expressed on cells.21. The composition of claim 19 , wherein modified shoulder domain is capable of specific binding to receptors or ligands not expressed on cells.22. The composition of claim 19 , wherein modified shoulder domain is on an outer facing domain of the MVP.23. The composition of claim 22 , wherein the outer facing domain is a loop region.24. A method of producing a modified major vault ...

Bivalent IL-2 Fusion Toxins

IL-2 fusion toxins, e.g., bivalent-IL2 fusion toxins, and methods of use thereof. 1. A bivalent IL-2 fusion toxin comprising:a first part comprising a cytotoxic protein, anda second part comprising at least two Interleukin 2 (IL-2) sequences, e.g., two human IL-2 sequences comprising amino acids 21-153 of SEQ ID NO:1, optionally with one or both of a linker between the two IL-2 sequences, and a linker between the first and second parts.2Pseudomonas. The fusion toxin of claim 1 , wherein the cytotoxic protein comprises diphtheria toxin claim 1 , exotoxin claim 1 , or cytotoxic portions or variants thereof.3. The fusion toxin of claim 1 , further comprising a linker between the first and second parts.4. A codon-optimized nucleic acid molecule optimized for expression in a methylotropic yeast encoding the fusion toxin of .5. A nucleic acid encoding the fusion toxin of .6. A vector comprising the nucleic acid molecule of .7. A host cell expressing the nucleic acid molecule of .8. The host cell of claim 6 , wherein the host cell is a methylotropic yeast.9Pichia Pastoris.. The host cell of claim 7 , wherein the host cell is a cell of the species10. A pharmaceutical composition comprising the fusion toxin of claim 1 , and a physiologically acceptable carrier.11. A method of treating a subject who has a cancer claim 1 , the method comprising administering to the subject a therapeutically effective amount of the fusion toxin of .12. The method of claim 10 , wherein the cancer comprises cancer cells that express CD25 claim 10 , optionally selected from the group consisting of B-cell neoplasms claim 10 , acute nonlymphocytic leukemias claim 10 , neuroblastomas claim 10 , tumor infiltrating lymphocytes claim 10 , and cutaneous T cell lymphoma.13. The method of claim 11 , further comprising administering an immunotherapy to the subject.14. The method of claim 12 , wherein the immunotherapy comprises administration of one or more of: dendritic cells or peptides with adjuvant; DNA ...

FUSION PROTEINS FOR USE AS IMMUNOGENIC ENHANCERS FOR INDUCING ANTIGEN-SPECIFIC T CELL RESPONSES

A fusion protein for use as an immunogen enhancer for enhancing antigen-specific T cell responses is disclosed. The fusion protein comprises: (a) an antigen-presenting cell (APC)-binding domain or a CD receptor-binding domain; (b) a protein transduction domain; and (c) an antigen of a pathogen, wherein the APC-binding domain or the CD receptor-binding domain is located at the N-terminus of the fusion protein, and the antigen of the pathogen is located at the C-terminus of the protein transduction domain. The protein transduction domain is selected from the group consisting of: (i) a fusion polypeptide, comprising a T cell sensitizing signal-transducing peptide, a linker, and a translocation peptide; (ii) a T cell-sensitizing signal-transducing peptide; and (iii) a translocation peptide of 34-112 amino acid residues in length. 1. A fusion protein comprising:(a) an antigen-presenting cell (APC)-binding domain or a CD91 receptor-binding domain, located at the N-terminus of the fusion protein; [{'sup': 8', '10', '11', '17, '(1) a T cell sensitizing signal-transducing peptide consisting of 28-53 amino acid residues in length, comprising the amino acid sequence of SEQ ID NO: 31, in which Xaais I; Xaais V, F or A, Xaais M or L, Xaais L or I, being located at the N-terminus of the fusion polypeptide;'}, '(2) a translocation peptide consisting of 34-112 amino acid residues in length, comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 3, 20 or 4; and', '(3) a linker, comprising SEQ ID NO: 15 linking the T cell sensitizing signal-transducing peptide and the translocation peptide; and, '(b) a protein transduction domain, located at the C-terminus of the APC-binding domain or the CD91 receptor-binding domain, wherein the protein transduction domain is a fusion polypeptide consisting of(c) an antigen of a pathogen or a cancer cell, located at the C-terminus of the protein transduction domain;wherein:the pathogen is at least one selected from the group ...

Combination of parp inhibitor and brd4 inhibitor for the treatment of cancer

Provided herein are methods of treating cancer comprising administering a PARP inhibitor which may be combined with a BRD4 inhibitor. In one embodiment, the present disclosure provides a method for treating cancer in a subject comprising administering an effective amount of a poly-ADP-ribose polymerase (PARP) inhibitor in combination with a bromodomain-containing protein 4 (BRD4) inhibitor to the subject. In some aspects, the administration of the PARP inhibitor and BRD4 inhibitor results in greater reduction in tumor growth or greater reduction in tumor mass relative to administration of PARP inhibitor or BRD4 inhibitor alone.

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. The present disclosure relates to a non-toxic mutant form of the Cholix gene (ntCholix), a variant of Cholix truncated at amino acid A(Cholix) and the use of other various Cholix-derived polypeptide sequences to enhance intestinal delivery of biologically-active therapeutics. The systems and methods described herein provide for: the ability to deliver macromolecule doses without injections; the ability to deliver cargo such as siRNA or antisense molecules into intracellular compartments where their activity is required; and the delivery of nanoparticles and dendrimer-based carriers across biological membranes. 116.-. (canceled)17. A method for delivering a therapeutic cargo across an epithelium of a subject , the method comprising:orally administering to the subject a pharmaceutical composition comprising a non-toxic Cholix toxin coupled to the therapeutic cargo; anddelivering the therapeutic cargo across the epithelium of the subject.18. The method of comprising delivering the therapeutic cargo via transcytosis through a polarized gut epithelial cell.19. The method of comprising transporting the therapeutic cargo preferentially across a polarized epithelial cell versus a cell comprising a CD91 cell receptor.20. The method of comprising delivering the therapeutic cargo via binding a cell receptor not bound by a non-toxic ExoA.21. The method of claim 17 , wherein the non-toxic Cholix toxin lacks a domain III or lacks a functional domain III.22. The method of claim 17 , wherein the non-toxic Cholix toxin is truncated.23. The method of claim 17 , wherein the non-toxic Cholix ...

Modified forms of pseudomonas exotoxin a

Pseudomonas exotoxin A or “PE” is a 66 kD, highly potent, cytotoxic protein secreted by the bacterium Pseudomonas aeruginosa. Various forms of PE have been coupled to other proteins, such as antibodies, to generate therapeutically useful cytotoxin conjugates that selectively target cells of a desired phenotype (such as tumor cells). In the present invention, peptides spanning the sequence of an approximately 38 kD form of Pseudomonas exotoxin A protein were analyzed for the presence of immunogenic CD4+ T cell epitopes. Six immunogenic T cell epitopes were identified. Residues were identified within each epitope for introduction of targeted amino acid substitutions to reduce or prevent immunogenic T-cell responses in PE molecules which may be administered to a heterologous host.

TARGETING PEPTIDES AND USES THEREOF

Provided are peptides, fusion proteins which include the peptide sequences, compositions comprising such peptides and fusion proteins, and methods for making and using the compositions. The peptides are characterized as being able to selectively bind to components of the endothelial compartment that are exposed during the period between 1 and 7 days after androgen deprivation. 1. A peptide having a peptide sequence selected from GAMHLPWHMGTL (SEQ ID NO:5) , KPPQNTSAPYLP (SEQ ID NO:6); SPHWQPNAIFVN (SEQ ID NO:8); TLQRTHFPPAFS (SEQ ID NO:9) , TMGFTAPRFPHY (SEQ ID NO:10) , SPHWQPNAI (SEQ ID NO:19) , and GAMHLPWHMGT (SEQ ID NO:100) , wherein the peptide sequence does not comprise bacteriophage coat protein amino acid sequence.2. The peptide of claim 1 , wherein the peptide sequence is present in a fusion protein claim 1 , wherein the fusion protein does not comprise bacteriophage coat protein.3. The peptide of claim 2 , wherein the fusion protein that comprises the peptide sequence comprises a detectable label.4. The peptide of claim 3 , wherein the detectable label comprised by the fusion protein that comprises the peptide sequence is a radiolabel.5. The peptide of claim 2 , wherein the fusion protein that comprises the peptide sequence comprises a chemotherapeutic agent.6. The peptide of claim 5 , wherein the chemotherapeutic agent comprises a polypeptide sequence that is an enzymatically active toxin.7. The peptide of claim 4 , wherein the fusion protein comprising the peptide sequence is bound to a human endothelial cell or human vascular basement membrane.8. The peptide of claim 5 , wherein the fusion protein comprising the peptide sequence is bound to a human endothelial cell.9. A method of forming a complex comprising a peptide comprising a peptide sequence selected from GAMHLPWHMGTL (SEQ ID NO:5) claim 5 , KPPQNTSAPYLP (SEQ ID NO:6); SPHWQPNAIFVN (SEQ ID NO:8); TLQRTHFPPAFS (SEQ ID NO:9) claim 5 , TMGFTAPRFPHY (SEQ ID NO:10) claim 5 , SPHWQPNAI (SEQ ID NO:19) ...

USE OF RNAI INHIBITING PARP ACTIVITY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination. 1. Use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination.2. The use as claimed m wherein the enzyme is poly(ADP-ribose) polymerase (PARP).3. The use as claimed in wherein the agent is a PARP inhibitor.4. The use as claimed in wherein the PARP inhibitor is selected from the group consisting of PARP-1 claim 3 , PARP-2 claim 3 , PARP-3 claim 3 , PARP-4 claim 3 , tankyrase 1 and tankyrase 2.5. The use as claimed in wherein the PARP is PARP-1.6. The use as claimed in or wherein the agent is an RNAi molecule specific to a PARP gene.7. The use as claimed in wherein the RNAi molecule is derived from a nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of:{'figref': {'@idref': 'DRAWINGS', 'FIG. 9, 10, 11, 12, 13 or 14'}, 'a) a nucleic acid sequence as represented by the sequence in , or a fragment thereof;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 9, 10, 11, 12, 13 or 14'}, 'b) a nucleic acid sequence which hybridises to the nucleic acid sequences of , and encodes a gene for PARP; or'}c) a nucleic acid sequence which comprises sequences which are degenerate as a result of the genetic code to the nucleic acid sequences defined in (a) and (b).8. The use as claimed in or wherein the RNAi molecule comprises the nucleic acid sequence aaa agc cau ggu gga gua uga.9. The use as claimed in or wherein the RNAi molecule consists of the nucleic acid sequence aag acc aau cuc ucc agu uca ac.10. The use as claimed in or wherein the RNAi molecule consists of the nucleic acid sequence aag acc aac auc gag aac aac. ...

HB-EGF INHIBITOR DERIVED FROM THE R DOMAIN OF DIPHTHERIA TOXIN FOR THE TREATMENT OF DISEASES ASSOCIATED WITH THE ACTIVATION OF THE HB-EGF/EGFR PATHWAY

A ligand recombinant protein inhibiting HB-EGF (Heparin-Binding Epidermal Growth Factor like), from the R domain of diphtheria toxin, which can be used for the treatment and diagnosis of diseases involving the activation of the HB-EGF/EGFR pathway. 1. A recombinant protein comprising an amino acid sequence having at least 70% similarity with residues 380 to 535 of the amino acid sequence SEQ ID NO: 1 which correspond to a R domain of diphtheria toxin ,whereinthe amino acid sequence comprises a substitution of at least one residue selected from the group consisting of Y380, P382, Q387, P388 and L390 of the R domain with another amino acid selected from the group consisting of: S, T, N, C, Y, Q, R, K, H, D and E,the amino acid sequence is devoid, at the N- or C-terminal end of the R domain, of the sequence of the T domain or of the C domain and of the T domain of diphtheria toxin, and of the sequence of a protein or of a protein domain capable of improving stability or purification of the R domain, andthe recombinant protein is a ligand inhibiting HB-EGF.2. The protein as claimed in claim 1 , comprising at least two substitutions selected from the group consisting of Y380K claim 1 , Y380E claim 1 , P382T claim 1 , Q387E claim 1 , Q387K claim 1 , P388T claim 1 , L390T and L390N.3. The protein as claimed in claim 2 , comprising at least the substitutions Y380K and L390T or Y380K and Q387E.4. The protein as claimed in claim 3 , comprising at least the substitutions Y380K claim 3 , Q387E and L390T.5. The protein as claimed in claim 1 , further comprising a substitution A395T.6. The protein as claimed in claim 1 , further comprising at least one substitution of F389Y and G510A.7. The protein as claimed in claim 1 , further comprising at least one substitution selected from the group consisting of: N399K claim 1 , V452T claim 1 , T517E claim 1 , V483Q claim 1 , H492E claim 1 , S494K claim 1 , T436H and E497D.8. The protein as claimed in claim 7 , comprising substitutions ...

CHIMERIC PROTEIN TOXINS FOR EXPRESSION BY THERAPEUTIC BACTERIA

Bacteria with tumor-targeting capability express, surface displayed, secreted and/or released modified chimeric therapeutic proteins with enhanced therapeutic activity against a neoplastic tissue including solid tumors, lymphomas and leukemias. The bacteria may be attenuated, non-pathogenic, low pathogenic or a probiotic. The chimeric proteins may be protease sensitive and may optionally be further accompanied by co-expression of a secreted protease inhibitor as a separate molecule or as a fusion. 1Pseudomonas. A genetic construct which causes a live host bacterium to express a peptide selected from the group consisting of at least one of: (a) a reorganized polycistronic cytolethal distending toxin fusion with antineoplastic activity expressed or secreted in an absence of sty and ttsa , (b) a modified chimeric cytolethal distending toxin:apoptin fusion with antineoplastic activity expressed or secreted in an absence of in an absence of sty and ttsa , and (c) a functionally active modified chimeric ToxA therapeutic molecule with antineoplastic activity.2. The genetic construct according to claim 1 , which causes a live host bacterium to express a peptide comprising a reorganized polycistronic cytolethal distending toxin fusion with antineoplastic activity expressed or secreted in an absence of sty and ttsa.3. The genetic construct according to claim 1 , which causes a live host bacterium to express a peptide comprising a modified chimeric cytolethal distending toxin:apoptin fusion with antineoplastic activity expressed or secreted in an absence of in an absence of sty and ttsa.4Pseudomonas. The genetic construct according to claim 1 , which causes a live host bacterium to express a peptide comprising a functionally active modified chimeric ToxA therapeutic molecule with antineoplastic activity.5. The genetic construct according to claim 1 , in a pharmaceutically acceptable dosage form.6. The genetic construct according to claim 1 , where the peptide comprises a ...

KUB5/HERA AS A DETERMINANT OF SENSITIVITY TO DNA DAMAGE

The present disclosure is directed to methods of detecting KUB5/HERA expression levels, copy number and mutation status, particularly in cancer cells. The methods permit physicians to tailor therapies to subject having certain genotypes/phenotypes, and to exclude therapies unlikely to be effective. 1. A method of treating a cancer patient determined to (a) express low/undetectable levels of Kub-5-Hera (K-H) , (b) have reduced K-H gene copy number relative to a normal cell , and/or (c) have a loss/reduction of function mutation in a K-H coding region , such as mutation in a K-H RPR (CID) domain , and/or mutation in K-H coiled-coil domain , comprising administering to said subject a PARP1 inhibitor , ionizing radiation , or a chemotherapeutic agent that induces DNA double-strand breaks.2. The method of claim 1 , further performing the determination of (a) low/undetectable levels of K-H claim 1 , (b) reduced K-H gene copy number and/or (c) mutation in a K-H coding region.3. The method of claim 1 , wherein said chemotherapeutic agent that induces DNA double-strand breaks is doxorubicin claim 1 , a Topoisomerase I or II poison claim 1 , paclitaxel claim 1 , cisplatin claim 1 , or gemcitabine.4. (canceled)5. The method of claim 1 , wherein said cancer is selected from breast cancer claim 1 , lung cancer claim 1 , pancreatic cancer claim 1 , brain cancer claim 1 , ovarian cancer claim 1 , head and neck cancer and cervical cancer.6. The method of claim 5 , wherein said breast cancer is a BRCA-proficient breast or pancreatic cancer.7. The method of claim 2 , wherein analysis comprises expression analysis.8. The method of claim 7 , wherein expression analysis comprises quantitative mRNA level analysis.9. (canceled)10. The method of claim 7 , wherein expression analysis comprises protein analysis.11. (canceled)12. The method of claim 2 , wherein analysis comprises structural analysis.13. The method of claim 12 , wherein structural analysis comprises copy number variation ...

COVALENTLY LINKED POLYPEPTIDE TOXIN-ANTIBODY CONJUGATES

Herein is reported a conjugate of a haptenylated polypeptide toxin and an anti-hapten antibody, wherein a disulfide bond is formed between a cysteine residue either before or after the lysine residue that is used for hapten-conjugation and a cysteine residue in the CDR2 of the antibody, whereby the CDR2 is determined according to Kabat. 1. A conjugate comprising a haptenylated polypeptide toxin and an anti-hapten antibody ,wherein the polypeptide toxin is conjugated to the hapten at a lysine residue,wherein the haptenylated polypeptide toxin is conjugated to the anti-hapten antibody by a disulfide bond, i) a cysteine residue of the haptenylated polypeptide toxin that is one or two residues either before or after the lysine residue that is used for hapten-conjugation, and', 'ii) a cysteine residue in the heavy chain CDR2 of the antibody,, 'wherein the disulfide bond is formed between'}wherein the CDR2 is determined according to Kabat.2. The conjugate according to claim 1 , wherein the alpha carbon atom of the cysteine residue in the heavy chain CDR2 of the antibody is about 10 to 11 Angstrom apart from the atom of lysine residue of the polypeptide toxin to which the hapten is conjugated.3. The conjugate according to claim 1 , wherein the cysteine residue on the polypeptide toxin is two residues before or after the lysine residue.4. The conjugate according to claim 1 , wherein the lysine residue is within the ten N-terminal amino acid residues of the polypeptide toxin.5. The conjugate according to claim 1 , wherein the polypeptide toxin comprises exactly one lysine residue in its amino acid sequence.6. The conjugate according to claim 1 , wherein the cysteine residue in the heavy chain CDR2 of the antibody is at position 52b or at position 53 according to the heavy chain variable domain numbering of Kabat.7. The conjugate according to claim 1 , wherein the antibody is a bispecific antibody comprising a first binding specificity to a non-hapten antigen and a second ...

ASSAY FOR TELOMERE LENGTH REGULATORS

The present invention provides an assay that identifies genes required for telomerase-dependent telomere elongation by measuring the de novo telomere addition at a single chromosome. 1. A method of identifying a regulator of telomere length comprising:a) culturing a mammalian cell comprising a modified chromosome containing an internal telomere seed sequence and an endonuclease cleavage site downstream of the telomere seed sequence, wherein the cell conditionally expresses an endonuclease that cleaves and exposes the telomere seed sequence;b) contacting the cell of (a) with an agent that modulates expression of a selected gene or pathway in the cell; andc) measuring de novo telomere addition to the seed sequence in the presence and absence of the agent, wherein addition of telomere sequence in the presence of the agent, but not in the absence of the agent, and the degree of addition, is indicative of identification of the agent as being a regulator of telomere length, thereby identifying a regulator of telomere length.2. The method of claim 1 , wherein the mammalian cell further comprises a recombinant nucleic acid sequence encoding telomerase.3. The method of claim 2 , wherein the nucleic acid sequence is operably linked to a nucleic acid sequence encoding a reporter.4. The method of claim 3 , wherein the reporter is selected from the group consisting of luciferase (LUC) claim 3 , β-lactamase claim 3 , chloramphenicol acetyltransferase (CAT) claim 3 , adenosine deaminase (ADA) claim 3 , aminoglycoside phosphotransferase (neo claim 3 , G418) claim 3 , dihydrofolate reductase (DHFR) claim 3 , hygromycin-B-phosphotransferase (HPH) claim 3 , thymidine kinase (TK) claim 3 , β-galactosidase (β-gal) claim 3 , and xanthine guanine phophoribosyltransferase (XGPRT) claim 3 , an affinity or epitope tag claim 3 , and a fluorescent protein.5. The method of claim 4 , wherein the reporter protein is a fluorescent protein.6. The method of claim 5 , wherein the fluorescent protein ...

USE OF PERTUSSIS TOXIN AS A THERAPEUTIC AGENT

The present application relates to the use of pertussis toxin, and its derivatives, analogs, salts and pharmaceutical equivalents. In one embodiment, the invention provides a method of treating or preventing a neurological disease or injury by administering pertussis toxin to the individual. 1. A method of increasing angiogenesis in a subject having , or suspected of having , multiple sclerosis , the method comprising the steps of:administering a therapeutically effective dosage of a composition comprising pertussis toxin (PTx) comprising subunits A and B to the subject.2. The method of claim 1 , wherein the composition is administered intracerebroventricularly (icv) or intraperitoneally (ip).3. The method of and further comprising inhibiting migration of T cells into neurologically damaged tissue via administration of the composition.4. The method of claim 1 , wherein the composition is administered to the subject in conjunction with G-protein claim 1 , chemokine and/or adhesion blocking agents.5. The method of and further comprising increasing permeability of the blood-brain barrier via administration of the composition.6. A method of reducing demylenation in a subject having claim 1 , or suspected of having claim 1 , multiple sclerosis claim 1 , the method comprising the steps of:administering a therapeutically effective dosage of a composition comprising pertussis toxin (PTx) comprising subunits A and B to the subject.7. The method of claim 6 , wherein the composition is administered intracerebroventricularly (icv) or intraperitoneally (ip).8. The method of and further comprising reducing inflammation in a spinal cord of the subject via administration of the composition.9. The method of claim 6 , wherein the composition is administered to the subject in conjunction with G-protein claim 6 , chemokine and/or adhesion blocking agents. This application is a divisional of U.S. patent application Ser. No. 16/736,842, filed Jan. 8, 2020, which is a continuation of U.S. ...

Antitumor protocol

Improved protocols that enhance the effect of immunotherapy against tumors are described. The protocol involves enhancing the immune response to an antitumor vaccine by maximizing the ability of T cells induced by the vaccine to extravasate into the tumor and also to modulate the effect of Tregs so that the effectiveness of the vaccine is not undermined. The former effect is achieved by radiation at the site of the tumor or lesions. This latter effect is achieved by an initial depletion of Tregs in combination with modulating their effect during the vaccine administration protocol.

Fusion proteins for use as immunogenic enhancers for inducing antigen-specific t cell responses

A vaccine composition comprising a fusion protein for inducing enhanced pathogen antigen-specific T cell responses is disclosed. The fusion protein comprises: (a) an antigen-presenting cell (APC)-binding domain or a CD91 receptor-binding domain, located at the N-terminus of the fusion protein; (b) a translocation peptide of 34-112 amino acid residues in length, comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 4, 2, 3, or 6, located at the C-terminus of the APC-binding domain or the CD91 receptor-binding domain; and (c) an antigen of a pathogen, located at the C-terminus of the translocation peptide; (d) a nuclear export signal, comprising the amino acid sequence of SEQ ID NO: 13; and (e) an endoplasmic reticulum retention sequence, located at the C-terminus of the fusion protein.

Fusion proteins for use as immunogenic enhancers for inducing antigen-specific t cell responses

A fusion protein for use as an immunogen enhancer for enhancing antigen-specific T cell responses is disclosed. The fusion protein comprises: (a) an antigen-presenting cell (APC)-binding domain or a CD91 receptor-binding domain; (b) a protein transduction domain; and (c) an antigen of a pathogen, wherein the APC-binding domain or the CD91 receptor-binding domain is located at the N-terminus of the fusion protein, and the antigen of the pathogen is located at the C-terminus of the protein transduction domain. The protein transduction domain is selected from the group consisting of: (i) a fusion polypeptide, comprising a T cell sensitizing signal-transducing peptide, a linker, and a translocation peptide; (ii) a T cell-sensitizing signal-transducing peptide; and (iii) a translocation peptide of 34-112 amino acid residues in length.

TARGETING PARP1 FOR TREATMENT OF TSC AND CANCERS

The present invention relates to methods of treating a condition associated with mTORC1 hyperactivation or TSC2-deficient cancer, the method comprising administering to a subject having the cancer a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor. In some embodiments, the condition associated with mTORC1 hyperactivation is tuberous sclerosis complex (TSC). In some embodiments, the condition associated with mTORC1 hyperactivation is lymphangioleiomyomatosis (LAM). In some embodiments, the condition associated with mTORC1 hyperactivation is TSC2-deficient cancer. 1. A method of treating a subject for a condition associated with mTORC1 hyperactivation , wherein the condition comprises the growth of a tumor , the method comprising:receiving results of an assay on a sample from the subject's tumor showing that the tumor is TSC2 deficient; andadministering to the subject having the condition a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor.2. The method of claim 1 , wherein the condition associated with mTORC1 hyperactivation is selected from the group consisting of tuberous sclerosis complex (TSC) claim 1 , lymphangioleiomyomatosis (LAM) claim 1 , and TSC2-deficient cancer.3. The method of claim 1 , wherein the condition associated with mTORC1 hyperactivation is tuberous sclerosis complex (TSC).4. The method of claim 1 , wherein the condition associated with mTORC1 hyperactivation is lymphangioleiomyomatosis (LAM).5. The method of claim 1 , wherein the PARP1 inhibitor is selected from the group consisting of a small molecule claim 1 , a nucleic acid claim 1 , a nucleic acid analog or derivative claim 1 , a peptide claim 1 , a peptidomimetic claim 1 , a protein claim 1 , an antibody or an antigen-binding fragment thereof claim 1 , a monosaccharide claim 1 , a disaccharide claim 1 , a trisaccharide claim 1 , an oligosaccharide claim 1 , a polysaccharide claim 1 , a lipid claim 1 , a ...

Modified forms of pseudomonas exotoxin a

Pseudomonas exotoxin A or “PE” is a 66 kD, highly potent, cytotoxic protein secreted by the bacterium Pseudomonas aeruginosa . Various forms of PE have been coupled to other proteins, such as antibodies, to generate therapeutically useful cytotoxin conjugates that selectively target cells of a desired phenotype (such as tumor cells). In the present invention, peptides spanning the sequence of an approximately 38 kD form of Pseudomonas exotoxin A protein were analyzed for the presence of immunogenic CD4+ T cell epitopes. Six immunogenic T cell epitopes were identified. Residues were identified within each epitope for introduction of targeted amino acid substitutions to reduce or prevent immunogenic T-cell responses in PE molecules which may be administered to a heterologous host.

Functionalized DNA Dendrimers For Gene Delivery To Cells

Compositions are disclosed which comprise a DNA dendrimer having one or more DNA sequences linked thereto, the DNA sequences comprising DNA sequences encoding a polypeptide or regulatory RNA linked to DNA sequences that regulate expression of the DNA sequences encoding a polypeptide or regulatory RNA to produce an RNA coding for the polypeptide or to produce the regulatory RNA. Also disclosed are methods for treating diseases and conditions of cells by delivering the dendrimers to the cells, with subsequent expression of the encoded polypeptide or regulatory RNA. 1. A composition comprising a DNA dendrimer having linked thereto a gene construct and a targeting moiety that directs the DNA dendrimer to a specific cell type, wherein the gene construct comprises a promoter operably linked to one or more DNA sequences encoding a polypeptide or regulatory RNA. This is a continuation of U.S. application Ser. No 15/454,612, filed Mar. 9, 2017, which is a continuation of U.S. application Ser. No. 14/764,388, filed Jul. 29, 2015, which is a National Phase entry of International Application No. PCT/US2014/014104, filed Jan. 31, 2014, which claims priority to U.S. Provisional Application No. 61/759,558, filed Feb. 1, 2013, the disclosures of which are incorporated herein by reference in their entireties.The material contained in the text file identified as DSC0054-00WO_ST25.txt (created Apr. 15, 2014, 773 bytes) is hereby incorporated by reference.The present invention relates to the field of functionalized DNA dendrimers for delivery of genes to cells, and expression of the genes in the cells.Gene therapy is a promising treatment for a variety of cellular abnormalities, diseases and conditions because delivery of therapeutic DNA allows for direct treatment of the affected cell. In theory, the ability to target delivery of the DNA to the desired cell, and to control expression once the DNA is taken up by the cell, should provide an improved level of therapeutic efficiency and ...

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. 1. A pharmaceutical composition comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers , and formulated for oral delivery to a subject , wherein the fusion molecule comprises: (i) a modified Cholix toxin consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof conjugated to (ii) a biologically active cargo selected from:an interleukin-10 consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 82 or a fragment thereof;an interleukin-22 consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof;a human growth hormone consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof;an anti-TNF-α antibody or antibody fragment consisting of at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS: 88-91 or a combination thereof; ora GLP-1 agonist peptide consisting of at least 90% sequence identity to the amino sequence set forth in any one of SEQ ID NOS: 93-94 or a fragment thereof.2. The pharmaceutical composition of claim 1 , wherein the modified Cholix toxin comprises a truncation at an amino acid residue within Cholix toxin domain Ib.3. The pharmaceutical composition of claim 1 , wherein the fusion molecule has the ability to activate the receptor for the biologically active cargo claim 1 , or to enable the catalytic process of a catalytically-active material.4. The ...

METHOD FOR REGULATION OF TELOMERE LENGTH

Provided herein are methods for increasing telomere length comprising contacting a cell with an agent that activates the ataxia telangiectasia mutated (ATM) kinase pathway or a cyclin dependent kinase pathway, thereby elongating telomeres in the cell. Also provided is a method for treating disorders such as cancer and telomere syndromes. 1. A method of increasing telomere length comprising contacting a cell with an agent that activates the ataxia telangiectasia mutated (ATM) kinase pathway or a cyclin dependent kinase pathway , thereby elongating telomeres in the cell.2. The method of claim 1 , wherein the agent is a small molecule claim 1 , a peptide claim 1 , a nucleic acid molecule claim 1 , or a protein.3. The method of claim 2 , wherein the nucleic acid molecule is an siRNA claim 2 , shRNA claim 2 , miRNA claim 2 , Locked Nucleic Acid (LNA) claim 2 , antisense oligonucleotide claim 2 , a chemically modified oligonucleotide claim 2 , or a combination thereof.4. The method of claim 1 , wherein the agent increases expression or activity of ATM kinase.5. The method of claim 1 , wherein the agent increases expression or activity of cyclin dependent kinase 1 (Cdk1).6. The method of claim 4 , wherein the agent is an inhibitor of poly (ADP-ribose) polymerase 1 (PARP1).7. The method of claim 6 , wherein the PARP1 inhibitor is Olaparib (AZD2281) claim 6 , Talazoparib (BMN-673) claim 6 , Rucaparib (AG014699 or PF-01367338) claim 6 , Veliparib (ABT-888) claim 6 , CEP 9722 claim 6 , Niraparib (MK 4827) claim 6 , BGB-290 claim 6 , E7016 claim 6 , E7449 or INO-1001.8. The method of claim 1 , wherein the cell is a mammalian cell.9. The method of claim 8 , wherein the cell is a human or murine cell.10. The method of claim 1 , wherein telomere length is increased at least 50% as compared to telomere length prior to contacting with the agent.11. The method of claim 1 , further comprising measuring telomere length.12. The method of claim 11 , wherein telomere length is measured ...

Fusion polypeptide for immuno-enhancement and method for enhancing stimulation of immune response using the same

A fusion polypeptide is disclosed, which includes: (a) a mucosa targeting polypeptide; (b) a translocating peptide for translocation; and (c) a antigenic epitope. In addition, a method for enhancing a stimulation of an immune response using the aforementioned fusion polypeptide is also disclosed. 1. A fusion polypeptide , comprising:(a) a mucosa targeting polypeptide;(b) a first translocating peptide for translocation; and(c) a first antigenic epitope.2. The fusion polypeptide of claim 1 , wherein the mucosa targeting polypeptide is located at an N-terminal of the fusion polypeptide claim 1 , the first antigenic epitope is located at a C-terminal of the fusion polypeptide claim 1 , and the first translocation peptide is located between the mucosa targeting polypeptide and the first antigenic epitope.3. The fusion polypeptide of claim 1 , wherein the mucosa targeting polypeptide is an M-cell targeting polypeptide or an intestine epithelial targeting polypeptide.4. The fusion polypeptide of claim 1 , wherein the mucosa targeting polypeptide comprises an amino acid sequence selected from SEQ ID NOs: 1 to 4.5pseudomonas. The fusion polypeptide of claim 1 , wherein the first translocating peptide is from exotoxin.6pseudomonas. The fusion polypeptide of claim 1 , wherein the first translocating peptide comprises a exotoxin A fragment deleted of only domain III.7. The fusion polypeptide of claim 1 , wherein the first antigenic epitope is a Th1 antigenic epitope.8. The fusion polypeptide of claim 1 , wherein the first antigenic epitope is an HPV antigenic epitope claim 1 , a Myostatin epitope claim 1 , or a PRRSV antigenic epitope.9. The fusion polypeptide of claim 8 , wherein the HPV antigenic epitope is an E7 peptide sequence or an E6 peptide sequence of human papillomavirus type 16.10. The fusion polypeptide of claim 1 , wherein the first antigenic epitope is selected from SEQ ID NOs: 10 claim 1 , 12 claim 1 , 17 claim 1 , 18 claim 1 , 21 claim 1 , 22 and 23.11. A method ...

C3 FUSION PROTEIN AND METHODS OF MAKING AND USING THEREOF

The present invention provides, among other things, improved therapeutic compositions comprising a C3 fusion protein and methods of making and using the same. In particular, the present invention provides improved methods for the treatment of spinal cord injury and other CNS trauma and/or facilitate axon growth or other tissue repair. 1. A pharmaceutical composition comprising:(a) a population of polypeptides, each having an amino acid sequence at least 95% identical to SEQ ID NO:1,wherein the first amino acid of each polypeptide is not a methionine, or the amino acid sequence is not SEQ ID NO:2, andwherein the population of the polypeptides constitutes greater than 85% of the total amount of polypeptides in the composition;or(b) a first polypeptide and a second polypeptide, wherein:the first polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:1 but does not contain a methionine at the N-terminus,the second polypeptide is otherwise identical to the first polypeptide but contains a methionine at the N-terminus, andthe weight ratio of the first polypeptide to the second polypeptide is at least 6:1;or(c) a polypeptide having an amino acid sequence at least 95% identical to SEQ ID NO:1, wherein the polypeptide does not contain a methionine at the N-terminus, andwherein the polypeptide is present at a concentration ranging from 1.0 mg/mL-40 mg/mL, as determined by UV spectrometry at 280 nm, orwherein the composition contains less than 100 ng/mg host cell protein (HCP), or{'sup': '−4', 'wherein the composition contains less than 2.9×10EU/mg Endotoxin, or'}wherein the pharmaceutical composition comprises a buffer and has a pH ranging from 5.5-7.5 at 25° C.;or(d) a purified recombinant C3 fusion protein having an amino acid sequence at least 95% identical to SEQ ID NO:1, wherein the purified recombinant C3 fusion protein has a purity of equal to or greater than 80% measured by main peak of IE-HPLC.244-. (canceled)45. The pharmaceutical ...

METHODS AND COMPOSITIONS FOR MODULATING IMMUNE TOLERANCE

The instant invention provides methods and compositions for modulation of the immune system. Specifically, the present disclosure provides methods and compositions for increasing T cell mediated immune response useful in the treatment of cancer and chronic infection. 1. A pharmaceutical composition comprising a fusion molecule comprising a chemokine receptor ligand and a toxin moiety and a pharmaceutically acceptable carrier.2. The pharmaceutical composition of claim 1 , wherein the chemokine receptor ligand is selected from the group consisting of a chemokine and a chemoattractant.3. The pharmaceutical composition of claim 2 , wherein the chemokine receptor ligand is a chemokine.4. The pharmaceutical composition of claim 2 , wherein the chemokine is selected from the group consisting of MC148 claim 2 , 1-309 claim 2 , MDC claim 2 , and vMIP-1.5. The pharmaceutical composition of claim 1 , wherein the chemokine receptor ligand is specific for a chemokine receptor selected from the group consisting of CCR8 claim 1 , CCR4 claim 1 , CXCR1 CXCR4 claim 1 , CXCR2 claim 1 , CXCR3 claim 1 , CXCR5 claim 1 , CXCR6 claim 1 , CCR1 claim 1 , CCR2 claim 1 , CCR3 claim 1 , CCR4 claim 1 , CCR5 claim 1 , CCR6 claim 1 , CCR7 claim 1 , CCR8 claim 1 , CCR9 and CCR10.6. The pharmaceutical composition of claim 1 , wherein the toxin moiety is a proteinaceous toxin claim 1 , or fragment thereof.7Pseudomonas. The pharmaceutical composition of claim 6 , wherein the proteinaceous toxin is eosinophil-derived RNase claim 6 , exotoxin claim 6 , diphtheria toxin claim 6 , or anthrax toxin.8. The pharmaceutical composition of claim 1 , wherein the toxin moiety is a non-proteinaceous toxin.9. The pharmaceutical composition of claim 8 , wherein the non-proteinaceous toxin is selected from the group consisting of a maytansinoid claim 8 , a calicheamicin or a taxane.10. The pharmaceutical composition of claim 4 , wherein the chemokine is MC148.11. The pharmaceutical composition of claim 5 , wherein ...

C3 FUSION PROTEIN AND METHODS OF MAKING AND USING THEREOF

The present invention provides, among other things, improved therapeutic compositions comprising a C3 fusion protein and methods of making and using the same. In particular, the present invention provides improved methods for the treatment of spinal cord injury and other CNS trauma and/or facilitate axon growth or other tissue repair. 1. A method for producing recombinant ADP-ribosyl transferase C3 (C3 fusion protein) , comprising: cultivating host cells comprising a nucleic acid encoding a recombinant C3 fusion protein having an amino acid sequence of SEQ ID NO:2 in a large scale vessel under conditions that:promote expression of the C3 fusion protein at a titer concentration of greater than 1 g/L; and/orinvolve a fermentation process to promote expression of the C3 fusion protein.2. The method of claim 1 , wherein the fermentation process is a fed batch culturing process.3. The method of claim 2 , wherein:the fed batch culturing process includes a batch mode, a first stage of exponential feeding, and a second stage of constant feeding;the carbon source is selected from glycerol, glucose, sucrose, lactose, arabinose, maltotriose, sorbitol, xylose, rhamnose, and/or mannose; and/orthe method further comprises a step of adding an inducing agent to trigger expression of the C3 fusion protein.4. The method of claim 3 , wherein:the batch mode lasts for at least about 7 hours, the first stage of exponential feeding lasts for about 7-8 hours and the second stage of constant feeding lasts for about 8 hours;the second stage of constant feeding is at a feed rate at the end of the exponential feeding stage;the first exponential feeding stage is maintained at a temperature between 34° C. to 40° C., and wherein the second and/or third constant feeding stage is maintained at a temperature between 24° C. to 32° C.; and/orthe method further comprises a third stage of constant feeding.5. The method of claim 4 , wherein:the feed rate at the third stage of constant feeding is the same ...

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. 177-. (canceled)78. A method for delivering an interleukin-22 to a subject , the method comprising orally delivering to the subject a pharmaceutical composition comprising (i) a carrier consisting of the amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in any one of SEQ ID NOS: 3 , 42 , 52 , 70 , or 80 , and wherein the carrier is conjugated to (ii) the interleukin-22 consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof.79. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 52.80. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 3.81. The method of claim 78 , wherein the interleukin-22 consists of at least 92% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof.82. The method of claim 78 , wherein the interleukin-22 consists of at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof.83. The method of claim 78 , wherein the interleukin-22 consists of at least 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof.84. The method of claim 78 , wherein the interleukin-22 consists of at least 97% sequence identity to the amino ...

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. 177-. (canceled)78. A method for delivering a human growth hormone to a subject , the method comprising orally delivering to the subject a pharmaceutical composition comprising (i) a carrier consisting of the amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in any one of SEQ ID NOS: 3 , 42 , 52 , 70 , or 80 , and wherein the carrier is conjugated to (ii) the human growth hormone consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof.79. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 52.80. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 3.81. The method of claim 78 , wherein the human growth hormone consists of at least 92% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof.82. The method of claim 78 , wherein the human growth hormone consists of at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof.83. The method of claim 78 , wherein the human growth hormone consists of at least 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof.84. The method of claim 78 , wherein the human growth hormone consists of at least ...

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. 177-. (canceled)78. A method for delivering an anti-TNF-α antibody or antibody fragment to a subject , the method comprising orally delivering to the subject a pharmaceutical composition comprising (i) a carrier consisting of the amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in any one of SEQ ID NOS: 3 , 42 , 52 , 70 , or 80 , and wherein the carrier is conjugated to (ii) the anti-TNF-α antibody or antibody fragment consisting of at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS: 88-91 or a combination thereof.79. The method of claim 78 , wherein the anti-TNF-α antibody or antibody fragment consists of at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS: 88-89 or a combination thereof.80. The method of claim 78 , wherein the anti-TNF-α antibody or antibody fragment consists of at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS: 90-91 or a combination thereof.81. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 52.82. The method of claim 78 , wherein the fragment of the amino acid sequence set forth in SEQ ID NO: 1 consists of the amino acid sequence set forth in SEQ ID NO: 3.83. The method of claim 78 , wherein the anti-TNF-α antibody or antibody fragment consists of at least 92% sequence identity to ...

Methods and Compositions for Treating Disease

The present invention relates to methods and compositions for treating a subject comprising destroying diseased cells in the subject. The methods comprise obtaining a population of cells from a subject and determining the activity of at least one disease marker gene within the population of the obtained cells. A polynucleotide molecule that encodes a polypeptide that is lethal to the cells is then introduced into the cells, where the expression of the lethal polypeptide is controlled by the promoter of at least one of the disease marker genes previously identified. After introduction of the polynucleotide, the cells are treated with conditions to induce expression of the lethal polypeptide to destroy the cells that are expressing the disease marker gene(s). After destruction of the diseased cells, the remaining live cells, which did not express the lethal polypeptide to an extent necessary to kill the cells, are separated from the dead cells, and the live cells are restored to the subject. 131-. (canceled)32. A method of treating a disease by destroying diseased cells in a subject , said method comprising(a) isolating a population of cells from said subject;(b) determining the activity of at least one disease marker gene within said population of said cells;(c) introducing into said cells a polynucleotide molecule that encodes a polypeptide that is lethal to said cells, wherein the promoter of said at least one disease marker gene drives expression of an inducer, and wherein said inducer induces a promoter driving expression of said polynucleotide encoding said lethal polypeptide;(d) treating said cells with conditions to induce expression of said lethal polypeptide, wherein said expression of said lethal polypeptide kills said cells expressing said at least one disease marker gene;(e) separating said killed cells from the remaining live, non-diseased cells, wherein said live cells do not express said lethal polypeptide to an extent sufficient to kill said non- ...

COMPOSITIONS AND METHODS FOR TREATING CANCER

The invention generally relates to compositions and methods for treating cancer. In certain embodiments, the invention provides methods that involve treating a cancer in a patient in which cancerous cells overexpress epidermal growth factor receptor as compared to non-cancerous cells. The methods involve administering a first composition including anthrax protective antigen modified to bind an epidermal growth factor receptor of a cell, and administering a second composition including anthrax lethal factor N-terminus fused to a catalytic domain of Diphtheria Toxin A. Binding of anthrax lethal factor N-terminus to anthrax protective antigen results in internalization of Diphtheria Toxin A into the cancerous cell, which triggers apoptosis by inactivation of critical elongation factors. 1. A composition comprising:a first component comprising an epidermal growth factor receptor (EGFR) binding moiety linked to an anthrax protective antigen; anda second component comprising anthrax lethal factor N-terminus linked to a catalytic domain of diphtheria toxin.2. The composition of wherein the EGFR binding moiety is epidermal growth factor (EGF).3. The composition of wherein the first component is a fusion protein of the EGFR binding moiety and the anthrax protective antigen.4. The composition of wherein the second component is a fusion protein of the anthrax lethal factor N-terminus and the catalytic domain of diphtheria toxin.5. The composition of wherein the first component comprises the EGFR binding moiety chemically linked to the anthrax protective antigen.6. The composition of wherein the second component comprises the anthrax lethal factor N-terminus chemically linked to the catalytic domain of diphtheria toxin.7. A method for treating a cancer in a mammal in which a cancerous cell overexpresses epidermal growth factor receptor (EGFR) as compared to a non-cancerous cell claim 1 , comprising administering to said mammal a therapeutic dose of the composition of .8. The ...

DE-IMMUNIZED SHIGA TOXIN A SUBUNIT EFFECTOR POLYPEPTIDES FOR APPLICATIONS IN MAMMALS

The present invention relates to Shiga toxin effector polypeptides with reduced antigenic and/or immunogenic potential. Immunogenicity can be a limitation for the repeated administration to mammals of proteins and polypeptides derived from Shiga toxins. The Shiga toxin effector polypeptides of the present invention have uses as components of therapeutics, diagnostics, and immunization materials. The cytotoxic proteins of the present invention have uses for selective killing of specific cell types and as therapeutics for the treatment of a variety of diseases, including cancers, immune disorders, and microbial infections. The proteins of the present invention also have uses for detecting specific cell types, collecting diagnostic information, and monitoring the treatment of a variety of diseases, such as, e.g., cancers, immune disorders, and microbial infections. 1. A Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1 ,wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and further comprises:i) a plurality of disrupted endogenous B-cell epitope regions, wherein the disrupted endogenous B-cell epitope regions contain the following amino acid substitutions: S45 of SEQ ID NO: 1 to I, R55 of SEQ ID NO: 1 to L, 157 of SEQ ID NO: 1 to F, P59 of SEQ ID NO: 1 to F, E60 of SEQ ID NO: 1 to T, E61 of SEQ ID NO: 1 to L, G110 of SEQ ID NO: 1 to A, R188 of SEQ ID NO: 1 to A, R248 of SEQ ID NO: 1 to A and R251 of SEQ ID NO: 1 to A;and ii) the amino acid substitution C242 of SEQ ID NO: 1 to S; andwherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid residue corresponding to position 167 of SEQ ...

COMPOUNDS AND METHODS USED IN ASSESSING MONO-PARP ACTIVITY

Mutant mono ADP-ribose-polymerases (mono-PARP) proteins and small molecule compound substrates specific for the mutant mono-PARP proteins as well as methods of using these compositions to identify protein targets of the mono-PARPs and to screen for antagonists of the mono-PARPs are described. 2. The method of claim 1 , wherein the SMC comprises 5-Bn-6-a-NAD.3. The method of claim 1 , further comprising conjugating a label to the SMC.4. The method of claim 3 , wherein the label comprises biotin or a fluorescent molecule.5. The method of claim 1 , further comprising detecting the one or more cellular proteins to which the SMC is covalently attached via a method that comprises mass spectrometry.6. The method of claim 1 , wherein the polypeptide comprises a sequence selected from SEQ ID NO: 9 claim 1 , SEQ ID NO: 10 claim 1 , SEQ ID NO: 11 claim 1 , SEQ ID NO: 12 claim 1 , SEQ ID NO: 13 claim 1 , SEQ ID NO: 14 claim 1 , SEQ ID NO: 15 claim 1 , SEQ ID NO: 16 claim 1 , SEQ ID NO: 17 claim 1 , SEQ ID NO: 18 claim 1 , SEQ ID NO: 19 claim 1 , SEQ ID NO: 20 claim 1 , SEQ ID NO: 21 claim 1 , SEQ ID NO: 22 claim 1 , SEQ ID NO: 23 claim 1 , SEQ ID NO: 24 claim 1 , ora polypeptide with 90% identity thereto provided that the polypeptide catalyzes the addition of the SMC to a PARP protein target.8. The method of claim 7 , wherein the SMC comprises 5-Bn-6-a-NAD.9. The method of claim 7 , wherein the mono-PARP protein target was selected using the method of .10. The method of claim 9 , wherein the polypeptide comprises SEQ ID NO: 15 claim 9 , SEQ ID NO: 17 claim 9 , or SEQ ID NO: 23.11. The method of claim 10 , wherein the mono-PARP protein target comprises at least a fragment of SRPK2 that is mono-ADP-ribosylated by PARP10.12. The method of claim 7 , further comprising conjugating a label to the SMC.13. The method of claim 7 , wherein the contacting occurs within a cell.14. The method of claim 7 , wherein the polypeptide comprises a sequence selected from SEQ ID NO: 9 claim 7 , SEQ ...

EXPRESSION SYSTEM

Compositions and methods related to periplasmic expression of a toxin including diphtheria toxin or CRM197 are provided herein. 2. The process of wherein the 3′ toxin sequence encodes a polypeptide having the amino acid sequence of SEQ ID NO: 32.3. The process of wherein the 3′ toxin sequence comprises SEQ ID NO: 31.4. The process of wherein the 3′ toxin sequence encodes CRM197.5. The process of wherein the 3′ toxin sequence encodes a polypeptide having at least 95% sequence identity to SEQ ID NO: 32.6. The process of wherein the polynucleotide encodes a polypeptide comprising any one of SEQ ID NOs: 33-45.7. The process of wherein the 5′ signal sequence is directly 5′ of the 3′ toxin sequence of the polynucleotide.8. The process of wherein the 5′ signal sequence encodes a signal peptide having an amino acid sequence selected from:(a) SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26;(b) variants of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 containing 1, 2 or 3 point mutations, insertions or deletions, which variants are capable of directing transport of said bacterial toxin polypeptide to the periplasm of said bacterial host cell, and(c) fragments of at least 10 amino acids of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, which fragments are capable of directing transport of said bacterial toxin polypeptide to the periplasm of said bacterial host cell.9. The process of wherein the 5′ signal sequence encodes a signal peptide having an amino acid sequence selected from:(i) SEQ ID NO: 24;(ii) variants of SEQ ID NO: 24 containing 1, 2 or 3 point mutations, insertions or deletions, which variants are capable of directing transport of said bacterial toxin polypeptide to the periplasm of said bacterial host cell; and(iii) fragments of at least 10 amino acids of SEQ ID NO: 24, which fragments are capable of directing transport of said bacterial toxin polypeptide to the periplasm of said bacterial host cell.10. The process of ...

METHODS AND COMPOSITIONS FOR BI-SPECIFIC TARGETING OF CD19/CD22

Methods and composition involving genetically engineered targeting conjugates with reversed orientation of Vand Vchains are provided. For example, in certain aspects targeting conjugates comprising Vand Vchains of anti-CD22 and anti-CD19 are described. In a further aspect, the invention provides methods and targeting conjugates comprising therapeutic agents or diagnostic agents for delivery to B cells. 1. A conjugate comprising a therapeutic agent conjugated to a targeting moiety comprising at least a first antigen-binding fragment that binds a first antigen and a second antigen-binding fragment that binds a second antigen , wherein the first antigen-binding fragment comprises a first Vdomain which is linked at its carboxy terminus to a first Vdomain (V-Vorientation) , and/or the second antigen-binding fragment comprises a second Vdomain which is linked at its carboxy terminus to a second Vdomain (V-Vorientation).2. The conjugate of claim 1 , wherein said conjugate is further defined as a fusion protein.3. The conjugate of claim 2 , wherein said fusion protein is DT2219ARL having an amino acid sequence of SEQ ID NO:01.4. The conjugate of claim 1 , wherein said agent and targeting moiety is chemically conjugated.5. The conjugate of claim 1 , wherein the first and/or second antigen-binding fragment is an Fv fragment.6. The conjugate of claim 1 , wherein the first and/or second antigen-binding fragment is an scFv fragment.7. The conjugate of claim 1 , wherein the first Vdomain is linked to the first Vdomain via a first peptide linker.8. The conjugate of claim 1 , wherein the second Vdomain is linked to the second Vdomain via a second peptide linker.9. The conjugate of claim 7 , wherein the first peptide linker comprises at least three charged resides selected from the group consisting of lysine claim 7 , arginine claim 7 , glutamic acid claim 7 , aspartic acid claim 7 , and histidine.10. The conjugate of claim 8 , wherein the second peptide linker comprises at least ...

PLANT SYNTHESIZING HYPOALLERGENIC PAUCIMANNOSE TYPE N-GLYCAN AND USES THEREOF

A quadruple mutant (qm) plant is deficient of functions of core α1,3-fucosyltransferase A (FucTA), core α1,3-fucosyltransferase B (FucTB), β1,2-xylosyltransferase (XylT), and β1,2-N-acetylglucosaminyltransferase II (GnTII), and produces a protein containing hypoallergenic pauci-mannose-type N-glycan that does not include α1,3-fucose and β1,2-xylose residues. A method for producing a transgenic plant for a production of a protein containing hypoallergenic pauci-mannose-type N-glycan that does not include α1,3-fucose and β1,2-xylose residues but includes α1,6-fucose residue includes preparing the quadruple mutant (qm) plant, and transforming the quadruple mutant plant with a recombinant vector containing a gene encoding the human-derived α1,6-fucosyltransferase (FUT8) protein to overexpress FUT8 gene, and selecting a transgenic plant which is deficient of the functions of FucTA, FucTB, XylT and GnTII proteins. 1. A quadruple mutant (qm) plant which is deficient of functions of core α1 ,3-fucosyltransferase A (FucTA) , core α1 ,3-fucosyltransferase B (FucTB) , β1 ,2-xylosyltransferase (XylT) , and β1 ,2-N-acetylglucosaminyltransferase II (GnTII) , and produces a protein containing hypoallergenic pauci-mannose-type N-glycan that does not include α1 ,3-fucose and β1 ,2-xylose residues.2. The quadruple mutant plant of claim 1 , wherein a part or all of each nucleotide sequence of FucTA gene claim 1 , FucTB gene claim 1 , XylT gene and GnTII gene is deleted or introduced with a foreign gene containing T-DNA in the quadruple mutant plant.3. The quadruple mutant (qm) plant of claim 1 , wherein the deficient functions of the FucTA claim 1 , the FucTB claim 1 , the XylT and the GnTII is achieved by one or more selected from the group consisting of genome modification claim 1 , gene deletion claim 1 , gene insertion claim 1 , T-DNA insertion claim 1 , homologous recombination claim 1 , and transposon tagging.4. The quadruple mutant plant of claim 1 , wherein the FucTA consists ...

HIGH-AFFINITY MONOCLONAL ANTIBODIES TO GLYPICAN-3 AND USE THEREOF

Described herein is the identification of a panel of high affinity monoclonal antibodies that bind GPC3. The disclosed antibodies recognize native GPC3 on the surface of cancer cells, as well as soluble GPC3. The highest affinity antibody (YP7) was further characterized and shown to be highly sensitive in that it was capable of detecting cancer cells with low expression of GPC3. YP7 also exhibited significant HCC tumor growth inhibition in vivo. Immunotoxins comprising the antibodies disclosed herein fused to PE38 exhibited very high binding affinity for GPC3-expressing cells and significantly inhibited GPC3-expressing cancer cell growth. Thus, the high-affinity monoclonal antibodies disclosed herein can be used for the diagnosis and treatment of GPC3-expressing cancers. 1. An isolated monoclonal antibody that binds glypican-3 (GPC3) , wherein:(i) the heavy chain of the antibody comprises SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, and the light chain of the antibody comprises SEQ ID NO: 44, amino acid residues 56-58 of SEQ ID NO: 14, and SEQ ID NO: 45; or(ii) the heavy chain of the antibody comprises SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43, and the light chain of the antibody comprises SEQ ID NO: 46, SEQ ID NO: 47 and SEQ ID NO: 45.2. The isolated monoclonal antibody of claim 1 , wherein:(i) the heavy chain of the antibody comprises amino acid residues 26-33, 51-60 and 99-106 of SEQ ID NO: 12, and the light chain of the antibody comprises amino acid residues 27-38, 56-58 and 95-103 of SEQ ID NO: 14;(ii) the heavy chain of the antibody comprises amino acid residues 26-33, 51-60 and 99-106 of SEQ ID NO: 8, and the light chain of the antibody comprises amino acid residues 27-38, 56-58 and 95-103 of SEQ ID NO: 10;(iii) the heavy chain of the antibody comprises amino acid residues 26-33, 51-60 and 99-106 of SEQ ID NO: 16, and the light chain of the antibody comprises amino acid residues 27-38, 56-58 and 95-103 of SEQ ID NO: 18; or(iv) the heavy chain of the ...

HUMAN MONOCLONAL ANTIBODIES SPECIFIC FOR CD22

Disclosed herein are isolated human monoclonal antibodies that specifically bind human CD22 with a dissociation constant (K) of 25 nM or less. Nucleic acids encoding these antibodies, expression vectors including these nucleic acid molecules, and isolated host cells that express the nucleic acid molecules are also disclosed. The antibodies can be used to detect human CD22 in a sample. In some cases, CD22 is soluble CD22. Methods of diagnosing a B-cell malignancy, or confirming a B-cell malignancy diagnosis, are disclosed herein that utilize these antibodies. Methods of treating a subject with a B-cell malignancy are also disclosed. 1. An isolated human monoclonal antibody that specifically binds human CD22 with a binding affinity of about 20 nM or less , wherein the heavy chain of the antibody comprises amino acid residues 26-35 , 53-61 and 100-113 of SEQ ID NO: 3 , and the light chain of the antibody comprises amino acid residues 27-32 , 50-52 and 89-97 of SEQ ID NO: 4.2. The isolated human monoclonal antibody of claim 1 , wherein the heavy chain of the antibody comprises SEQ ID NO: 3 claim 1 , or the light chain of the antibody comprises SEQ ID NO: 4 claim 1 , or both.3. The isolated human monoclonal antibody of claim 1 , wherein the antibody is an Fab claim 1 , scFv or IgG antibody.4. A composition comprising the human monoclonal antibody of in a pharmaceutically acceptable carrier.5. An isolated immunoconjugate comprising the human monoclonal antibody of and an effector molecule.6. The isolated immunoconjugate of claim 5 , wherein the effector molecule is a toxin or a detectable label.7Pseudomonas. The isolated immunoconjugate of claim 6 , wherein the toxin comprises a exotoxin.8. The isolated immunoconjugate of claim 6 , wherein the detectable label comprises a fluorescent claim 6 , enzymatic claim 6 , or radioactive label.9. A composition comprising the isolated immunoconjugate of in a pharmaceutically acceptable carrier.10. A method of treating a subject with ...

Compounds and methods used in assessing mono-parp activity

Mutant mono ADP-ribose-polymerases (mono-PARP) proteins and small molecule compound substrates specific for the mutant mono-PARP proteins as well as methods of using these compositions to identify protein targets of the mono-PARPs and to screen for antagonists of the mono-PARPs are described.

NOVEL ANTIBODY-DRUG CONJUGATES AND THE USE OF SAME IN THERAPY

Disclosed are novel antibody-drug conjugates and use thereof in therapy, in particular in anticancer or anti-inflammatory therapy, as well as synthetic products useful as linkers, composed of a linker head and a linker body, and also a method for preparing the linkers and the antibody-drug conjugates. 125-. (canceled)31. Product according to in which K represents a site of cleavage by an enzyme selected from the enzymes of the cathepsin B claim 29 , cathepsin C claim 29 , cathepsin D type claim 29 , the enzymes selected from plasmin claim 29 , lysosomal protease claim 29 , lysosomal enzyme claim 29 , or urokinase plasminogen activator (uPA) claim 29 , elastase claim 29 , proteinase 3 claim 29 , cathepsin G;or K represents a recognition site of cleavage by an enzyme of the matrix metalloproteinase (MMP) type preferably selected from collagenase 1, 2 and 3, gelatinase a and b, stromelysin 1 and 2, matrilysin 1, 2 and 3, macrophage metalloelastase, membrane MMP, enamelysin, CA-MMP, epilysin and PSMA.or K represents a recognition site of cleavage by an esterase, a carboxylesterase, alkaline phosphatases, proteases, peptidases, cathepsins, glucosidase, galactosidase, beta-D-galactosidase, induronidase, beta-glucuronidase, mannosidase, N-acetyl-D-glucosaminidase or N-acetyl-D-galactosaminidase.33. Product according to claim 26 , in which the drug M is selected from the group constituted by duocarmycin and its analogues claim 26 , dolastatins claim 26 , combretastatin claim 26 , calicheamicin claim 26 , N-acetyl-□-calicheamycin (CMC) claim 26 , a calicheamycin derivative claim 26 , maytansine and analogues thereof claim 26 , DM-I claim 26 , auristatin E claim 26 , auristatin EB (AEB) claim 26 , auristatin EFP (AEFP) claim 26 , monomethyl auristatin E (MMAE) claim 26 , monomethyl auristatin F (MMAF) claim 26 , tubulysin claim 26 , disorazole claim 26 , the epothilones claim 26 , Paclitaxel claim 26 , docetaxel claim 26 , Topotecan claim 26 , echinomycin claim 26 , ...

A NEW FUSION PROTEIN TO TARGET AND TREAT ACUTE MYLOID LEUKEMIA CELLS

A polypeptide which binds to the surface of AML blast cells and is internalised upon binding to the AML blast cells. 1. A polypeptide which binds to the surface of AML blast cells and is internalised upon binding to the AML blast cells comprising an antibody or antibody fragment comprising an amino acid sequence wherein the polypeptide is corresponding to the complementarity determining regions CDR1 , CDR2 and CDR3 of the heavy chain of the variable region of an antibody vhaving the amino acid sequences forCDR1: comprising a stretch of 2 polar neutral amino acids, followed by 2 nonpolar neutral amino acids, and followed by a polar neutral amino acid;CDR2 comprising a stretch of 10 amino acids which comprises 2 polar amino acids each with a positive side chain, one polar amino acid with a negative side chain and 1 proline which stretch is linked to a further stretch comprising a polar neutral amino acid, followed by a nonpolar neutral amino acid, followed by a polar amino acid having a negatively charged side chain, followed by a polar neutral amino acid, followed by a nonpolar neutral amino acid followed by a polar amino acid having a positively charged side chain, followed by a nonpolar neutral amino acid;{'sup': th', 'th, 'CDR3 comprising a stretch of 7 amino acids wherein the 5amino acid is nonpolar neutral, followed by a polar amino acid having a negatively charged side chain, followed by a 7amino acid which is polar neutral.'}2. The polypeptide of wherein the N-terminal of the polypeptide comprises 20 to 35 amino acids linked to the CDR1 which is followed by a stretch of 8 to 15 amino acids followed by CDR2 which is followed by a stretch of 20 to 35 amino acids which is linked to CDR3 followed by a stretch of 5 to 15 amino acids at the C-terminal of the polypeptide.3. The polypeptide of comprising an antibody or antibody fragment comprising an amino acid sequence wherein the polypeptide is corresponding to the complementarity determining regions CDR1 claim 1 , ...

IL3Ralpha ANTIBODY CONJUGATES AND USES THEREOF

The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα. 183.-. (canceled)84. A nucleic acid that encodes a single chain fragment variable (scFv) region of an antibody that binds CD123 , wherein said nucleic acid comprises nucleotide sequences that encode the complementarity determining regions (CDRs) of the variable heavy (VH) domain and the variable light (VL) domain of said antibody , and wherein said CDRs comprise the VH domain CDR1 presented in SEQ ID NO: 33 , the VH domain CDR2 presented in SEQ ID NO: 34 , the VH domain CDR3 presented in SEQ ID NO: 35 , the VL domain CDR1 presented in SEQ ID NO: 38 , the VL domain CDR2 presented in SEQ ID NO: 39 , and the VL domain CDR3 presented in SEQ ID NO: 40.85. A nucleic acid that encodes an anti-CD123 single chain fragment variable (scFv) antibody region , wherein said nucleic acid comprises SEQ ID NO: 31 and SEQ ID NO: 36.86. A nucleic acid that encodes the variable heavy (VH) domain of monoclonal antibody 32716 , wherein said VH domain comprises SEQ ID NO: 32.87. The nucleic acid of claim 86 , wherein said nucleic acid comprises SEQ ID NO: 31.88. A nucleic acid that encodes the variable light (VL) domain of ...

MHC Class I Epitope Delivering Polypeptides

The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions. 1105-. (canceled)106. A Shiga toxin A subunit effector polypeptide comprising an embedded , heterologous , CD8+ T-cell epitope;wherein the Shiga toxin A subunit effector polypeptide is derived from a parental Shiga toxin A subunit effector polypeptide by having the heterologous, CD8+ T-cell epitope embedded in the parental Shiga toxin A subunit effector polypeptide such that the embedded, heterologous, CD8+ T-cell epitope replaces an equivalent number of amino acid residues in the Shiga toxin A subunit effector polypeptide such that the Shiga toxin A subunit effector polypeptide comprising the embedded, heterologous, CD8+ T-cell epitope has the same total number of amino acids as the parental Shiga toxin A subunit effector polypeptide absent the embedded, heterologous, CD8+ T-cell epitope.107. The Shiga toxin A subunit effector polypeptide of claim 106 , wherein the Shiga toxin A subunit effector polypeptide is capable of exhibiting one or more Shiga toxin effector functions selected from the ...

USE OF PERTUSSIS TOXIN AS A THERAPEUTIC AGENT

The present application relates to the use of pertussis toxin, and its derivatives, analogs, salts and pharmaceutical equivalents. In one embodiment, the invention provides a method of treating or preventing a neurological disease or injury by administering pertussis toxin to the individual. 1. A method of increasing expression of vascular endothelial growth factor (VEGF) in a subject having , or suspected of having , multiple sclerosis , the method comprising the steps of:administering a therapeutically effective dosage of a composition comprising pertussis toxin (PTx) comprising subunits A and B to the subject.2. The method of claim 1 , wherein the composition is administered intracerebroventricularly (icv) or intraperitoneally (ip).3. The method of and further comprising inhibiting migration of T cells into neurologically damaged tissue via administration of the composition.4. The method of claim 1 , wherein the composition is administered to the subject in conjunction with G-protein claim 1 , chemokine and/or adhesion blocking agents.5. The method of and further comprising increasing blood vessel density in the subject's brain cortex and/or spinal gray matter via administration of the composition.6. The method of claim 1 , wherein the therapeutically effective dosage comprises at least 500 ng PTx.7. The method of claim 1 , wherein the therapeutically effective dosage comprises at least 1000 ng PTx.8. The method of claim 1 , wherein the therapeutically effective dosage comprises at least 2000 ng PTx.9. The method of claim 1 , wherein the therapeutically effective dosage comprises at least 3000 ng PTx.10. The method of claim 1 , wherein the therapeutically effective dosage is between 500 ng/day and 1000 ng/day PTx.11. The method of claim 1 , wherein the therapeutically effective dosage is between 1000 ng/day and 2000 ng/day PTx.12. A method of increasing angiogenesis in a subject having claim 1 , or suspected of having claim 1 , multiple sclerosis claim 1 , the ...

MHC CLASS I EPITOPE DELIVERING POLYPEPTIDES

The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions. 1. A cell-targeting molecule comprisingi) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the cellular surface of a cell, and wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and comprises: amino acid substitutions V54, R55L, I57F, P59F, E60T, and E61L in SEQ ID NO: 1,', 'wherein the endogenous B-cell epitope regions are natively positioned in a wild-type Ship toxin A Subunit within amino acid residues: 39-48 of SEQ ID NO:1; 94-115 of SEQ ID NO:1; 179-190 of SEQ ID NO:1; and 243-251 of SEQ ID NO:1; and', 'wherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid residue corresponding to position 167 of SEQ ID NO: 1, an arginine at ...

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. 1. A pharmaceutical composition comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers , and formulated for oral delivery to a subject , wherein the fusion molecule comprises: (i) a modified Cholix toxin consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof conjugated to (ii) a biologically active cargo selected from:an interleukin-10 consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 82 or a fragment thereof;an interleukin-22 consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 85 or a fragment thereof;a human growth hormone consisting of at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 95 or a fragment thereof;an anti-TNF-α antibody or antibody fragment consisting of at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS: 88-91 or a combination thereof; ora GLP-1 agonist peptide consisting of at least 90% sequence identity to the amino sequence set forth in any one of SEQ ID NOS: 93-94 or a fragment thereof.2. The pharmaceutical composition of claim 1 , wherein the modified Cholix toxin comprises a truncation at an amino acid residue within Cholix toxin domain Ib.3. The pharmaceutical composition of claim 1 , wherein the fusion molecule has the ability to activate the receptor for the biologically active cargo claim 1 , or to enable the catalytic process of a catalytically-active material.4. The ...

LYMPHOCYTE MEDIATED DELIVERY OF PROTEINS

The invention is directed to methods and compositions for cell-based targeted delivery of predetermined compounds to a population of target cells. In some embodiments, methods of the invention include providing cytotoxic lymphocytes genetically modified to produce and sequester in lytic granules fusion proteins comprising a granzyme, or other effector agent, and a predetermined protein, so that upon specific contact of the cytotoxic lymphocytes with the target cells, the granzyme-perforin pathway of the cytotoxic lymphocytes is activated, leading to the delivery of the fusion protein to the cytosols of the target cells. 1. A method of delivering a compound to target cells , the method comprising the steps ofproviding cytotoxic lymphocytes specific for the target cells and having a granzyme-perforin pathway;genetically modifying the cytotoxic lymphocytes to express a fusion protein comprising an effector agent and a predetermined protein to form a population of delivery lymphocytes, such that the fusion protein is sequestered in lytic granules of the delivery lymphocyte;contacting the target cells with the delivery lymphocytes so that granzyme-perforin pathways thereof are activated, thereby delivering the fusion protein to cytosols of the target cells.2. The method of wherein said step of contacting includes administering said delivery lymphocytes to an individual so that said delivery lymphocytes contact said target cells of the individual.3. The method of further including a step of expanding said population of delivery lymphocytes prior to said step of administration.4. The method of wherein said cytotoxic lymphocytes are matched with said target cells.5. The method of wherein said cytotoxic lymphocytes are autologous to said individual.6. The method of wherein said cytotoxic lymphocytes are cytotoxic T cells and wherein said contact of said delivery lymphocytes with said target cells includes binding of T cell receptors of said delivery lymphocytes with WHC ...

ANTITUMOUR AGENT, MARKER FOR TUMOUR DETECTION, AND ORAL VACCINE AGENT

An object of the present invention is to provide an antitumor agent and/or a marker fur tumor detection with low invasiveness, few side effects, and high target specificity. Through the use of a recombinant obligate anaerobic gram-positive bacterium as an active ingredient containing a nucleic acid encoding a secretory fusion protein comprising a signal peptide, a low-molecular-weight single-chain antibody, and a functional peptide, an antitumor agent that enables delivery of a functional peptide to a target cell and/or a marker for tumor detection that enables monitoring of therapeutic effects over time are provided. 1. A recombinant obligate anaerobic gram-positive bacterium , comprising a nucleic acid encoding a fusion protein comprising a signal peptide , one or more single-chain antibodies , and one or more functional peptides , in an secretable state.2Bifidobacterium.. The recombinant obligate anaerobic gram-positive bacterium according to claim 1 , wherein the obligate anaerobic gram-positive bacterium belongs to the genus3. The recombinant obligate anaerobic gram-positive bacterium according to claim 1 , wherein the single-chain antibody is a low-molecular-weight antibody having a molecular weight of 35 kDa or less.4. The recombinant obligate anaerobic gram-positive bacterium according to claim 1 , wherein the nucleic acid encodes two or more single-chain antibodies.5. The recombinant obligate anaerobic gram-positive bacterium according to claim 1 , wherein the single-chain antibodies recognize and bind to the surface antigen of a target cell.6. The recombinant obligate anaerobic gram-positive bacterium according to claim 5 , wherein the target cell is a tumor cell.7. The recombinant obligate anaerobic gram-positive bacterium according to claim 5 , wherein the functional peptide is an exotoxin and/or a labeling protein.8. The recombinant obligate anaerobic gram-positive bacterium according to claim 7 , wherein the labeling protein is a fluorescent protein or ...

MOLECULAR SIGNATURE OF CANCER

The present invention provides compounds, compositions, and methods for detecting, diagnosing and treating cancers such as glioblastoma multiforme. 123-. (canceled)24. A method of treating a cancer tumor expressing the oncogenic receptor EphA2 in a subject , comprising:administering ephrinA1 in monomeric form to said subject in a treatment effective amount, wherein said ephrinA1 is coupled to a therapeutic agent.25. The method of claim 24 , wherein said therapeutic agent is a radionuclide claim 24 , chemotherapeutic agent or cytotoxic agent.26Pseudomonas. The method of claim 24 , wherein said therapeutic agent comprises a exotoxin.27. The method of claim 24 , wherein said cancer is selected from the group consisting of breast cancer claim 24 , bladder cancer claim 24 , pancreatic cancer claim 24 , colorectal cancer claim 24 , head and neck cancer claim 24 , thyroid cancer claim 24 , prostate cancer claim 24 , and gliomas.28. A method of treating cancer in a subject claim 24 , comprising:administering a first compound that specifically binds to an Eph receptor to said subject in a treatment effective amount, wherein said first compound is coupled to a first therapeutic agent, and concurrentlyadministering a second compound that specifically binds to an IL-13 receptor to said subject in a treatment effective amount, wherein said second compound is coupled to a second therapeutic agent.29. The method of claim 28 , wherein said first compound comprises monomeric ephrinA1.30. The method of claim 28 , wherein said first compound consists essentially of monomeric ephrinA1.31. The method of claim 28 , wherein said second compound comprises IL-13 or anti-IL-13Rα2 antibody or peptide.32. The method of claim 28 , wherein said first therapeutic agent and said second therapeutic agent are each independently selected from the group consisting of radionuclides claim 28 , chemotherapeutic agents claim 28 , and cytotoxic agents.33. The method of claim 28 , wherein said first ...

Pharmaceutical composition for preventing or treating ldl cholesterol-related diseases, containing ribosome-binding preparation

The present invention relates to: a pharmaceutical composition for preventing or treating LDL cholesterol-related diseases, containing a ribosome-binding preparation; a food composition; and a method for preventing or treating LDL cholesterol-related diseases by using the composition. According to the present invention, the ribosome-binding preparation selectively increases the expression of an LDL receptor in intestinal epithelial cells so as to promote LDL absorption in blood and tissue, such that LDL level in the blood can be reduced, thereby being useful for preventing or treating various LDL cholesterol-related diseases including LDL hypercholesterolemia, hyperlipidemia, hypertension and apoplexy.

CHOLIX TOXIN-DERIVED FUSION MOLECULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. The present disclosure relates to a non-toxic mutant form of the Cholix gene (ntCholix), a variant of Cholix truncated at amino acid A(Cholix) and the use of other various Cholix-derived polypeptide sequences to enhance intestinal delivery of biologically-active therapeutics. The systems and methods described herein provide for: the ability to deliver macromolecule doses without injections; the ability to deliver cargo such as siRNA or antisense molecules into intracellular compartments where their activity is required; and the delivery of nanoparticles and dendrimer-based carriers across biological membranes. 116.-. (canceled)17. An isolated fusion molecule comprising a Cholix polypeptide and a macromolecule , wherein the Cholix polypeptide is capable of transcytosing across a polarized epithelial cell.18. The isolated fusion molecule of claim 17 , wherein the Cholix polypeptide is non-toxic.19. A pharmaceutical composition comprising the isolated fusion molecule of and a pharmaceutically acceptable carrier. This application is a continuation of U.S. patent application Ser. No. 16/151,533, filed Oct. 4, 2018, which is a continuation of U.S. patent application Ser. No. 15/616,140, filed Jun. 7, 2017, now U.S. Pat. No. 10,130,688, which is a continuation-in-part of U.S. patent application Ser. No. 14/733,940, filed Jun. 8, 2015, which is a continuation of U.S. patent application Ser. No. 13/822,435, filed Mar. 12, 2013 now U.S. Pat. No. 9,090,691, which is a U.S. National Stage Application pursuant to 35 U.S.C. § 371 of PCT/US2011/001602, filed Sep. 15, 2011, which claims ...

Functionalized DNA Dendrimers For Gene Delivery To Cells

Compositions are disclosed which comprise a DNA dendrimer having one or more DNA sequences linked thereto, the DNA sequences comprising DNA sequences encoding a polypeptide or regulatory RNA linked to DNA sequences that regulate expression of the DNA sequences encoding a polypeptide or regulatory RNA to produce an RNA coding for the polypeptide or to produce the regulatory RNA. Also disclosed are methods for treating diseases and conditions of cells by delivering the dendrimers to the cells, with subsequent expression of the encoded polypeptide or regulatory RNA. 1. A composition comprising a DNA dendrimer , wherein one or more linear DNA sequences encoding a cytotoxin operably linked to a promoter having specific transcriptional activity in pancreatic cancer cells or prostate cancer cells are linked to the DNA dendrimer.2. The composition of claim 1 , wherein the promoter is MSLN or K5.3. The composition of claim 1 , wherein the cytotoxin is Diphtheria toxin A chain.4. The composition of claim 1 , comprising a plurality of linked DNA sequences claim 1 , wherein the linked DNA sequences encode a plurality of cytotoxins.5. The composition of claim 1 , further comprising a cellular internalization moiety linked to the DNA dendrimer.6. The composition of claim 5 , wherein the internalization moiety is an antibody that binds to a cell surface protein claim 5 , a peptide that binds to a cell surface protein or a ligand that binds to a cell surface receptor.7. The composition of claim 6 , wherein the internalization moiety is an antibody or peptide that binds to the transferrin receptor.8. The composition of claim 1 , wherein the DNA dendrimer is constructed from DNA monomers claim 1 , each of which comprises two DNA strands having a sequence of complementarity located in a central portion of each strand forming a central double-stranded waist bordered by four single-stranded arms claim 1 , and the DNA dendrimer is assembled by base pairing between single-stranded arms of ...

Compositions and methods for the modulation of dna damage responses using bal1 and bbap

The invention provides methods and compositions for enhancing the efficacy of cancer therapies through modulation of BAL1 and/or BBAP. Also provided are methods for predicting the efficacy of cancer therapies or treating cancer in a subject through modulation of BAL1 and/or BBAP. Further provided are methods for identifying compounds that are capable of modulating BAL1-BBAP complexes.

Methods for providing a homogenous solution of lyophilized mutant diptheria toxin in dimethylsulfoxide

A method is described for reconstituting lyophilized mutant diphtheria toxin in dimethyl sulfoxide for use in producing pneumococcal capsular polysaccharide mutant diphtheria toxin conjugates.

MHC CLASS I EPITOPE DELIVERING POLYPEPTIDES

The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions. 1105.-. (canceled)106. A Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1;wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and further comprises:a heterologous, CD8+ T-cell epitope embedded at amino acid residue positions 53-61 of SEQ ID NO: 1 and having mutated residues at V54L, R55L, I57F, P59F, E60T, and E61L,wherein the endogenous B-cell epitope regions are natively positioned in a wild-type Shiga toxin A Subunit within amino acid residues: 39-48 of SEQ ID NO:1; 94-115 of SEQ ID NO:1; 179-190 of SEQ ID NO:1; and 243-251 of SEQ ID NO:1; andwherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid ...

POROUS NANOPARTICLE-SUPPORTED LIPID BILAYERS (PROTOCELLS) FOR TARGETED DELIVERY INCLUDING TRANSDERMAL DELIVERY OF CARGO AND METHODS THEREOF

The present invention is directed to protocells for specific targeting of hepatocellular and other cancer cells which comprise a nanoporous silica core with a supported lipid bilayer; at least one agent which facilitates cancer cell death (such as a traditional small molecule, a macromolecular cargo (e.g. siRNA or a protein toxin such as ricin toxin A-chain or diphtheria toxin A-chain) and/or a histone-packaged plasmid DNA disposed within the nanoporous silica core (preferably supercoiled in order to more efficiently package the DNA into protocells) which is optionally modified with a nuclear localization sequence to assist in localizing protocells within the nucleus of the cancer cell and the ability to express peptides involved in therapy (apoptosis/cell death) of the cancer cell or as a reporter, a targeting peptide which targets cancer cells in tissue to be treated such that binding of the protocell to the targeted cells is specific and enhanced and a fusogenic peptide that promotes endosomal escape of protocells and encapsulated DNA. Protocells according to the present invention may be used to treat cancer, especially including hepatocellular (liver) cancer using novel binding peptides (c-MET peptides) which selectively bind to hepatocellular tissue or to function in diagnosis of cancer, including cancer treatment and drug discovery. 1nanoponms silica or metal oxide core with a supported lipid bilayer and at least one further component selected from the group consisting of a cell targeting species;a fusogenic peptide that promotes endosomal escape of protooells and encapsulated DNA, and other cargo comprising at least one cargo component selected from the group consisting of double stranded linear DNA;plasmid DNA;drugan imaging agent,small interfering RNA, small hairpin RNA, mieroRNA, or a mixture thereof, wherein one, of said cargo components is optionally conjugated further with a nuclear localization sequence.. A cell-targeting pon:.ms protocell comprising: ...

METHODS FOR DETERMINING RESPONSE TO PARP INHIBITORS

Methods and compositions are provided for determining whether an adenocarcinoma or squamous cell carcinoma patient is likely to respond to PARP inhibitor treatment. Specifically, a method of assessing whether a patient's adenocarcinoma (AD) lung cancer subtype is terminal respiratory unit (TRU), proximal inflammatory (PI), or proximal proliferative (PP) or a patient's squamous cell carcinoma (SQ) is primitive, classical, secretory or basal is provided herein. The method entails detecting the levels of classifier biomarkers at the nucleic acid level, in an AD or SQ lung cancer sample obtained from the patient. Based in part on the levels of the classifier biomarkers, the AD lung cancer sample is classified as a TRU, PI, or PP AD sample or the SQ lung cancer sample is classified as primitive, classical, secretory or basal and a determination of whether the patient is likely to respond to PARP inhibitor treatment can be made. 1. A method of determining whether an adenocarcinoma or squamous cell carcinoma patient is likely to respond to PARP inhibitor treatment , the method comprising ,determining the adenocarcinoma subtype or the squamous cell carcinoma subtype of a lung tissue sample from the patient, wherein the adenocarcinoma subtype is selected from the group consisting of squamoid (proximal inflammatory), bronchoid (terminal respiratory unit) and magnoid (proximal proliferative), and the squamous cell carcinoma subtype is selected from the group consisting of primitive, classical, secretory and basal; andbased on the subtype, assessing whether the patient is likely to respond to PARP inhibitor treatment.2. A method for selecting an adenocarcinoma or squamous cell carcinoma patient for PARP inhibitor treatment , the method comprising , determining an adenocarcinoma subtype or squamous cell carcinoma subtype of a lung tissue sample from the patient , based on the subtype; and selecting the patient for PARP inhibitor treatment.3. The method of or , wherein the ...

MOLECULAR SIGNATURE OF CANCER

The present invention provides compounds, compositions, and methods for detecting, diagnosing and treating cancers such as glioblastoma multiforme. 127.-. (canceled)28. A method of treating cancer in a subject , comprising:administering a first compound that specifically binds to an Eph receptor to said subject in a treatment effective amount, wherein said first compound is coupled to a first therapeutic agent, and concurrentlyadministering a second compound that specifically binds to an IL-13 receptor to said subject in a treatment effective amount, wherein said second compound is coupled to a second therapeutic agent.29. The method of claim 28 , wherein said first compound comprises monomeric ephrinA1.30. The method of claim 28 , wherein said first compound consists essentially of monomeric ephrinA1.31. The method of claim 28 , wherein said second compound comprises IL-13 or anti-IL-13Rα2 antibody or peptide.32. The method of claim 28 , wherein said first therapeutic agent and said second therapeutic agent are each independently selected from the group consisting of radionuclides claim 28 , chemotherapeutic agents claim 28 , and cytotoxic agents.33. The method of claim 28 , wherein said first therapeutic agent and said second therapeutic agent each comprise a cytotoxic agent.34Pseudomonas. The method of claim 28 , wherein said first therapeutic agent and said second therapeutic agent each comprise a exotoxin.35. The method of claim 28 , further comprising:concurrently administering a third compound comprising a Frataxin-1 (Fra-1) antagonist to said subject in a treatment effective amount, wherein said third compound is coupled to a third therapeutic agent.36. The method of claim 28 , wherein said cancer is selected from the group consisting of breast cancer claim 28 , bladder cancer claim 28 , pancreatic cancer claim 28 , colorectal cancer claim 28 , head and neck cancer claim 28 , thyroid cancer claim 28 , prostate cancer claim 28 , and gliomas.37. The method of ...

Method for the treatment of pulmonary disease and method of producing proteins of use therein

Methods of treating a subject with pulmonary disease by administering a therapeutically effective amount of a defensin polypeptide including at least one arginine residue susceptible to ADP-ribosylation and nicotinamide adenine dinucleotide (NAD), are described. The polypeptide and/or NAD can be administered via inhalation. Also disclosed is a pharmaceutical composition including at least one defensin polypeptide and NAD. In vitro methods of producing a polypeptide with altered activity, including contacting the polypeptide with NAD and an arginine-specific mono-ADP-ribosyltransferase to produce a polypeptide including at least one ADP-ribosylated arginine residue, incubating the ADP-ribosylated polypeptide under conditions sufficient for conversion of at least one ADP-ribosylated arginine residue to ornithine, and isolating the ornithine-containing polypeptide, are also described. Methods of treating a subject with pulmonary disease by administering a therapeutically effective amount of a modified defensin polypeptide including at least one ornithine residue in place of an arginine residue are also disclosed.

Methods and Compositions for Modulating Immune Tolerance

The instant invention provides methods and compositions for modulation of the immune system. Specifically, the invention provides methods and compositions for increasing T cell mediated immune response useful in the treatment of cancer and chronic infection. 1. A method for increasing T cell mediated immune response in a subject comprising:administering to the subject a fusion molecule comprising a chemokine receptor ligand and a toxin moiety;thereby increasing the T cell mediated immune response.2. The method of claim 1 , wherein the subject has cancer.3. The method of claim 2 , wherein the cancer is a T cell malignancy.4. The method of claim 3 , wherein the T cell malignancy is selected from the group consisting of cutaneous T cell leukemia and myeloma.5. The method of claim 1 , wherein the subject has a chronic infection.6. The method of claim 5 , wherein the chronic infection is selected from the group consisting of HIV infection claim 5 , HCV infection claim 5 , HBV infection and TB infection.7. The method of claim 2 , wherein the fusion molecule is administered to the location of a tumor.8. The method of claim 1 , wherein chemokine receptor ligand is selected from the group consisting of a chemokine and a chemoattractant.9. The method of claim 1 , wherein the chemokine receptor ligand is a chemokine.10. The method of claim 9 , wherein the chemokine is selected from the group consisting of MC148 claim 9 , TARC claim 9 , I-309 claim 9 , MDC claim 9 , and vMIP-1.11. The method of claim 9 , wherein the chemokine receptor ligand is specific for a chemokine receptor selected from the group consisting of CCR8 claim 9 , CCR4 claim 9 , CXCR1 CXCR4 claim 9 , CXCR2 claim 9 , CXCR3 claim 9 , CXCR5 claim 9 , CXCR6 claim 9 , CCR1 claim 9 , CCR2 claim 9 , CCR3 claim 9 , CCR4 claim 9 , CCR5 claim 9 , CCR6 claim 9 , CCR7 claim 9 , CCR8 claim 9 , CCR9 and CCR10.12. The method of claim 1 , wherein the toxin moiety is a proteinaceous toxin claim 1 , or fragment thereof. ...

USE OF RNAI INHIBITING PARP ACTIVITY FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF CANCER

The present invention relates to the use of an agent that inhibits the activity of an enzyme that mediates repair of a DNA strand break in the manufacture of a medicament for the treatment of diseases caused by a defect in a gene that mediates homologous recombination. 132.-. (canceled)33. A method of treatment of homologous recombination (HR) defective tumours in a human patient , the method comprising;administering a therapeutically effective amount of a compound which inhibits PARP-1 to a human patient.34. The method of wherein the compound which inhibits PARP-1 is selected from the group consisting of benzimidazole-carboxamides claim 33 , quinazolin-4-[3H]-ones and isoquinolone derivatives.35. The method of wherein the compound which inhibits PARP-1 is selected from the group consisting of 2-(4-hydroxyphenyl)benzimidazole-4-carboxamide claim 34 , 8-hydroxy-2-methylquinazolin-4-[3H]one claim 34 , 6(5H)phenanthridinone claim 34 , 3-aminobenzamide claim 34 , benzimidazole-4-carboxamides and tricyclic lactam indoles.36. The method of wherein the gene that mediates HR is selected from the group consisting of XRCC1 claim 33 , CTPS claim 33 , RPA claim 33 , RPA1 claim 33 , RPA2 claim 33 , RPA3 claim 33 , XPD claim 33 , ERCC1 claim 33 , XPF claim 33 , MMS19 claim 33 , RAD51 claim 33 , RAD51B claim 33 , RAD51C claim 33 , RAD51D claim 33 , DMC1 claim 33 , XRCC2 claim 33 , XRCC3 claim 33 , BRCA1 claim 33 , BRCA2 claim 33 , RAD52 claim 33 , RAD54 claim 33 , RAD50 claim 33 , MRE11 claim 33 , NBS1 claim 33 , WRN claim 33 , BLM claim 33 , Ku70 claim 33 , Ku80 claim 33 , ATM claim 33 , ATR claim 33 , chkl claim 33 , chk2 claim 33 , FANCA claim 33 , FANCB claim 33 , FANCC claim 33 , FANCD1 claim 33 , FANCD2 claim 33 , FANCE claim 33 , FANCF claim 33 , FANCG claim 33 , RAD1 claim 33 , RADS claim 33 , FEN-1 claim 33 , Mus81 claim 33 , Emel claim 33 , DDS1 and BARD.37. The method of wherein the cancer is selected from the group consisting of lung claim 33 , colon claim 33 , ...

EXPRESSION SYSTEM

Methods for producing a conjugate of a bacterial toxin, including toxin or CRM197, are provided. 1. A process for producing a conjugate of a bacterial toxin , comprising:{'i': Escherichia coli', 'E. coli, 'claim-text': (a) a 3′ toxin sequence encoding a mature bacterial toxin polypeptide having an amino acid sequence at least 90% identical to SEQ ID NO:32, and', {'i': Corynebacterium diphtheriae', 'C. diphtheriae, '(b) a 5′ signal sequence encoding a signal peptide, wherein the signal peptide directs transport of said bacterial toxin polypeptide to the bacterial periplasm when expressed in said host cell, and wherein the 5′ signal sequence is not derived from (); and'}, 'inducing expression of said polynucleotide such that said bacterial toxin polypeptide is expressed periplasmically; and, '(1) growing a culture of () host cells containing a polynucleotide comprising(2) harvesting cell paste from the culture and purifying said bacterial toxin polypeptide; and(3) conjugating said purified bacterial toxin to an antigen;wherein the process of (1) is carried out in a fermentor.2. The process of wherein the 3′ toxin sequence encodes a polypeptide selected from the group consisting of (a) a polypeptide having the amino acid sequence of SEQ ID NO: 32 claim 1 , (b) a polypeptide having at least 95% sequence identity to SEQ ID NO: 32 claim 1 , (c) a polypeptide comprising SEQ ID NO:31 claim 1 , and (d) CRM197.3. The process of wherein the polynucleotide encodes a polypeptide comprising any one of SEQ ID NOs: 33-45.4. The process of wherein the 5′ signal sequence is directly 5′ of the 3′ toxin sequence of the polynucleotide.5. The process of wherein the 5′ signal sequence encodes a signal peptide having an amino acid sequence selected from:(a) SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, and(b) variants of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 containing 1, 2 or 3 point mutations, insertions or deletions, which variants are capable of ...

Modified forms of pseudomonas exotoxin a

Pseudomonas exotoxin A or “PE” is a 66 kD, highly potent, cytotoxic protein secreted by the bacterium Pseudomonas aeruginosa . Various forms of PE have been coupled to other proteins, such as antibodies, to generate therapeutically useful cytotoxin conjugates that selectively target cells of a desired phenotype (such as tumor cells). In the present invention, peptides spanning the sequence of an approximately 38 kD form of Pseudomonas exotoxin A protein were analyzed for the presence of immunogenic CD4+ T cell epitopes. Six immunogenic T cell epitopes were identified. Residues were identified within each epitope for introduction of targeted amino acid substitutions to reduce or prevent immunogenic T-cell responses in PE molecules which may be administered to a heterologous host.

DEIMMUNIZED THERAPEUTIC COMPOSITIONS AND METHODS

This disclosure provides a bispecific ligand directed toxin (BLT) that includes a diphtheria toxin (DT) molecule that has been mutated to create a DT molecule that induces less of an immune response than native diphtheria toxin. The deimmunized DT molecule is fused with targeting ligands to create a fusion protein that can selectively deliver the deimmunized DT to target cells to kill the target cells. 1. A polypeptide comprising: the DT catalytic site; and', 'at least one amino acid substitution that decreases induction of anti-toxin antibodies compared to wild-type diphtheria toxin; and, 'a diphtheria toxin (DT) domain comprisingat least one targeting domain that selectively binds to a target.2. The polypeptide of wherein the polypeptide exhibits measurable diphtheria toxin toxicity.3. The polypeptide of wherein the targeting domain selectively binds to a component of a tumor cell.4. The polypeptide of wherein the targeting domain comprises an epidermal growth factor (EGF) polypeptide that selectively binds epidermal growth factor receptor (EGFR).5. The polypeptide of wherein the targeting domain comprises an IL-13 polypeptide that selectively binds to IL-13 receptor.6. The polypeptide of wherein the targeting domain comprises a polypeptide that selective binds to CD22.7. The polypeptide of wherein the targeting domain comprises a polypeptide that selective binds to CD19.8. The polypeptide of wherein the DT domain comprises DT390.9. The polypeptide of wherein the polypeptide comprises at least two targeting domains.10. The polypeptide of wherein a first targeting domain comprises an IL-13 polypeptide and a second targeting domain comprises an EGF polypeptide.11. The polypeptide of wherein a first targeting domain comprises a polypeptide that selective binds CD19 and a second targeting domain comprises a polypeptide that selectively binds CD22.12. The polypeptide of wherein the DT domain comprises a variant of DT390 comprising at least three amino acid ...

COMPOSITIONS AND METHODS FOR TREATING IMMUNE AND VIRAL DISORDERS AND MODULATING PROTEIN-RNA INTERACTION

The present invention relates to methods of treating or decreasing the likelihood of developing a disorder associated with immune misregulation, such as, an autoimmune disorder, or viral or virus-associated disorder in a subject including administering to the subject a composition comprising an activator of a CCCH zinc finger-containing PARP, such as, PARP13 or PARP12. The present invention also relates to methods of treating a TRAIL-resistant disorder, such as, TRAIL-resistant cancer including administering to the subject a composition comprising an activator of a CCCH zinc finger-containing PARP, such as, PARP13 or PARP12. The present invention further relates to methods of modulating a CCCH zinc finger-containing PARP-RNA interaction including contacting a CCCH zinc finger-containing PARP protein or a CCCH zinc finger-containing PARP fusion protein with a CCCH zinc finger-containing PARP activator. 1. A method of treating or decreasing the likelihood of developing a disorder associated with immune misregulation , a viral disorder , or a virus-associated disorder in a subject , the method comprising administering to the subject a therapeutically effective amount of a composition comprising an activator of a CCCH zinc finger-containing PARP , thereby treating or decreasing the likelihood of developing the disorder associated with immune misregulation , the viral disorder , or the virus-associated disorder in the subject.2. The method of claim 1 , wherein the disorder associated with immune misregulation is an autoimmune disorder claim 1 , wherein the autoimmune disorder is selected from the group consisting of systemic lupus erythematosus (SLE) claim 1 , CREST syndrome (calcinosis claim 1 , Raynaud's syndrome claim 1 , esophageal dysmotility claim 1 , sclerodactyl claim 1 , and telangiectasia) claim 1 , opsoclonus claim 1 , inflammatory myopathy claim 1 , systemic scleroderma claim 1 , primary biliary cirrhosis claim 1 , celiac disease claim 1 , dermatitis ...

CHOLIX TOXIN-DERIVED FUSION MOELCULES FOR ORAL DELIVERY OF BIOLOGICALLY ACTIVE CARGO

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. The present disclosure relates to a non-toxic mutant form of the Cholix gene (ntCholix), a variant of Cholix truncated at amino acid A(Cholix) and the use of other various Cholix-derived polypeptide sequences to enhance intestinal delivery of biologically-active therapeutics. The systems and methods described herein provide for: the ability to deliver macromolecule doses without injections; the ability to deliver cargo such as siRNA or antisense molecules into intracellular compartments where their activity is required; and the delivery of nanoparticles and dendrimer-based carriers across biological membranes. 1. A pharmaceutical composition comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers , formulated for oral delivery to a subject , wherein the fusion molecule comprises a modified Cholix toxin coupled to a biologically active cargo , wherein the modified Cholix toxin is mutated at an amino acid residue within Cholix toxin domain III that renders the Cholix toxin non-toxic , and wherein the fusion molecule has the ability to activate the receptor for the biologically active cargo , or to enable the catalytic process of a catalytically-active material.2. The pharmaceutical composition of claim 1 , wherein the modified Cholix toxin comprises the amino acid sequence set forth in SEQ ID NO: 81.3. The pharmaceutical composition according to claim 1 , wherein the biologically active cargo is a macromolecule claim 1 , small molecule claim 1 , peptide claim 1 , polypeptide claim 1 , nucleic acid claim 1 , mRNA claim 1 , ...

MODIFIED FORMS OF PSEUDOMONAS EXOTOXIN A

exotoxin A or “PE” is a 66 kD, highly potent, cytotoxic protein secreted by the bacterium . Various forms of PE have been coupled to other proteins, such as antibodies, to generate therapeutically useful cytotoxin conjugates that selectively target cells of a desired phenotype (such as tumor cells). In the present invention, peptides spanning the sequence of an approximately 38 kD form of exotoxin A protein were analyzed for the presence of immunogenic CD4+ T cell epitopes. Six immunogenic T cell epitopes were identified. Residues were identified within each epitope for introduction of targeted amino acid substitutions to reduce or prevent immunogenic T-cell responses in PE molecules which may be administered to a heterologous host. 1Pseudomonas. A polypeptide having at least one exotoxin A (PE-A) biological activity , wherein said polypeptide comprises one or more amino acid substitutions compared to a wild-type PE-A polypeptide , wherein said one or more amino acid substitutions is a substitution of a different amino acid at one or more positions corresponding to amino acid residues in the polypeptide of SEQ ID NO:1 , wherein one of said substitutions is selected from the group consisting of:a) isoleucine (I) at position 141 is substituted with a different non-polar amino acid; and,b) isoleucine (I) at position 141 is substituted with a different aliphatic amino acid.2. The polypeptide of claim 1 , wherein the different non-polar amino acid substitution for isoleucine (I) at position 141 is glycine (G) claim 1 , leucine (L) claim 1 , methionine (M) claim 1 , phenylalanine (F) claim 1 , proline (P) claim 1 , tryptophan (W) claim 1 , or valine (V).3. The polypeptide of claim 1 , wherein the different aliphatic amino acid substitution for isoleucine (I) at position 141 is glycine (G) claim 1 , valine (V) or leucine (L).4. (canceled)5. (canceled)6. (canceled)7. (canceled)8. (canceled)9. (canceled)10. (canceled)11. (canceled)12. (canceled)13. (canceled)14Pseudomonas. ...

NOVEL UBIQUITINATION SYSTEM AND THE USES THEREOF

An unprecedented mechanism of ubiquitination that is independent of E1 and E2 enzymes, instead relying on activation of ubiquitin by ADP-ribosylation, and which is mediated by members of the SidE effector family encoded by the bacterial pathogen is disclosed. The herein disclosed method demonstrates a method in which ubiquitination can be carried out by a single enzyme. In addition, the present disclosure also provides compositions that may be used in ubiquitination assays and/or methods of screening active substance that may inhibit the ubiquitination process. 2. The composition of further comprising a substrate of the ubiquitin claim 1 , wherein the substrate is conjugated to the ubiquitin through a ribose-phosphate link on the ADP-ribosylated ubiquitin.3. The composition of claim 2 , wherein the substrate is selected from the group consisting of Rab1 claim 2 , Rab6A claim 2 , Rab30 claim 2 , Rab33b claim 2 , Rtn4 claim 2 , Atlastin claim 2 , and any combination thereof.4. A composition comprising an ADP-ribosylated ubiquitin claim 2 , wherein the ADP-ribosylated ubiquitin is generated by a protein selected from the group consisting of SEQ ID Nos: 1-4 or the combination thereof claim 2 , and β-nicotinamide adenine dinucleotide (β-NAD) claim 2 , wherein the protein adds an ADP to an ubiquitin from β-NAD.5. A method of identifying an antagonist of ATP independent ubiquitination claim 2 , comprising:{'claim-ref': {'@idref': 'CLM-00004', 'claim 4'}, 'Providing an ATP independent ubiquitination system, wherein the ATP independent ubiquitin system comprising an ADP-ribosylated ubiquitin according to , and a substrate selected from the group consisting of Rab1, Rab6A, Rab30, Rab33b, Rtn4, and Atlastin;'}Providing a series of substance to the ATP independent ubiquitin system to observe the substance's effect on the substrate ubiquitination by the ADP-ribosylated ubiquitin; andIdentifying at least one substance that prevents the substrate ubiquitination.6. The method of ...

IMMUNOGENIC COMPOSITIONS AND REAGENTS FOR PREPARING

The invention described herein pertains to compounds and conjugates, to compositions, complexes and formulations comprising the compounds and/or conjugates, and to methods of use of the compounds, conjugates and their compositions, complexes and formulations in vaccines and vaccinations and generating immune responses. 130-. (canceled)32. The compound of wherein X is N-hydroxysuccinimide.33. The compound of wherein m is 1 or 2.34. The compound of wherein n is 1 or 2.35. The compound of claim 31 , wherein Q is optionally substituted alkyleneamino(alkyl) claim 31 , where each alkyl is independently selected.36. The compound of claim 31 , wherein Q is optionally substituted poly(oxyalkylene).37. A method of using the compound of claim 31 , wherein the method comprising reacting the compound of with a compound comprising a nucleophilic functional group claim 31 , wherein the nucleophilic functional group replaces the leaving group X to form a conjugate. This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application Ser. No. 61/437,271 filed on Jan. 28, 2011, the entire disclosure of which is incorporated herein by reference.The invention described herein pertains to compounds and conjugates, to compositions, complexes and formulations comprising the compounds and/or conjugates, and to methods of use of the compounds, conjugates and their compositions, complexes and formulations in vaccines and vaccinations and/or for generating an immune response.Vaccination is a highly effective medical intervention aimed at reducing the morbidity and mortality caused by infectious diseases in animals, including humans. Vaccination induces an immune response against antigens present in the vaccine that protects against subsequent exposure to infectious agent(s). It has been reported that adsorption of an antigen to aluminum-containing adjuvants may in some cases enhance the immunogenicity of the antigen. It has also been reported that complexation of antigen ...

Peptides Useful For Treating Cancer

Provided is a class of peptides which are useful for modulating the activity of poly (ADP-ribose) polymerase (PARP) and in particular for the treatment of cancer. The peptides include an active group and a cassette for delivering the active group to a cell. Also provided are peptides having an anionic group which is believed to act as a competitive inhibitor of proteases which cleave PARP.

IL3Ralpha ANTIBODY CONJUGATES AND USES THEREOF

The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα. 183.-. (canceled)84. A nucleic acid that encodes a single chain fragment variable (scFv) region of an antibody that binds CD123 , wherein said nucleic acid comprises nucleotide sequences that encode the complementarity determining regions (CDRs) of the variable heavy (VH) domain and the variable light (VL) domain of said antibody , and wherein said CDRs comprise the VH domain CDR1 presented in SEQ ID NO: 23 , the VH domain CDR2 presented in SEQ ID NO: 24 , the VH domain CDR3 presented in SEQ ID NO: 25 , the VL domain CDR1 presented in SEQ ID NO: 28 , the VL domain CDR2 presented in SEQ ID NO: 29 , and the VL domain CDR3 presented in SEQ ID NO: 30.85. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 21.86. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VL domain of said antibody comprises SEQ ID NO: 26.87. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 21 and wherein said ...

IL3Ralpha Antibody Conjugates and Uses Thereof

The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα. 183.-. (canceled)84. A nucleic acid that encodes a single chain fragment variable (scFv) region of an antibody that binds CD123 , wherein said nucleic acid comprises nucleotide sequences that encode the complementarity determining regions (CDRs) of the variable heavy (VH) domain and the variable light (VL) domain of said antibody , and wherein said CDRs comprise the VH domain CDR1 presented in SEQ ID NO: 13 , the VH domain CDR2 presented in SEQ ID NO: 14 , the VH domain CDR3 presented in SEQ ID NO: 15 , the VL domain CDR1 presented in SEQ ID NO: 18 , the VL domain CDR2 presented in SEQ ID NO: 19 , and the VL domain CDR3 presented in SEQ ID NO: 20.85. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 11.86. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VL domain of said antibody comprises SEQ ID NO: 16.87. The nucleic acid of claim 84 , wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 11 and wherein said ...

DE-IMMUNIZED SHIGA TOXIN A SUBUNIT EFFECTOR POLYPEPTIDES FOR APPLICATIONS IN MAMMALS

The present invention relates to Shiga toxin effector polypeptides with reduced antigenic and/or immunogenic potential. Immunogenicity can be a limitation for the repeated administration to mammals of proteins and polypeptides derived from Shiga toxins. The Shiga toxin effector polypeptides of the present invention have uses as components of therapeutics, diagnostics, and immunization materials. The cytotoxic proteins of the present invention have uses for selective killing of specific cell types and as therapeutics for the treatment of a variety of diseases, including cancers, immune disorders, and microbial infections. The proteins of the present invention also have uses for detecting specific cell types, collecting diagnostic information, and monitoring the treatment of a variety of diseases, such as, e.g., cancers, immune disorders, and microbial infections. 145-. (canceled)53. The de-immunized polypeptide of any one of - , wherein the disruption comprises an amino acid residue substitution within the epitope region.54. The de-immunized polypeptide of any one of claim 53 , wherein the disruption consists only of a plurality of amino acid residue substitutions.58. The de-immunized polypeptide of any one of - claim 53 , wherein an amino acid residue substitution occurs at the natively positioned amino acid selected from the group consisting of amino acid:1 of SEQ ID NO:1 or SEQ ID NO:2; 4 of SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3; 8 of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3; 9 of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3; 11 of SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3; 33 of SEQ ID NO: 1 or SEQ ID NO:2; 43 of SEQ ID NO:1 or SEQ ID NO:2; 45 of SEQ ID NO:1 or SEQ ID NO:2; 47 of SEQ ID NO: 1 or SEQ ID NO:2; 48 of SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3; 49 of SEQ ID NO: 1 or SEQ ID NO:2; 53 of SEQ ID NO: 1 or SEQ ID NO:2; 55 of SEQ ID NO:1 or SEQ ID NO:2; 58 of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3; 59 of SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3; 60 of SEQ ...

EXPRESSION SYSTEM

Methods for the production of a bacterial toxin such as diphtheria toxin, and methods for producing conjugates of a bacterial toxins, are provided. 1. A process for producing a conjugate of a bacterial toxin , comprising: (a) a 3′ toxin sequence encoding a mature bacterial toxin polypeptide having an amino acid sequence at least 90% identical to SEQ ID NO:32, and', {'i': Corynebacterium diphtheriae', 'C. diphtheriae, '(b) a 5′ signal sequence encoding a signal peptide, wherein the signal peptide directs transport of said bacterial toxin polypeptide to the bacterial periplasm when expressed in said host cell, and wherein the 5′ signal sequence is not derived from (); and'}], '(1) growing in a fermentor a culture of gram negative host cells containing a polynucleotide comprisinginducing expression of said polynucleotide such that said bacterial toxin polypeptide is expressed periplasmically; and(2) purifying said bacterial toxin polypeptide; and(3) conjugating said purified bacterial toxin to an antigen.2. The process of wherein the 3′ toxin sequence encodes a polypeptide selected from the group consisting of:(a) a polypeptide having the amino acid sequence of SEQ ID NO: 32,(b) a polypeptide having at least 95% sequence identity to SEQ ID NO: 32;(c) a polypeptide comprising SEQ ID NO:31; and(d) CRM197.3. The process of wherein the polynucleotide encodes a polypeptide comprising any one of SEQ ID NOs: 33-45.4. The process of wherein the 5′ signal sequence is directly 5′ of the 3′ toxin sequence of the polynucleotide.5. The process of wherein the 5′ signal sequence encodes a signal peptide having an amino acid sequence selected from:(a) SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26;(b) variants of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 containing 1, 2 or 3 point mutations, insertions or deletions, which variants direct transport of said bacterial toxin polypeptide to the periplasm of said bacterial host cell; and(c) fragments of at ...

MHC CLASS I EPITOPE DELIVERING POLYPEPTIDES AND CELL-TARGETED MOLECULES FOR DIRECT CELL KILLING AND IMMUNE STIMULATION VIA MHC CLASS I PRESENTATION AND METHODS REGARDING THE SAME

The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions. 171-. (canceled)106. A polypeptide comprising an embedded , heterologous , CD8+ T-cell epitope , wherein the polypeptide is capable of intracellular delivery of the T-cell epitope from an early endosomal compartment to a MHC class I molecule of a cell in which the polypeptide is present; andwherein the embedded, heterologous CD8+ T-cell epitope replaces an equivalent number of amino acid residues in a parental polypeptide such that the polypeptide comprising the epitope has the same total number of amino acids as the parental polypeptide.107. The polypeptide of claim 106 , comprising a proteasome delivering effector polypeptide.108. The polypeptide of claim 106 , comprising a toxin effector polypeptide capable of exhibiting one or more toxin effector functions.109. The polypeptide of claim 108 , wherein the toxin effector polypeptide comprises a proteasome delivering effector polypeptide.110. The polypeptide of or claim 108 , wherein the heterologous claim 108 , CD8+ T-cell epitope is ...

PARP9 AND PARP14 AS KEY REGULATORS OF MACROPHAGE ACTIVATION

The invention relates to compositions and methods for inhibiting macrophage activation via modulating PARP9 and/or PARP14 expression or activity, such as small molecules, RNAi and antibodies. 1. A method of inhibiting macrophage M1 activation comprising contacting a population of monocytes or macrophages with an effective amount of a small molecule that inhibits the expression or activity of poly (ADP-ribose) polymerase family , member 9 (PARP9).2. The method of claim 1 , wherein the small molecule is selected from the group consisting of: DR 2313 claim 1 , 3-aminobenzamide claim 1 , 4-HQN claim 1 , NU 1025 claim 1 , PJ 34 hydrochloride claim 1 , 3-Carbamoyl-1-D-ribofuranosylpyridinium hydroxide 5′-ester with adenosine 5′-pyrophosphate and derivatives thereof.3. The method of claim 1 , wherein the small molecule inhibits the expression of PARP9.4. The method of claim 1 , wherein the small molecule inhibits PARP9 protein's activity.5. The method of claim 1 , wherein small molecule increases the expression of PARP14 and/or PARP14 protein's activity.6. The method of claim 1 , wherein the small molecule suppresses pro-inflammatory M1 polarization.7. The method of claim 1 , wherein the small molecule increases the expression of an anti-inflammatory M2 marker.8. The method of claim 7 , wherein the anti-inflammatory M2 marker is arginase 1 (Arg1) or mannose receptor claim 7 , C type 1 (MRC1).9. The method of claim 1 , wherein the population of monocytes or macrophages are contacted ex vivo claim 1 , in vitro claim 1 , or in vivo.10. A method of inhibiting excessive or sustained inflammation in a subject in need thereof claim 1 , the method comprising: contacting a population of monocytes and/or macrophages from the subject with an effective amount of a small molecule that inhibits poly (ADP-ribose) polymerase family claim 1 , member 9 (PARP9).11. The method of claim 10 , wherein the small molecule is selected from the group consisting of: DR 2313 claim 10 , 3- ...

Functionalized DNA Dendrimers For Gene Delivery To Cells

Compositions are disclosed which comprise a DNA dendrimer having one or more DNA sequences linked thereto, the DNA sequences comprising DNA sequences encoding a polypeptide or regulatory RNA linked to DNA sequences that regulate expression of the DNA sequences encoding a polypeptide or regulatory RNA to produce an RNA coding for the polypeptide or to produce the regulatory RNA. Also disclosed are methods for treating diseases and conditions of cells by delivering the dendrimers to the cells, with subsequent expression of the encoded polypeptide or regulatory RNA. 1. A composition comprising a DNA Dendrimer , wherein one or more DNA sequences encoding a polypeptide or regulatory RNA operably linked to DNA sequences regulating gene transcription are linked to the DNA dendrimer.2. (canceled)3. The composition of claim 1 , wherein the DNA sequences linked to the DNA dendrimer comprise a promoter having specific transcriptional activity in virally infected cells claim 1 , cervical squamocolumnar junction cells claim 1 , diseased or damaged cells claim 1 , or tumor cells.4. The composition of claim 3 , wherein the promoter has specific transcriptional activity in HPV-infected cells claim 3 , pancreatic cancer cells or prostate cancer cells.5. The composition of claim 1 , wherein the DNA sequences linked to the DNA dendrimer encode a cytotoxin claim 1 , an immunomodulatory protein or a fluorescent protein.6. The composition of claim 5 , wherein the cytotoxin is Diphtheria toxin A chain.78.-. (canceled)9. The composition of claim 5 , wherein the fluorescent protein is GFP or CFP.10. The composition of claim 1 , further comprising a DNA sequence that encodes a regulatory RNA sequence.11. The composition of claim 1 , comprising a plurality of linked DNA sequences claim 1 , wherein the plurality of linked DNA sequences encode a plurality of polypeptides or regulatory RNAs claim 1 , or a combination thereof.12. The composition of claim 1 , further comprising a cellular ...

HIGH LEVEL EXPRESSION OF RECOMBINANT TOXIN PROTEINS

The present invention relates to the field of recombinant toxin protein production in bacterial hosts. In particular, the present invention relates to production processes for obtaining high levels of a recombinant CRM197, Diphtheria Toxin, Pertussis Toxin, Tetanus Toxoid Fragment C, Cholera Toxin B, Cholera holotoxin, and Exotoxin A, from a bacterial host. 1. A method for producing a recombinant toxin protein in a Pseudomonad host cell , said method comprising:ligating into an expression vector a nucleotide sequence encoding the toxin protein;transforming the Pseudomonad host cell with the expression vector; andculturing the transformed Pseudomonad host cell in a culture media suitable for the expression of the recombinant toxin protein;{'i': C. difficile', 'P. aeruginosa, 'wherein the recombinant toxin protein is CRM197, Diphtheria Toxin, Cholera holotoxin, Cholera Toxin B, Pertussis Toxin, Tetanus Toxin Fragment C, Toxin B, or Exotoxin A.'}2. The method of claim 1 , wherein the recombinant protein is produced at a yield of soluble and/or active toxin protein of 0.2 grams per liter to about 12 grams per liter.3. The method of claim 1 , wherein the nucleotide sequence encoding the toxin protein is fused to a secretion signal coding sequence that when expressed directs transfer of the toxin protein to the periplasm.4. The method of claim 1 , wherein the host cell is defective in the expression of at least one protease or wherein the host cell overexpresses at least one folding modulator claim 1 , or a combination thereof.5. The method of claim 1 , wherein the recombinant toxin protein is CRM197 and the host cell is defective in the expression of Hs1U claim 1 , Hs1V claim 1 , Prc1 claim 1 , DegP1 claim 1 , DegP2 claim 1 , and AprA.6. The method of claim 5 , wherein the recombinant toxin protein is fused to a secretion leader that is Azu claim 5 , IbpS31A claim 5 , CupA2 claim 5 , PbpA20V claim 5 , or Pbp.7. The method of claim 1 , wherein the recombinant toxin ...

Vault Immunotherapy

The invention relates to compositions of vault complexes for use as adjuvants for stimulating a cellular immune response to an antigen, for example a tumor antigen, and methods of using the vault complexes in the treatment of diseases, such as cancer. 1. A method for stimulating a cellular immune response in a subject , comprising administering to the subject an effective amount of an antigenic peptide or an antigenic fragment or variant thereof incorporated within a vault complex.2. The method of claim 1 , wherein the antigenic peptide is a tumor antigen.3. The method of claim 1 , wherein the vault complex comprises two or more vault complexes claim 1 , wherein each vault complex comprises two or more different antigenic peptides or antigenic fragments or variants.4. The method of claim 1 , wherein the antigenic peptide is fused to INT.5. The method of claim 4 , wherein the INT comprises the amino acid sequence of SEQ ID NO: 2.6. The method of claim 1 , wherein the antigenic peptide is fused to MVP.7. The method of claim 6 , wherein the antigenic peptide is fused to the N-terminus of MVP.8. The method of claim 1 , wherein the vault complex comprises MVP.9. The method of claim 8 , wherein the number of MVP is 1-78.10. The method of claim 8 , wherein the number of MVP is 78.11. The method of claim 8 , wherein the vault complex further comprises VPARP or modified VPARP claim 8 , or a portion of VPARP claim 8 , or a modified portion of VPARP.12. The method of claim 1 , wherein the cellular immune response is induction of CD8 and CD4 memory T-cells.13. The method of claim 1 , wherein the cellular immune response is production of INFγ.14. The method of claim 1 , further comprising administering to the subject a vault complex containing a chemokine.15. The method of claim 14 , wherein the chemokine is CCL21.16. A pharmaceutical composition for preventing or treating a subject for cancer claim 14 , comprising a tumor antigen or an antigenic fragment or variant thereof ...

UNDIFFERENTIATED CELL ELIMINATION METHOD

An object of the present invention is to provide a method for introducing a target substance into undifferentiated cells, and a carrier therefor, whereby the target substance can be specifically introduced into the undifferentiated cells by contacting the undifferentiated cells with an rBC2LCN-target substance fusion product in which rBC2LCN lectin is fused to the target substance. Particularly, an rBC2LCN-toxin fusion product in which rBC2LCN lectin is fused to a toxin functioning in cells or its domain having the ability to kill cells functions as an agent for eliminating undifferentiated stem cells and can be administered into a medium after inducing the differentiation of the stem cells to reliably kill only the stem cells in an undifferentiated state. 1. A method for introducing a target substance into undifferentiated cells , comprising chemically or electrically fusing the target substance to rBC2LCN , and contacting the resultant rBC2LCN-target substance fusion product with the undifferentiated cells.2. A carrier for introducing a target substance into undifferentiated cells , comprising rBC2LCN as an active ingredient.3. A composition for introducing a target substance into undifferentiated cells , comprising an rBC2LCN-target substance fusion product in which the target substance and rBC2LCN are chemically or electrically fused to each other , as an active ingredient.4. The composition for introduction into undifferentiated cells according to claim 3 , wherein the target substance is a toxic compound capable of exerting cytotoxicity in cells.5. The composition for introduction into undifferentiated cells according to claim 4 , wherein the toxic compound is a protein toxin or a domain thereof having the ability to kill cells claim 4 , a low molecular weight compound having cytotoxicity claim 4 , or a nucleic acid.6. An agent for eliminating undifferentiated stem cells claim 4 , comprising an rBC2LCN-toxic compound fusion product in which a toxic compound ...

AN IMMUNOTOXIN FOR USE IN THE TREATMENT OF LEISHMANIASIS

An immunotoxin for use in the treatment of leishmaniasis A wherein the immunotoxin comprises a portion which is specifically binding to the cellular surface receptor CD64 as a component A and a cell killing portion as a component B, wherein the cell killing portion alters the function, gene expression, or viability of a cell thereby killing -infected macrophages and by this eliminates 1LeishmaniaLeishmania.. An immunotoxin for use in the treatment of leishmaniasis wherein the immunotoxin comprises a portion which is specifically binding to the cellular surface receptor CD64 as a component A and a cell killing portion as a component B , wherein the cell killing portion alters the function , gene expression , or viability of a cell thereby killing -infected macrophages and by this eliminates2. The immunotoxin of wherein the cell killing portion is covalently bonded to the portion specifically binding to the cellular surface receptor CD64.3. The immunotoxin of wherein the immunotoxin is a recombinant protein or the portion specifically binding to the cellular surface receptor CD64 is linked directly to the cell killing portion or linked via a linking group.4. The immunotoxin of wherein the portion which is specifically binding to the cellular surface receptor CD64 is selected from the group consisting of antibodies or their derivatives or fragments claim 1 , such as scFv fragments; synthetic peptides or molecules; ligands; receptor binding molecules claim 1 , and their structural analogs; mutants and combinations thereof.5. The immunotoxin of wherein the portion which is specifically binding to the cellular surface receptor CD64 is a recombinant molecule.6. The immunotoxin of wherein the cell killing portion alters the function claim 1 , gene expression claim 1 , or viability of a cell by inactivating molecules responsible for protein biosynthesis or activating components of cell-inherent apoptosis pathways.7Pseudomonas. The immunotoxin of wherein the cell killing ...

MOLECULAR SENSORS

The invention relates to a sensor molecule for detecting a target molecule comprising: (a) a rod-like molecule L and a rod-like molecule R connected to each other by a joint molecule C to form a hinge; (b) a target binding molecule A bonded to the end of rod-like molecule L opposite to the joint molecule C; (c) a binding molecule A′ bonded to the end of rod-like molecule R opposite the joint molecule C; wherein the target binding molecule A is arranged to bind to the target molecule to be detected, and binding molecule A′ is arranged to bind to: i) the same target molecule as target binding molecule A; or ii) a complex of the target binding molecule A and the target; and wherein the hinge is biased into an open position, such that target binding molecule A and binding molecule A′ are biased apart by the hinge. 1. A sensor molecule for detecting a target molecule comprising:(a) a rod-like molecule L and a rod-like molecule R connected to each other by a joint molecule C to form a hinge;(b) a target binding molecule A bonded to the end of rod-like molecule L opposite to the joint molecule C;(c) a binding molecule A′ bonded to the end of rod-like molecule R opposite the joint molecule C;wherein the target binding molecule A is arranged to bind to the target molecule to be detected, and binding molecule A′ is arranged to bind to:i) the same target molecule as target binding molecule A; orii) a complex of the target binding molecule A and the target; andwherein the hinge is biased into an open position, such that target binding molecule A and binding molecule A′ are biased apart by the hinge.2. The sensor molecule according to claim 1 , wherein the presence and binding of a target molecule by target binding molecule A claim 1 , and the binding of binding molecule A′ to either i) the target molecule or ii) the complex of the target binding molecule and target molecule claim 1 , is arranged to bias the hinge into a closed position in opposition to the force of the hinge ...

NOVEL ANTIBODY-DRUG CONJUGATES AND THE USE OF SAME IN THERAPY

Disclosed are novel antibody-drug conjugates and use thereof in therapy, in particular in anticancer or anti-inflammatory therapy, as well as synthetic products useful as linkers, composed of a linker head and a linker body, and also a method for preparing the linkers and the antibody-drug conjugates. 6. The product according to in which K represents a site of cleavage by an enzyme selected from the enzymes of the cathepsin B claim 4 , cathepsin C claim 4 , cathepsin D type claim 4 , the enzymes selected from plasmin claim 4 , lysosomal protease claim 4 , lysosomal enzyme claim 4 , or urokinase plasminogen activator (uPA) claim 4 , elastase claim 4 , proteinase 3 claim 4 , cathepsin G;or K represents a recognition site of cleavage by an enzyme of the matrix metalloproteinase (MMP) type preferably selected from collagenase 1, 2 and 3, gelatinase a and b, stromelysin 1 and 2, matrilysin 1, 2 and 3, macrophage metalloelastase, membrane MMP, enamelysin, CA-MMP, epilysin and PSMA;or K represents a recognition site of cleavage by an esterase, a carboxylesterase, alkaline phosphatases, proteases, peptidases, cathepsins, glucosidase, galactosidase, beta-D-galactosidase, induronidase, beta-glucuronidase, mannosidase, N-acetyl-D-glucosaminidase or N-acetyl-D-galactosaminidase.8. The product according to claim 1 , in which the drug M is selected from the group constituted by duocarmycin and its analogues claim 1 , dolastatins claim 1 , combretastatin claim 1 , calicheamicin claim 1 , N-acetyl-γ-calicheamycin (CMC) claim 1 , a calicheamycin derivative claim 1 , maytansine and analogues thereof claim 1 , DM-I claim 1 , auristatin E claim 1 , auristatin EB (AEB) claim 1 , auristatin EFP (AEFP) claim 1 , monomethyl auristatin E (MMAE) claim 1 , monomethyl auristatin F (MMAF) claim 1 , tubulysin claim 1 , disorazole claim 1 , the epothilones claim 1 , Paclitaxel claim 1 , docetaxel claim 1 , Topotecan claim 1 , echinomycin claim 1 , estramustine claim 1 , cemadotine claim 1 , ...

Compositions and Methods for Oral Delivery of Therapeutic Cargo

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders. The present disclosure relates to a non-toxic mutant form of the Cholix gene (ntCholix), a variant of Cholix truncated at amino acid A(Cholix) and the use of other various Cholix-derived polypeptide sequences to enhance intestinal delivery of biologically-active therapeutics. The systems and methods described herein provide for: the ability to deliver macromolecule doses without injections; the ability to deliver cargo such as siRNA or antisense molecules into intracellular compartments where their activity is required; and the delivery of nanoparticles and dendrimer-based carriers across biological membranes. 1. A method for delivering a therapeutic cargo to a subject , the method comprising orally administering to the subject a pharmaceutical composition comprising a delivery construct comprising the therapeutic cargo coupled to a non-toxic carrier that utilizes a Cholix pathway , thereby transporting the therapeutic cargo across a polarized epithelial cell of the subject.2. The method of claim 1 , wherein the delivery construct is not directed to a destructive lysosomal pathway.3. The method of claim 1 , wherein the delivery construct is directed to a non-destructive trafficking pathway through the polarized epithelial cell.4. The method of claim 1 , wherein the non-toxic carrier interacts with a receptor present on the apical membrane of the epithelial cell that is part of the Cholix pathway.5. The method of claim 1 , wherein the transporting across the polarized epithelial cell comprises transporting via transcytosis.6. The method of claim 5 , wherein the transcytosis ...

COMPOSITIONS OF PARP14 MODULATORS AND/OR MUTANTS AND THERAPEUTIC USE THEREOF

The invention provides compositions comprising agents which modulate poly(ADP-ribose)polymerase 14 (PARP14), or compositions comprising PARP14 mutants. Such compositions can modulate the levels of nicotinamide adenine dinucleotide (NAD+) and are useful in methods for treating or preventing cancer, aging, aging-related disorders, cell death, radiation damage, radiation exposure, disorders associated with inflammation, among others. Such compositions and methods may also improve DNA repair, cell proliferation, cell survival, modulate inflammatory response, among others, and may increase the life span of a cell or protect it against certain stresses, apoptosis, among others. 5. The method of claim 4 , wherein the cell is a mammalian cell claim 4 , yeast cell claim 4 , fungal cell claim 4 , plant cell claim 4 , or microbial cell.6. The method of any one of - claim 4 , wherein the agent inhibits the level of claim 4 , activity of claim 4 , or expression of the PARP14 claim 4 , or a fragment thereof claim 4 , or a nucleic acid encoding same.7. The method of claim 6 , wherein the agent inhibits the level of claim 6 , activity of claim 6 , or expression of the PARP14 claim 6 , or homologs thereof claim 6 , as set forth in Table 1.8. The method of any one of - claim 6 , wherein the PARP14 mutant comprises at least one substitution claim 6 , mutations claim 6 , insertion claim 6 , deletion claim 6 , or combination thereof claim 6 , in Macro Domain 1 as set forth in Table 1 or 2.9. The method of claim 8 , wherein the PARP14 mutant comprises at least two claim 8 , three claim 8 , four claim 8 , five claim 8 , six claim 8 , seven claim 8 , eight claim 8 , nine claim 8 , ten claim 8 , or more substitution claim 8 , mutations claim 8 , insertion claim 8 , deletion claim 8 , or combinations thereof claim 8 , in Macro Domain 1 as set forth in Table 1 or 2.10. The method of any one of - claim 8 , wherein the PARP14 mutant comprises at least one substitution claim 8 , mutations claim ...

Protease-cleavage resistant, shiga toxin a subunit effector polypeptides and cell-targeted molecules comprising the same

The present invention provides protease-cleavage resistant molecules comprising Shiga toxin effector polypeptides capable of exhibiting potent, Shiga toxin functions ( e.g . subcellular routing and cytotoxicity). The present invention also provides protease-cleavage resistant, cell-targeted molecules for targeting specific cell types, e.g ., infected or malignant cells. Certain molecules of present invention are cytotoxic, and certain cell-targeted molecules of present invention may be used for the targeted killing of specific cell types and treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections. Certain cell-targeted molecules of the invention exhibit improved, in vivo tolerability as compared to related cell-targeted molecules comprising protease-cleavage sensitive, wild-type, Shiga toxin effector polypeptides. The cell-targeted molecules of the invention can deliver additional materials, such as, e.g ., antigens, cytotoxic agents, and detection-promoting agents, into interiors of target cells.

Compositions and methods for treating cancer

The invention generally relates to compositions and methods for treating cancer. In certain embodiments, the invention provides methods that involve treating a cancer in a patient in which cancerous cells overexpress epidermal growth factor receptor as compared to non-cancerous cells. The methods involve administering a first composition including anthrax protective antigen modified to bind an epidermal growth factor receptor of a cell, and administering a second composition including anthrax lethal factor N-terminus fused to a catalytic domain of Diphtheria Toxin A. Binding of anthrax lethal factor N-terminus to anthrax protective antigen results in internalization of Diphtheria Toxin A into the cancerous cell, which triggers apoptosis by inactivation of critical elongation factors.

Human monoclonal antibodies specific for cd22

Disclosed herein are isolated human monoclonal antibodies that specifically bind human CD22 with a dissociation constant (K d ) of 25 nM or less. Nucleic acids encoding these antibodies, expression vectors including these nucleic acid molecules, and isolated host cells that express the nucleic acid molecules are also disclosed. The antibodies can be used to detect human CD22 in a sample. In some cases, CD22 is soluble CD22. Methods of diagnosing a B-cell malignancy, or confirming a B-cell malignancy diagnosis, are disclosed herein that utilize these antibodies. Methods of treating a subject with a B-cell malignancy are also disclosed.

A new fusion protein to target and treat acute myloid leukemia cells

A polypeptide which binds to the surface of AML blast cells and is internal- ised upon binding to the AML blast cells.