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Небесная энциклопедия

Космические корабли и станции, автоматические КА и методы их проектирования, бортовые комплексы управления, системы и средства жизнеобеспечения, особенности технологии производства ракетно-космических систем

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Мониторинг СМИ

Мониторинг СМИ и социальных сетей. Сканирование интернета, новостных сайтов, специализированных контентных площадок на базе мессенджеров. Гибкие настройки фильтров и первоначальных источников.

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Форма поиска

Поддерживает ввод нескольких поисковых фраз (по одной на строку). При поиске обеспечивает поддержку морфологии русского и английского языка
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Применить Всего найдено 6454. Отображено 100.
15-03-2012 дата публикации

Therapeutic use of anti-cs1 antibodies

Номер: US20120064083A1
Автор: Gao Liu, J. Yun Tso, Marna Williams, Nicholas F. Landolfi
Принадлежит: Abbott Biotherapeutics Corp

The present invention is directed to antagonists of CS1 that bind to and neutralize at least one biological activity of CS1. The invention also includes a pharmaceutical composition comprising such antibodies or antigen-binding fragments thereof. The present invention also provides for a method of preventing or treating disease states, including autoimmune disorders and cancer, in a subject in need thereof, comprising administering into said subject an effective amount of such antagonists.

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Номер записи: 1
31-05-2012 дата публикации

Crystal of Human Glycoprotein VI Collagen Binding Domain

Номер: US20120135880A1
Автор: Andrew B. Herr, Katsunori Horii
Принадлежит: Individual

A crystal comprising the collagen binding domain of human GPVI is provided and defined by structural atomic coordinates. Employing computer modeling based on the crystal structure, including methods for identifying inhibitors of GPVI collagen binding activity, methods for screening libraries of compounds for potential to bind to the GPVI collagen binding domain, and methods of identifying a compound useful for the treatment of a GPVI-mediated disorder, are also provided.

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Номер записи: 2
12-07-2012 дата публикации

Compositions and methods for treatment of cervical dysplasia

Номер: US20120177678A1
Автор: John Rothman, Yvonne Paterson
Принадлежит: Individual

The present invention provides methods of treating, protecting against, and inducing an immune response against cervical dysplasia and cancer, comprising the step of administering to a subject a recombinant Listeria strain, comprising a fusion peptide that comprises an LLO fragment and an E7 and/or E6 antigen. The present invention also provides methods for inducing an anti-E7 CTL response in a human subject and treating HPV-mediated diseases, disorders, and symptoms, comprising administration of the recombinant Listeria strain.

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Номер записи: 3
11-10-2012 дата публикации

Methods of using btl-ii proteins

Номер: US20120258097A1
Автор: Joanne L. Viney, Peter R. Baum, Sabine S. Escobar
Принадлежит: Immunex Corp

The invention provides isolated BTL-II proteins, nucleic acids, antibodies, antagonists, and agonists and methods of making and using the same. Diagnostic, screening, and therapeutic methods using the compositions of the invention are provided. For example, the compositions of the invention can be used for diagnosis and treatment of inflammatory bowel diseases and for enhancing a mucosal immune response to an antigen.

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Номер записи: 4
25-04-2013 дата публикации

NOVEL GLYCOSYLATED PEPTIDE TARGET IN NEOPLASTIC CELLS

Номер: US20130101588A1
Автор: Vollmers Heinz Peter
Принадлежит: PATRYS LIMITED

The invention provides polypeptide, nucleic acid and other compositions. Polypeptide, nucleic acid and other compositions are useful in treatment and diagnostic methods. One treatment method includes inhibiting growth or proliferation of hyperproliferative cells or inducing regression of hyperproliferative cells, such as cells of a cellular hyperproliferative disorder, or reducing levels of LDL or oxLDL. 1117-. (canceled)118. An isolated or purified glycoprotein denoted as SAM-6 Receptor (SAM-6/R) , wherein said SAM-6/R glycoprotein is free of other proteins and has an apparent molecular weight in a range of about 80-82 kilodaltons (kDa) as determined by denaturing gel electrophoresis , has at least one oxygen (O)-linked carbohydrate moiety distinct from a carbohydrate moiety of Grp78 , and wherein an antibody comprising SEQ ID NOs:13 and 15 specifically binds to the glycoprotein , and wherein treatment of the glycoprotein with an O-glycosidase enzyme reduces binding of the antibody to the glycoprotein.119. An isolated or purified glycoprotein denoted as SAM-6 Receptor (SAM-6/R) , wherein said SAM-6/R glycoprotein is free of other proteins and has an apparent molecular weight in a range of about 80-82 kilodaltons (kDa) as determined by denaturing gel electrophoresis , has at least one oxygen (O)-linked carbohydrate moiety distinct from a carbohydrate moiety of Grp78 , and has at least 60% sequence homology to SEQ ID NO:1.120. The glycoprotein of claim 119 , wherein the glycoprotein comprises a sequence of about 655 amino acids.121. The glycoprotein of claim 119 , wherein the glycoprotein has a transmembrane domain of about 17 amino acids.122. The glycoprotein of claim 119 , wherein the glycoprotein has an extracellular domain of about 220 amino acids.123. The glycoprotein of claim 119 , wherein the glycoprotein has an intracellular domain of about 411 amino acids.124. The glycoprotein of claim 119 , wherein the carbohydrate moiety is linked to an asparagine claim ...

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Номер записи: 5
06-06-2013 дата публикации

RAGE Fusion Protein Compositions And Methods Of Use

Номер: US20130142792A1
Автор: Bleck Gregory T., Katragadda Madan, RAJADHYAKSHA Manoj, Rothlein Robert, Violand Bernard N., Webster Jeffrey C., Wentland Jo-Ann
Принадлежит:

Disclosed are fusion proteins comprising a RAGE polypeptide, wherein the RAGE polypeptide comprises a fragment of a mammalian wild type RAGE peptide and at least one point mutation in the RAGE polypeptide portion of the fusion protein relative to the wild type RAGE peptide. The point mutation may remove and/or alter a glycosylation site or an enzyme cleavage site. Also disclosed are nucleic acids encoding such proteins as well as methods of using such proteins for treating RAGE-mediated pathologies. 129-. (canceled)30. A fusion protein comprising a Receptor for Advanced Glycation Endproducts (RAGE) polypeptide linked to an immunoglobulin polypeptide , wherein the RAGE polypeptide comprises a fragment of a mammalian RAGE having a ligand binding domain , and wherein the RAGE fusion protein comprises at least one mutation relative to the wild-type sequence in at least one of the RAGE polypeptide or the immunoglobulin polypeptide , wherein the mutation removes and/or alters at least one of a glycosylation site or an enzyme cleavage site.31. The fusion protein of claim 30 , wherein the RAGE polypeptide is a human RAGE polypeptide.32. The fusion protein of claim 30 , wherein the mutation changes the sequence in the wild-type RAGE polypeptide present at a glycosylation site.33. The fusion protein of claim 30 , wherein the glycosylation site has the amino acid sequence NXS or NXT claim 30 , where X is any amino acid.34. The fusion protein of claim 30 , wherein the mutation changes the sequence in the wild-type RAGE polypeptide from at least one of NIT to QIT claim 30 , or NGS to QGS claim 30 , or NGS to NSS claim 30 , or NST to QST to remove at least one glycosylation site.35. The fusion protein of claim 30 , wherein the glycosylation site is within the ligand binding site or the ligand binding domain of the RAGE polypeptide.36. The fusion protein of claim 30 , wherein the enzyme cleavage site is a furin cleavage site claim 30 , such that the mutation changes the sequence ...

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Номер записи: 6
13-06-2013 дата публикации

T CELL RECEPTOR MUTANTS

Номер: US20130149289A1
Автор: Jakobsen Bent Karsten, Liddy Nathaniel Ross
Принадлежит: Immunocore Limited

A T cell receptor (TCR) having the property of binding to EVDPIGHLY HLA-A1 complex and comprising a specified wild type TCR which has specific mutations in the TCR alpha variable domain and/or the TCR beta variable domain to increase affinity. Such TCRs are useful for adoptive therapy. 1. (canceled)2. (canceled)3. (canceled)4. (canceled)5. (canceled)6. A nucleic acid encoding a TCR having the property of binding to SEQ ID NO: 1-Human Leukocyte Antigen (HLA)-A1 complex and comprising a TCR α variable domain and a TCR β variable domain , wherein:the TCR α variable domain has the amino acid sequence from K1 to P114 of SEQ ID NO: 2 and the TCR β variable domain has the amino acid sequence from K1 to T112 of SEQ ID NO: 3except that, in the TCR α variable domain, at least one of the following mutations is present, namely50I is mutated to 50V;51Q is mutated to 51R;52S is mutated to 52P;53S is mutated to 53Y; and/orin the TCR β variable domain, at least one of the following mutations is present, namely50F is mutated to 50T;51S is mutated to 51D;52E is mutated to 52M;53T is mutated to 53L;54Q is mutated to 54L.7. A cell comprising a TCR expression vector comprising the nucleic acid as claimed in in a single open reading frame or two distinct open reading frames.8. A cell comprising a first expression vector comprising a nucleic acid encoding the alpha chain of the TCR of and a second expression vector comprising a nucleic acid encoding the beta chain of the TCR of .9. A cell displaying on its surface a TCR encoded by the nucleic acid of .10. A cell as claimed in presenting a TCR having an α chain variable domain of SEQ ID NO: 8 and a β chain variable domain of SEQ ID NO: 3.11. A cell as claimed in presenting a TCR having an α chain variable domain of SEQ ID NO: 9 and a β chain variable domain of SEQ ID NO: 3.12. A cell as claimed in presenting a TCR having an α chain of SEQ ID NO: 2 and a β chain variable domain of SEQ ID No: 10.13. A cell as claimed in presenting a TCR ...

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Номер записи: 7
04-07-2013 дата публикации

NCAM-VASE AND NEURODEGENERATION

Номер: US20130171139A1
Автор: Anderson Alexandra Antoinette, Delves Michael Jonathan, Saffell Jane Louise
Принадлежит:

Inhibitors of NCAM-VASE, compositions comprising said inhibitors, and methods of using said inhibitors for stimulation of neuroplasticity and/or neuroregeneration in the central nervous system, and for increasing neuronal cell response to agents that stimulate neuroplasticity and/or neuroregeneration in the central nervous system, are provided. The inhibitor or composition may be used, for example, for treating brain or spinal cord injury; schizophrenia, motor neurone disease; a neurodegenerative disorder such as Alzheimer's disease, multiple sclerosis or Parkinson's disease; ischaemia caused by stroke; or for improving learning and/or memory. 1. (canceled)2. (canceled)3. The method of wherein the inhibitor is an antisense RNA molecule or an interfering RNA that is capable of causing a reduction of NCAM-VASE mRNA transcription.4. The method of wherein the inhibitor is a soluble polypeptide comprising the Ig4 domain of NCAM-VASE.5. The method of wherein the inhibitor is a soluble polypeptide comprising a further sequence from NCAM-VASE in addition to the Ig4 domain.6. The method of wherein the inhibitor is an antibody or antibody fragment or derivative able to bind selectively to NCAM-VASE.7. The method of claim 12 , wherein the inhibitor is administered in combination with a second agent which promotes neuroplasticity and/or neuroregeneration.8. The method of claim 7 , wherein the second agent is selected from the list consisting of NGF claim 7 , BDNF claim 7 , FGF claim 7 , CNTF claim 7 , GDNF claim 7 , NT3 claim 7 , NT4/5 dbcAMP and forskolin.9. The method of claim 12 , wherein the method is for treating brain or spinal cord injury.10. The method of claim 12 , wherein the method is for treating schizophrenia claim 12 , motor neurone disease claim 12 , for treating a neurodegenerative disorder including Alzheimer's disease claim 12 , multiple sclerosis or Parkinson's disease; for treating ischaemia caused by stroke; or for improving learning and/or memory.11. ( ...

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Номер записи: 8
01-08-2013 дата публикации

T cell receptors and related materials and methods of use

Номер: US20130195819A1
Автор: James C. Yang, Kenichi Hanada, Qiong J. Wang
Принадлежит: US Department of Health and Human Services

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a cancer antigen, e.g., a renal cell carcinoma antigen, wherein the TCR recognizes the cancer antigen in a major histocompatibility complex (MHC)-independent manner. Also provided are related polypeptides, proteins, nucleic acids, recombinant expression vectors, isolated host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions. The invention further provides a method of detecting the presence of cancer in a host and a method of treating or preventing cancer in a host using the inventive TCRs or related materials.

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Номер записи: 9
29-08-2013 дата публикации

CD47 Antibodies and Methods of Use Thereof

Номер: US20130224188A1
Автор: Deveraux Quinn, Eckelman Brendan, JONES Kyle, NGUY Peter L., RAZAI Amir, Timmer John
Принадлежит: INHIBRX LLC

This invention relates generally to monoclonal antibodies that recognize CD47, more specifically to CD47 antibodies that do not cause a significant level of agglutination of cells, to methods of generating these antibodies, and to methods of using these monoclonal antibodies as therapeutics. 1. An isolated monoclonal antibody that binds to CD47 or an immunologically active fragment thereof , wherein the antibody does not cause a significant level of agglutination of cells after administration.2. The antibody of claim 1 , wherein the antibody is chimeric claim 1 , humanized claim 1 , or fully human.3. The antibody of claim 1 , wherein the CD47 is human CD47.4. The antibody of claim 1 , wherein the antibody or immunologically active fragment thereof prevents CD47 from interacting with signal-regulatory-protein a (SIRPα).5. The antibody of claim 4 , wherein the antibody or immunologically active fragment thereof promotes macrophage-mediated phagocytosis of a CD47-expressing cell.6. The antibody of claim 1 , wherein the antibody or immunologically active fragment thereof is an IgG isotype selected from the group consisting of IgG1 isotype claim 1 , IgG2 isotype claim 1 , IgG3 isotype claim 1 , and IgG4 isotype.7. The antibody of claim 1 , wherein the antibody or immunologically active fragment thereof comprises a variable heavy (VH) chain region selected from the group consisting of SEQ ID NOs: 5-30.8. The antibody of claim 1 , wherein the antibody or immunologically active fragment thereof comprises a variable light (VL) chain region selected from the group consisting of SEQ ID NOs: 31-47.9. The antibody of claim 1 , wherein the antibody or immunologically active fragment thereof comprises a VH region provided in any one of SEQ ID NOs: 5-30 and a VL region provided in any one of SEQ ID NOs: 31-47.10. The antibody of claim 9 , wherein the antibody or immunologically active fragment thereof comprises a VH region provided in any one of SEQ ID NOs: 5 claim 9 , 7 claim 9 , ...

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Номер записи: 10
19-09-2013 дата публикации

Chimeric protein

Номер: US20130243765A1
Автор: Elliott A. Gruskin, Eric Theodore Cjojnicki, Gargi Roy
Принадлежит: Acorda Therapeutics Inc

A chimeric protein is disclosed for promoting repair and regeneration of neurons damaged by disease or physical injury wherein the chimeric protein is a combination of a first polypeptide possessing matrix modification activity and a second polypeptide possessing regenerating activity for neural cells.

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Номер записи: 11
17-10-2013 дата публикации

System for Immunotherapy Targeting Tumor Propagation and Progression

Номер: US20130273083A1
Автор: Laning Joseph C., Parenteau Nancy L., Young Janet H.
Принадлежит: INGENIUM BIOTHERAPY CORPORATION

Finding biologically relevant cancer markers is key to developing an effective treatment. Once specific antigens have been identified that are present on the cell population responsible for propagating tumors, T cells can be genetically altered to target these antigens and then used for personalized T cell therapy. A method to identify and select peptide antigens that effectively associate with and are presented by host HLA surface molecules originating from tumor cells responsible for the persistence and propagation of a cancer has been developed. The system of using these data to produce T cells engineered to express T cell receptors recognizing the peptide antigens is used in the production of a personalized adoptive T cell therapy for cancer that eliminates the cells capable of tumor propagation and cancer progression. The system is especially useful in the production of cancer treatments to achieve complete durable remission of cancers of epithelial origin. 1. A method of identifying regeneration-capable (C-RC) populations of cancer cells in an individual comprising(a) obtaining a tumor sample from an individual;(b) cultivating the tumor sample under conditions that induce a stress response in differentiating and differentiated cells but permits C-RC cells to propagate and which activate a regenerative response;(c) isolating the dominant actively expanding, most rapidly dividing population of cells from step (b); and(d) culturing the cells to 60 to 95% confluence to obtain a population of 51% to 100% C-RC.2. The method of claim 1 , wherein the conditions that activate a regenerative response are selected from the group consisting of serum-free claim 1 , defined cell culture medium claim 1 , inducing the apoptosis and/or necrosis of the cells claim 1 , medium containing cAMP elevating agents claim 1 , medium designed to inhibit cell-cell adhesion claim 1 , medium containing nitric oxide claim 1 , medium containing tumor necrosis factor-alpha (TNF-α) claim 1 , ...

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Номер записи: 12
17-10-2013 дата публикации

Antigen-Specific T Cell Receptors and T Cell Epitopes

Номер: US20130273647A1
Автор: Omokoko Tana, Sahin Ugur, SIMON Petra, Tureci Ozlem
Принадлежит:

The present invention relates to efficient methods for providing antigen-specific lymphoid cells. These lymphoid cells may be used to provide antigen specific T cell receptors having a defined MHC restriction and to identify immunologically relevant T cell epitopes. Furthermore, the present invention relates to antigen-specific T cell receptors and T cell epitopes and their use in immunotherapy. 17.-. (canceled)8. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 108 to 139 , 172 , 173 , 175 , 178 to 187 and 196 or a variant of said amino acid sequence.9. A nucleic acid encoding the peptide of .10. (canceled)11. An immunoreactive cell reactive with a peptide of .12. A T cell receptor α-chain or a T cell receptor comprising said T cell receptor α-chain claim 8 , wherein said T cell receptor α-chain is selected from the group consisting of:(i) a T cell receptor α-chain comprising one, two, or three of the CDR sequences of a T cell receptor α-chain selected from SEQ ID NOs: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 176, 188, 190, 192, and 194 or a variant thereof and(ii) a T cell receptor α-chain comprising a T cell receptor α-chain sequence selected from SEQ ID NOs: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 176, 188, 190, 192, and 194 or a variant thereof.13. A T cell receptor β-chain or a T cell receptor comprising said T cell receptor β-chain claim 8 , wherein said T cell receptor β-chain is selected from the group consisting of:(i) a T ...

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Номер записи: 13
24-10-2013 дата публикации

ANTI-ANGIOGENIC AGENT AND METHODS OF USING SUCH AGENT

Номер: US20130281357A1
Автор: Liu Zhi-Ren, Lu Yin, Yang Jenny J.
Принадлежит: GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION

Anti-angiogenic agents or polypeptides comprising an amino acid segment substantially similar to domain one of CD2 wherein the polypeptide has a β-sheet formed by two segments. Methods of using such agents and polypeptide are also included. 1. A method of reducing angiogenesis in an individual , the method comprising: administering to an individual an effective dose of a variant of human or mouse domain one of CD2 polypeptide , wherein the administration provides for reduction of angiogenesis in the individual , wherein the polypeptide has a β-sheet formed by two segments , an anti-parallel fold , an inward-facing hydrophobic surface , an outward-facing hydrophilic surface; and the two segment of have at least five amino acids alternating between hydrophilicity and hydrophobicity.2. The method as claimed in claim 1 , wherein the polypeptide reduces angiogenesis associated with a disorder selected from tumor growth claim 1 , atherosclerosis claim 1 , diabetic retinopathy claim 1 , age-related maculopathy claim 1 , and retrolental fibroplasia.3. The method as claimed in claim 1 , wherein said administering is by a route selected from intravenous claim 1 , in or around a solid tumor claim 1 , systemic claim 1 , intraarterial claim 1 , intraocular claim 1 , intraperitoneal claim 1 , and topical.4. The method as claimed in claim 1 , the polypeptide is selected from the group consisting of Sequence Id. No. 1 claim 1 , Sequence Id. No. 2 claim 1 , Sequence Id. No. 3 claim 1 , Sequence Id. No. 4 claim 1 , Sequence Id. No. 5 claim 1 , Sequence Id. No. 6 claim 1 , Sequence Id. No. 7 claim 1 , Sequence Id. No. 8 claim 1 , Sequence Id. No. 9 claim 1 , Sequence Id. No. 10 claim 1 , and Sequence Id. No. 11.5. The method as claimed in claim 1 , wherein the anti-angiogenic agent induces apoptosis of endothelial cells.6. The method as claimed in claim 1 , further comprising administering a therapeutically effective or prophylactic amount of a chemotherapeutic agent.7. The method as ...

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Номер записи: 14
31-10-2013 дата публикации

THERAPEUTIC AND DIAGNOSTIC CLONED MHC-UNRESTRICTED RECEPTOR SPECIFIC FOR THE MUC1 TUMOR ASSOCIATED ANTIGEN

Номер: US20130289261A1
Автор: Alajez Nehad M., Alter Mark D., Finn Olivera J., Schmielau Jan
Принадлежит: University of Pittsburgh - of the Commonwealth System of Higher Education

The invention provides an isolated nucleic acid encoding a receptor, other than an immunoglobulin, wherein the receptor binds to a MUC1 tumor antigen independently of an major histocompatibility complex (MHC). The invention provides a method of activating a signaling pathway and/or killing a cancer cell using a receptor that is similar to or is a T cell receptor 1. An isolated nucleic acid encoding a receptor , other than an immunoglobulin , wherein the receptor binds to a MUC1 tumor antigen independently of a major histocompatibility complex (MHC).2. The isolated nucleic acid of claim 1 , wherein the receptor binds to MUC1 tumor antigen with about the same affinity for MUC1 as the MA TCR.3. The isolated nucleic acid of claim 1 , wherein the receptor binds to MUC1 tumor antigen with a higher affinity for MUC1 as the MA TCR.4. The isolated nucleic acid of claim 1 , wherein the receptor binds to MUC1 tumor antigen with a lower affinity for MUC1 as the MA TCR.5. The isolated nucleic acid of claim 1 , wherein the receptor is a T cell receptor.6. The isolated nucleic acid of claim 1 , wherein the receptor{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'a. has a first amino acid sequence having at least 85% identity with the portion of MA Vα23 shown in (SEQ ID NO:1),'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'b. has a second amino acid sequence having at least 85% identity with the portion of MA Vβ8.3 shown in (SEQ ID NO:2),'}7. The isolated nucleic acid of claim 1 , wherein the receptor{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'a. has a first amino acid sequence having at least 90% identity with the portion of MA Vα23 shown in (SEQ ID NO:1),'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'b. has a second amino acid sequence having at least 90% identity with the portion of MA Vβ8.3 shown in (SEQ ID NO:2),'}8. The isolated nucleic acid of claim 1 , wherein the receptor{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'a. has a first amino acid sequence having at least 95% ...

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Номер записи: 15
06-03-2014 дата публикации

Affinity Maturated T Cell Receptors And Use Thereof

Номер: US20140065111A1
Автор: Eisenbach Lea, Gozlan Yosi, Tzehoval Esther
Принадлежит:

The present invention relates to methods and systems for increasing the affinity of a T cell receptor (TCR) to its ligand by subjecting the TCR gene to somatic hypermutation. The present invention further relates to use of affinity maturated TCRs to create T cells reactive against a selected antigen. 1. A method for increasing the affinity of a T cell receptor (TCR) to its ligand , the method comprising the steps of:(i) expressing in a host cell a nucleic acid construct encoding a TCR gene or fragment thereof,(ii) mutating the TCR gene or fragment thereof using somatic hypermutation (SHM), and(iii) selecting cells expressing a TCR with high affinity to the ligand.2. The method of claim 1 , wherein the TCR gene encodes a TCRα chain and a TCRβ chain or wherein the fragment of a TCR gene comprises a variable domain of a TCRα or TCRβ chain.3. The method of claim 1 , wherein the SHM of step (ii) comprises expressing Activation Induced cytidine Deaminase (AID) in said host cell.4. The method of claim 3 , comprising transiently expressing AID.5. The method of claim 4 , wherein transiently expressing AID comprises expressing in said host cell a nucleic acid construct encoding AID.6. The method of claim 5 , wherein AID has the nucleic acid sequence as set forth in SEQ ID NO:3 or wherein the nucleic acid construct encoding AID comprises an inducible promoter.7. The method of claim 6 , wherein the inducible promoter is a Tet-on promoter.8. The method of claim 1 , further comprising expressing CD3 in the host cell.9. The method of claim 1 , wherein steps (ii) and (iii) are repeated at least twice.10. The method of claim 1 , wherein the ligand is a peptide-MHC complex.11. The method of claim 10 , wherein the peptide is a tumor associated antigens (TAA).12. The method of claim 11 , wherein the TAA is selected from antigens associated with hematological malignancies and solid tumors.13. The method of claim 12 , wherein the solid tumor is selected from the group consisting of colon ...

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Номер записи: 16
20-03-2014 дата публикации

ANTI-CD147 ANTIBODIES, METHODS AND USES

Номер: US20140079711A1
Автор: Cunningham Mark, Swencki-Underwood Bethany, Tang Yi, Yan Li
Принадлежит: JANSSEN BIOTECH, INC.

The present invention provides antibodies immunospecific for human CD147 capable of blocking bioactivity of CD147 associated with malignant disease such as the stimulation of MMPs from fibroblast cells by tumor cells, the release of VEGF, and the promotion of angiogenesis. The antibodies of the present invention of are useful in treating malignant disease and those diseases in which CD147 activity is plays a pathogenic role, such as diseases of the eye, lung, and cardiovascular system. 1. An isolated monoclonal antibody or antigen-binding fragment thereof that competes for binding to the epitope on CD147 bound by the monoclonal antibody selected from the group consisting of 2H3 , 4A5 , and 5F6 having the amino acid sequences of the light chain complementarity determining regions (CDRs) of one of SEQ ID NOs: 9 , 11 , and 13 and the amino acid sequences of the heavy chain CDRs of one of SEQ ID NOs: 10 , 12 , and 14.2. An isolated antibody having heavy chain CDR1 , CDR 2 and CDR3 (Hc-CDR1 , Hc-CDR2 and Hc-CDR3) amino acid sequences selected from the sequences shown in SEQ ID NOs: 10 , 12 and 14 respectively and a light chain CDR3 (Lc-CDR3) as shown in Formula (I):{'br': None, 'sub': 1', '2', '3, 'Gln Gln XaaTyr Ser XaaPro XaaThr\u2003\u2003(I)'}{'sub': 1', '2', '3', '4, 'wherein Xaais Tyr or Asp; Xaais Tyr or Ser; Xaais Phe or Tyr or absent; and Xaais Thr or Phe; and light chain CDR1 (Lc-CDR1) and light chain CDR2 (Lc-CDR2) amino acid sequences selected from the sequences as shown in SEQ ID NOs: 9 and 11, respectively.'}3. An isolated antibody having Hc-CDR1 , Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 10 and Lc-CDR1 Lc-CDR2 , and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 9.4. An isolated antibody having Hc-CDR1 , Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 12 and Lc-CDR1 Lc-CDR2 , and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 11.5. An isolated antibody having Hc-CDR1 , Hc-CDR2 and Hc-CDR3 amino acid sequences ...

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Номер записи: 17
06-01-2022 дата публикации

CEACAM1 BASED CANCER THERAPY AND DIAGNOSIS

Номер: US20220001041A1
Автор: Markel Gal
Принадлежит:

The invention relates to methods and compositions for the treatment and diagnosis of cancers. At least one aspect of the present invention relates to methods and compositions for enhancing the efficacy of tumor-infiltrating lymphocyte (TIL) therapy in the treatment of cancer by negatively modulating the activity of the CEACAM1 protein. 1. A method for enhancing the efficacy of Tumor Infiltrating Lymphocyte cancer therapy comprising the modulation of CEACAM1 protein function.2. The method of claim 1 , wherein said modulation of CEACAM1 protein function comprises the disruption of a target CEACAM1 homotypic or heterotypic protein-protein interaction.3. The method of claim 2 , wherein the disruption of said target CEACAM1 homotypic or heterotypic protein-protein interaction comprises contacting at least one protein involved in said protein-protein interaction with an inhibitory agent that partially or completely inhibit or disrupt said protein-protein interaction claim 2 , said inhibitory agent comprising an amino acid sequence claim 2 , nucleic acid sequence claim 2 , small molecule compound claim 2 , or combinations thereof.4. The method of claim 2 , wherein the disruption of said target CEACAM1 homotypic or heterotypic protein-protein interaction comprises contacting at least one protein involved in said protein-protein interaction with an inhibitory agent that partially or completely inhibits or disrupts said protein-protein interaction claim 2 , said inhibitory agent comprising an amino acid sequence derived from a CEACAM family protein sequence.5. The method of claim 2 , wherein the disruption of said target CEACAM1 homotypic or heterotypic protein-protein interaction comprises contacting at least one protein involved in said protein-protein interaction with an inhibitory agent that partially or completely inhibits or disrupts said protein-protein interaction claim 2 , said inhibitory agent comprising an immunoglobulin or fragment thereof.6. The method of claim 2 ...

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Номер записи: 18
04-01-2018 дата публикации

CD33 SPECIFIC CHIMERIC ANTIGEN RECEPTORS

Номер: US20180002397A1
Автор: Chan Tim, Emtage Peter, SHAH Rutul, YARLAGADDA Ramya
Принадлежит:

Provided herein are chimeric antigen receptors (CARs) for cancer therapy, and more particularly, CARs containing a scFv from a CD33 monoclonal antibody. Provided are immune effector cells containing such CARs, and methods of treating proliferative disorders such as acute myeloid leukemia (AML), and relapsed or refractory AML. 113.-. (canceled)14. A vector comprising a backbone and a nucleic acid sequence encoding:(1) a truncated epidermal growth factor receptor comprising at least one of HER1t, HER1t-1 or a functional variant thereof; and (a) a CD33 antigen binding domain;', '(b) a stalk domain;', '(c) a transmembrane domain;', '(d) a costimulatory signaling domain comprising 4-1BB or CD28, or both; and', '(e) a CD3 zeta signaling domain., '(2) a chimeric antigen receptor (CAR), wherein the CAR comprises'}15. (canceled)16. The vector of claim 14 , wherein the vector is a lentivirus vector claim 14 , a retroviral vector claim 14 , or a non-viral vector.17. The vector of claim 14 , wherein the truncated epidermal growth factor receptor comprises a polypeptide having at least 90% claim 14 , 91% claim 14 , 92% claim 14 , 93% claim 14 , 94% claim 14 , 95% claim 14 , 96% claim 14 , 97% claim 14 , 98% claim 14 , 99% or 100% identity with the amino acid sequence of SEQ ID NO:32 or SEQ ID NO: 54.1823.-. (canceled)24. The vector of claim 14 , wherein the CD33 antigen binding domain comprises at least one of:(a) a polypeptide having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of SEQ ID NO:8 (hM195scFv);(b) a polypeptide having at least 900/%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99°/or 100% identity with the amino acid sequence of SEQ ID NOs:9 and 10 (M2H12);(c) a polypeptide having at least 900%, 91%, 92%, 93%, 94%, 95%, 96%, 97°/%, 98%, 99%0 or 100% identity with the amino acid sequence of SEQ ID NOs:11 and 12 (DRB2); and(d) a polypeptide having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% ...

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Номер записи: 19
04-01-2018 дата публикации

Methods, Arrangements and Systems for Obtaining Information Associated with an Anatomical Sample Using Optical Microscopy

Номер: US20180002398A1
Автор: Yun Seok-Hyun
Принадлежит:

Arrangements and methods are provided for obtaining information associated with an anatomical sample. For example, at least one first electro-magnetic radiation can be provided to the anatomical sample so as to generate at least one acoustic wave in the anatomical sample. At least one second electro-magnetic radiation can be produced based on the acoustic wave. At least one portion of at least one second electro-magnetic radiation can be provided so as to determine information associated with at least one portion of the anatomical sample. In addition, the information based on data associated with the second electro-magnetic radiation can be analyzed. The first electro-magnetic radiation may include at least one first magnitude and at least one first frequency. The second electro-magnetic radiation can include at least one second magnitude and at least one second frequency. The data may relate to a first difference between the first and second magnitudes and/or a second difference between the first and second frequencies. The second difference may be approximately between −100 GHz and 100 GHz, excluding zero. 1. An arrangement comprising:at least one first arrangement configured to provide at least one first electro-magnetic radiation to an anatomical sample so as to generate at least one acoustic wave in the anatomical sample, wherein at least one second electro-magnetic radiation is produced based on the at least acoustic wave; andat least one second arrangement configured to receive at least one portion of the at least one second electro-magnetic radiation so as to determine information associated with at least one portion of the anatomical sample.2. The arrangement according to claim 1 , wherein the anatomical sample is at least one of an organ claim 1 , a tissue or cell.3. The arrangement according to claim 1 , further comprising at least one third arrangement configured to image the at least one portion of the anatomical sample based on data associated with the ...

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Номер записи: 20
07-01-2021 дата публикации

METHODS FOR PREVENTING FUNGAL INFECTIONS

Номер: US20210002346A1
Автор: BARTIZAL Kenneth, DARUWALA Paul, Forrest Kevin, HANNAH Brendan, ONG Voon, RODEN Maureen, SANDISON Taylor
Принадлежит:

Provided herein are methods for preventing or reducing the likelihood of a fungal infection or related conditions thereto in a human subject in need thereof. The methods include the administration of one or multiple doses of a pharmaceutical composition including CD1 01 and any pharmaceutically acceptable excipients, wherein the treatment reduces or eliminates the likelihood of developing a fungal infection. 1. A method of reducing the likelihood of a fungal infection in a subject comprising administering to the subject a pharmaceutical composition comprising CD101 salt , or a neutral form thereof , and one or more pharmaceutically acceptable excipients , wherein the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce the likelihood of the fungal infection.2. The method of claim 1 , wherein the pharmaceutical composition is administered in two or more doses.3. The method of or claim 1 , wherein the pharmaceutical composition is administered one or more times per month claim 1 , one or more times per week claim 1 , or one or more times per day.4. The method of any one of - claim 1 , further comprising administering a second antifungal agent selected from the group consisting of glucan synthase inhibitors claim 1 , ergosterol inhibitors claim 1 , and pharmaceutically acceptable salts thereof.5. The method of claim 4 , wherein the second antifungal agent is selected from the group consisting of CD101 claim 4 , caspofungin claim 4 , micafungin claim 4 , anidulafungin claim 4 , enfumafungin claim 4 , clindamycin claim 4 , trimethoprim claim 4 , sulfamethoxazole claim 4 , cotrimoxazole claim 4 , VT-1161 claim 4 , VT-1129 claim 4 , VT-1598 claim 4 , VL-2397 claim 4 , fluconazole claim 4 , albaconazole claim 4 , bifonazole claim 4 , butoconazole claim 4 , clotrimazole claim 4 , econazole claim 4 , efinaconazole claim 4 , fenticonazole claim 4 , isavuconazole claim 4 , isoconazole claim 4 , itraconazole claim 4 , ketoconazole claim ...

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Номер записи: 21
13-01-2022 дата публикации

Immunoglobulin chimeric monomer-dimer hybrids

Номер: US20220010000A1
Автор: Adam R. Mezo, Alan J. Bitonti, Daniel S. Rivera, Robert T. Peters, Susan C. Low
Принадлежит: Bioverativ Therapeutics Inc

The invention relates to a chimeric monomer-dimer hybrid protein wherein the protein comprises a first and a second polypeptide chain, the first polypeptide chain comprising at least a portion of an immunoglobulin constant region and a biologically active molecule, and the second polypeptide chain comprising at least a portion of an immunoglobulin constant region without the biologically active molecule of the first chain. The invention also relates to methods of using and methods of making the chimeric monomer-dimer hybrid protein of the invention.

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Номер записи: 22
20-01-2022 дата публикации

IMMUNOMODULATORY CELLS AND USES THEREOF

Номер: US20220016181A1
Автор: HARDING Jeffrey, NAGY Andras, NAGY Kristina
Принадлежит:

Featured are cells and methods of use thereof for modulating an antigen-specific immune response in a subject. The cells comprise a set of transgenes comprising two or more of PD-L1, HLA-G or H2-M3, Cd47, Cd200, FASG or FasL, Ccl21 or Ccl21b, MfgeS and Serpin B9 or Spi6, that shield the cells from immune surveillance (ie. “cloaking genes”). The cells can be used to induce immune tolerance to an antigen (e.g., a donor alloantigen or a self-antigen), or to induce an immune response to (e.g., induce the production of antibodies directed against) a non-self antigen. 1. A cell genetically modified to comprise at least one mechanism for inducing immune tolerance to an antigen when administered to a subject , the genetically modified cell comprising a set of transgenes comprising two or more of the following genes: PD-L1 , HLA-G or H2-M3 , Cd47 , Cd200 , FASLG or FasL , Ccl21 or Ccl21b , Mfge8 , and Serpin B9 or Spi6 or a gene encoding a biologic that acts as an agonist of PD-L1 , HLA-G or H2-M3 , Cd47 , Cd200 , FASLG or FasL , Ccl21 or Ccl21b , Mfge8 , or Serpin B9 or Spi6; and a transgene encoding a polypeptide comprising an antigen.2. The cell of claim 1 , wherein the set of transgenes comprises three claim 1 , four claim 1 , five claim 1 , six claim 1 , seven claim 1 , or all eight of the following genes: PD-L1 claim 1 , HLA-G or H2-M3 claim 1 , Cd47 claim 1 , Cd200 claim 1 , FASLG or FasL claim 1 , Ccl21 or Ccl21b claim 1 , Mfge8 claim 1 , and Serpin B9 or Spi6 or a gene encoding a biologic that acts as an agonist of PD-L1 claim 1 , HLA-G or H2-M3 claim 1 , Cd47 claim 1 , Cd200 claim 1 , FASLG or FasL claim 1 , Ccl21 or Ccl21b claim 1 , Mfge8 claim 1 , or Serpin B9 or Spi6.3. The cell of claim 1 , wherein the set of transgenes comprises PD-L1 claim 1 , HLA-G or H2-M3 claim 1 , Cd47 claim 1 , Cd200 claim 1 , FASLG or FasL claim 1 , Ccl21 or Ccl21b claim 1 , Mfge8 claim 1 , and Serpin B9 or Spi6 or a gene encoding a biologic that acts as an agonist of PD-L1 claim 1 , ...

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Номер записи: 23
14-01-2021 дата публикации

METHODS OF MAKING AND USING GUIDANCE AND NAVIGATION CONTROL PROTEINS

Номер: US20210008113A1
Автор: BYKOVA Katrina, Gao Zeren, Huang Hui, JELLYMAN David, KHALILI Jahan, LUNDY Steven K., Olsen Ole, ROUSSEAU Anne-Marie, WANG Camilla, XIA Dong, ZHU Yi
Принадлежит:

The application provides methods for generating a therapeutic composition. The method includes the steps of providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, and formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA. The first GNC protein comprises a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor. The first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the first cytotoxic cell receptor. 1. A method for generating a therapeutic composition , comprisingproviding a cell material comprising a cytotoxic cell, wherein the first GNC protein comprising a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell through the binding with the first cytotoxic cell receptor, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor, and', 'wherein the first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the binding interaction with the first cytotoxic cell receptor, and, 'incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell,'}formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic ...

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Номер записи: 24
12-01-2017 дата публикации

FUSION PROTEINS COMPRISING IGG2 HINGE DOMAINS

Номер: US20170008951A1
Автор: Block David S., Olsen Henrik
Принадлежит:

The present invention relates to biologically active fusion proteins containing the IgG2 hinge as a multimerization domain capable of multimerizing proteins, peptides and small molecules which are active or more active in multimeric form; compositions comprising such fusion proteins; and methods of making and using such fusion proteins. 1151-. (canceled)152. A fusion protein comprising an IgG2 hinge domain monomer and an immunoglobulin Fc domain monomer , wherein the immunoglobulin Fc domain monomer is selected for poor binding to Fc gamma receptors.153. The fusion protein of claim 152 , wherein the IgG2 hinge domain monomer is at least 95% homologous to SEQ ID NO: 1.154. The fusion protein of claim 152 , wherein the IgG2 hinge domain monomer is 100% homologous to SEQ ID NO: 1.155. The fusion protein of claim 152 , wherein the IgG2 hinge domain monomer comprises at least two C-X-X-C motifs.156. The fusion protein of claim 155 , wherein the XX in the C-X-X-C motif comprises V-E or P-P.157. The fusion protein of claim 152 , wherein the immunoglobulin Fc domain monomer is an IgG1 claim 152 , IgG2 claim 152 , IgG3 or IgG4 Fc domain monomer selected for poor binding to Fc gamma receptors.158. The fusion protein of claim 152 , wherein the immunoglobulin Fc domain monomer is an IgE Fc domain monomer.159. The fusion protein of or wherein said immunoglobulin Fc domain monomer is mutated to bind poorly to Fc gamma receptors.160. The fusion protein of claim 159 , wherein said Fc domain is mutated at one or more of positions 233 claim 159 , 234 claim 159 , 235 claim 159 , 236 claim 159 , 238 claim 159 , 239 claim 159 , 265 claim 159 , 269 claim 159 , 270 claim 159 , 292 claim 159 , 293 claim 159 , 295 claim 159 , 296 claim 159 , 297 claim 159 , 303 claim 159 , 327 claim 159 , 329 claim 159 , 338 claim 159 , 376 claim 159 , and/or 414.161. The fusion protein of or wherein said immunoglobulin Fc domain monomer is modified to bind poorly to Fc gamma receptors.162. The fusion ...

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Номер записи: 25
10-01-2019 дата публикации

Peptides and combination of peptides for use in immunotherapy against cancers

Номер: US20190008937A1
Автор: Andrea MAHR, Oliver Schoor, Toni Weinschenk
Принадлежит: IMMATICS BIOTECHNOLOGIES GMBH

The present description relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present description relates to the immunotherapy of cancer. The present description further relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T-cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

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Номер записи: 26
14-01-2016 дата публикации

Methods and Compositions for Inhibiting the Effects of Amyloid Beta Oligomers

Номер: US20160009782A1
Автор: KIM Taeho, Shatz Carla J.
Принадлежит:

Methods and compositions are provided for reducing the effects of amyloid beta (Aβ) oligomers on a cell. Aspects of the methods generally include providing an agent that prevents Aβ oligomer activation of PirB/LILRB2 protein on cells, or providing a PirB/LILRB2 polypeptide composition to cells to prevent the Aβ oligomer activation of cells mediated by non-PirB/LILRB2 receptors. These methods find many uses, for example, in treating the decline in CNS function in individuals suffering from an Aβ-associated disease or disorder, and for screening candidate agents to identify new therapeutics that interfere with these toxic effects of Aβ in individuals having an Aβ-associated disease or disorder. 1. A method of treating an Aβ oligomer-associated nervous system disease or disorder in an individual , treating cognitive decline associated with the presence of Aβ oligomers in an individual , or inhibiting synapse loss in the presence of Aβ oligomers in an individual , the method comprising:administering to the individual an effective amount of an agent that inhibits Aβ oligomer activation of PirB/LILRB2.2. The method according to claim 1 , wherein the agent inhibits Aβ oligomer binding to PirB/LILRB2.3. The method according to claim 2 , wherein the agent comprises a PirB/LILRB2 polypeptide.4. The method according to claim 3 , wherein the PirB/LILRB2 polypeptide comprises the first two Ig-like domains of PirB or LILRB2.5. The method according to claim 3 , wherein the PirB/LILRB2 polypeptide consists essentially of the first two Ig-like domains of PirB or LILRB2.6. The method according to claim 3 , wherein the agent comprises a dimer of PirB/LILRB2 polypeptides.7. The method according to claim 6 , wherein each PirB/LILRB2 polypeptide of the dimer is fused to an Fc domain.8. The method according to claim 6 , wherein each PirB/LILRB2 polypeptide of the dimer comprises the first two Ig-like domains of PirB or LILRB2.9. The method according to claim 6 , wherein each PirB/LILRB2 ...

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Номер записи: 27
14-01-2021 дата публикации

Use of icos-based cars to enhance antitumor activity and car persistence

Номер: US20210009652A1
Автор: Carl H. June, John Scholler, Sonia Guedan Carrio, Yangbing Zhao
Принадлежит: University of Pennsylvania Penn

The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a genetically modified Th17 cell to express a CAR having an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

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Номер записи: 28
14-01-2021 дата публикации

LENTIVIRAL VECTORS FOR REGULATED EXPRESSION OF A CHIMERIC ANTIGEN RECEPTOR MOLECULE

Номер: US20210009653A1
Автор: AGAUGUE Sophie, AMIGORENA Sebastian, BAUCHE Cécile, EVEN-DESRUMAUX Klervi, PEREZ Franck, TIBALDI Lorenzo, TRUBETSKOY Dmitry
Принадлежит:

The invention relates to the regulated expression of a chimeric antigen receptor (CAR) within a lentiviral vector. The CAR comprises a hook-binding domain that interacts with a hook, preferably encoded by the same lentiviral vector, which prevents proper processing and release of the CAR to the cell membrane. The invention encompasses vectors, methods of making the vectors, and methods of using them, including medicinal uses. The vectors can be used for administration to humans to induce immune responses and to treat cancers and tumors. 118-. (canceled)19. An isolated cell comprising a nucleic acid molecule , a nucleic acid vector or a lentiviral vector encoding a chimeric antigen receptor , the said chimeric antigen receptor comprising:a binding domain;a transmembrane domain;a hook-binding domain comprising a streptavidin-binding peptide; andan activation domain comprising a T cell activating fragment of at least 100 amino acids of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8, SEQ ID NO:33, or SEQ ID NO:34.20. The isolated cell according to claim 19 , wherein the isolated cell is a cell of the immune system.21. The isolated cell according to claim 19 , wherein the isolated cell is(i) a T cell, or(ii) a NK cell.22. The isolated cell according to claim 19 , wherein the isolated cell is a mammalian cell claim 19 , particularly a human cell.23. The isolated cell according to claim 19 , wherein the binding domain comprises a single-chain Fv antibody or a nanobody.24. The isolated cell according to claim 19 , wherein the hook comprises the amino acid sequence of SEQ ID NO:31 or SEQ ID NO:32.25. The isolated cell according to claim 19 , wherein the nucleic acid vector or the lentiviral vector comprises a β2-microlobulin claim 19 , ubiquitin claim 19 , MHCI or MHCII promoter.26. The isolated cell according to claim 19 , wherein the chimeric antigen receptor comprises the amino acid sequence of any of SEQ ID NO:46 claim 19 , SEQ ID NO:48 ...

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Номер записи: 29
10-01-2019 дата публикации

Conditionally Active Chimeric Antigen Receptors for Modified T-Cells

Номер: US20190010219A1
Автор: Jay M. Short
Принадлежит: Bioatla Inc

This disclosure relates to a chimeric antigen receptor for binding with a target antigen. The chimeric antigen receptor comprises at least one antigen specific targeting region including a multispecific bivalent monovalent antibody evolved from a wild-type antibody or a fragment thereof and having at least one of: (a) a decrease CAB-scFv Affinity ELISA in activity in the assay at the normal physiological condition compared to the wild-type antibody or the fragment thereof, and (b) an increase in activity in the assay under the aberrant condition compared to the wild-type antibody or the fragment thereof. A method for using the chimeric antigen receptor and cytotoxic cells for cancer treatment is also provided.

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Номер записи: 30
10-01-2019 дата публикации

CONDITIONALLY ACTIVE CHIMERIC ANTIGEN RECEPTORS FOR MODIFIED T-CELLS

Номер: US20190010220A1
Автор: Chang Hwai Wen, FREY GERHARD, Short Jay M.
Принадлежит: BIOATLA, LLC

This disclosure relates to a chimeric antigen receptor for binding with a tumor specific target antigen. The chimeric antigen receptor comprises at least one antigen specific targeting region evolved from a parent protein or a fragment thereof and having a decrease in activity in the assay at the normal physiological condition compared to the activity in the assay under the aberrant condition. A method for producing the chimeric antigen receptor is also provided. 1. A chimeric antigen receptor for binding with a tumor specific target antigen , comprising:i. at least one antigen specific targeting region evolved from a parent or wild-type protein or a domain thereof and having a decrease in activity in an assay at a normal physiological condition compared to the activity of the antigen specific targeting region in an assay at an aberrant condition that deviates from the normal physiological condition;ii. a transmembrane domain; andiii. an intracellular signaling domain.2. The chimeric antigen receptor of claim 1 , wherein the tumor specific target antigen is selected from Axl claim 1 , ROR2 and CD22.3. The chimeric antigen receptor of claim 1 , wherein the at least one antigen specific targeting region is selected from an antibody claim 1 , a fragment of an antibody claim 1 , a single chain antibody claim 1 , a divalent single chain antibody or a diabody claim 1 , a ligand claim 1 , a receptor binding domain of a ligand claim 1 , a receptor claim 1 , a ligand binding domain of a receptor claim 1 , and an affibody.4. The chimeric antigen receptor of claim 1 , wherein the tumor specific target antigen is Axl and the at least one antigen specific targeting region is a single chain antibody having an amino acid sequence selected from SEQ ID NOS:9-12.5. The chimeric antigen receptor of claim 1 , wherein the tumor specific target antigen is ROR2 and the at least one antigen specific targeting region is a single chain antibody having an amino acid sequence of SEQ ID NO:15.6 ...

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Номер записи: 31
10-01-2019 дата публикации

METHOD FOR GENERATING T-CELLS COMPATIBLE FOR ALLOGENIC TRANSPLANTATION

Номер: US20190010514A1
Автор: Cabaniols Jean-Pierre, Duchateau Philippe, POIROT Laurent, Sourdive David
Принадлежит: CELLECTIS

The present invention pertains to engineered T-cells, method for their preparation and their use as medicament, particularly for immunotherapy. The engineered T-cells of the invention are characterized in that the expression of beta 2-microglobulin (B2M) and/or class II major histocompatibility complex transactivator (CIITA) is inhibited, e.g., by using rare-cutting endonucleases able to selectively inactivating by DNA cleavage the gene encoding H2M and/or CIITA or by using nucleic acid molecules which inhibit the expression of B2M and/or CIITA. In order to further render the T-cell non-alloreactive, at least one gene encoding a component of the T-cell receptor is inactivated, e.g., by using a rare-cutting endonucleases able to selectively inactivating by DNA cleavage the gene encoding said TCR component. In addition, expression of immunosuppressive polypeptide can be performed on those modified T-cells in order to prolong the survival of these modified T cells in host organism. Such modified T-cell is particularly suitable for allogeneic transplantations, especially because it reduces both the risk of rejection by the host's immune system and the risk of developing graft versus host disease. The invention opens the way to standard and affordable adoptive immunotherapy strategies using T-Cells for treating cancer, infections and auto-immune diseases. 1. A method for preparing an engineered T-cell comprising the steps of:a) providing a T-cell; andb) inhibiting the expression of beta 2-microglobulin (B2M) and/or class II major histocompatibility complex transactivator (CIITA) in said T-cell by using a rare-cutting endonuclease able to selectively inactivate by DNA cleavage gene encoding said B2M and/or CIITA.2. The method according to claim 1 , wherein step b) is performed by using a rare-cutting endonuclease able to selectively inactivate by DNA cleavage the gene encoding B2M.3. The method according to claim 1 , wherein step b) is performed by using a rare-cutting ...

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Номер записи: 32
03-02-2022 дата публикации

XBP1, CD138, AND CS1 PEPTIDES

Номер: US20220031821A1
Автор: Anderson Kenneth C., Bae Jooeun, Munshi Nikhil C.
Принадлежит:

The disclosure features, inter alia, immunogenic XBP1-, CD138-, and CS1-derived peptides (and pharmaceutical compositions thereof). The peptides can be used in a variety of methods such as methods for inducing an immune response, methods for producing an antibody, and methods for treating a cancer (e.g., a plasma cell disorder such as multiple myeloma or Waldenstrom's macroglobulinemia). The peptides can also be included in WIC molecule multimer compositions and used in, e.g., methods for detecting a T cell in a population of cells. 1128.-. (canceled)129. A method for inducing an immune response in a subject , the method comprising administering to the subject a composition comprising:(a) a first XBP-1 peptide comprising: (i) the amino acid sequence of SEQ ID NO:6, (ii) 0 to up to 10 amino acids immediately N-terminal of SEQ ID NO: 6, which, if present, are amino acids that flank SEQ ID NO: 2 in non-spliced XBP1, and (iii) 0 to up to 10 amino acids immediately C-terminal of SEQ ID NO: 6, which, if present, are amino acids that flank SEQ ID NO: 2 in non-spliced XBP1;(b) a second XBP-1 peptide comprising: (i) the amino acid sequence of SEQ ID NO:10, and (ii) 0 to up to 10 amino acids immediately N-terminal of SEQ ID NO: 10, which, if present, are amino acids that flank SEQ ID NO: 9 in spliced XBP1; and(c) a CD138 peptide comprising: (i) the amino acid sequence of SEQ ID NO:12, (ii) 0 to up to 10 amino acids immediately N-terminal of SEQ ID NO: 12, which, if present, are amino acids that flank SEQ ID NO: 12 in CD138, and (iii) 0 to up to 10 amino acids immediately C-terminal of SEQ ID NO: 12, which, if present, are amino acids that flank SEQ ID NO: 12 in CD138.130. The method of claim 129 , wherein:(a) the first XBP-1 peptide comprises 0 to up to 5 amino acids immediately N-terminal of SEQ ID NO: 6, which, if present, are amino acids that flank SEQ ID NO: 2 in non-spliced XBP1, and 0 to up to 5 amino acids immediately C-terminal of SEQ ID NO: 6, which, if present, are ...

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Номер записи: 33
03-02-2022 дата публикации

Inhibitory chimeric antigen receptors

Номер: US20220033462A1
Автор: Alexandre Juillerat, Arvind Rajpal, Barbra Johnson SASU, Donna Marie Stone, Laurent Poirot, Shobha Chowdary POTLURI, Thomas Charles PERTEL
Принадлежит: Allogene Therapeutics Inc, CELLECTIS SA

The invention relates to an inhibitory chimeric antigen receptor (N-CAR) comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain, and, an intracellular domain wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX 1 YX 2 X 3 X 4 , wherein X 1 is an amino acid X 2 is an amino acid X 3 is an amino acid and X 4 is V or I.

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Номер записи: 34
03-02-2022 дата публикации

Preparation and Application of Soluble Tim-3 Recombinant Protein and Mutant Protein Thereof

Номер: US20220033463A1
Автор: CHEN Zhi, Liu Yanning, Lou Guohua, SHI YU, Yang Ying, Zhu Haihong
Принадлежит:

The present application belongs to the field of biotechnology, and particularly relates to preparation and use of soluble Tim-3 recombinant protein and a mutant protein thereof. The soluble Tim-3 recombinant protein is used to prepare a drug with the function of regulating monocytes or a drug with the function of enhancing tumor immune response, and the amino acid sequence of the soluble Tim-3 recombinant protein is as shown in SEQ ID NO: 1. In addition, the present application further provides the mutant proteins of the sTim-3 recombinant protein and preparation and use of the mutant protein. The mutant recombinant protein is obtained by screening through a directed evolutionary technology, with the function of regulating monocytes or the function of enhancing tumor immune response, and combines with a host codon optimization method to improve the expression efficiency. 1. Use of Soluble Tim-3 recombinant protein in preparing a drug with the function of regulating monocytes or a drug with the function of enhancing tumor immune response , wherein the amino acid sequence of the soluble Tim-3 recombinant protein is as shown in SEQ ID NO: 1.2. Use according to claim 1 , wherein the drug with the function of regulating monocytes can be used for inhibiting overactivity of the monocytes in patients with inflammation claim 1 , and the drug with the function of enhancing tumor immune response can be used for enhancing immune response in cancer patients to avoid host's immune escape.3E. coli. A purification method of soluble Tim-3 recombinant protein claim 1 , comprising the following steps: performing fluid exchanging on cell culture solutions of eukaryotic CHO cells claim 1 , prokaryotic and insect baculovirus expression system containing recombinant human soluble Tim-3 through microfiltration clarification and ultrafiltration concentration claim 1 , and then passing through cation and anion chromatographic column claim 1 , molecular sieve chromatographic column claim 1 , ...

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Номер записи: 35
03-02-2022 дата публикации

METHODS FOR EX VIVO EXPANSION OF NATURAL KILLER CELLS AND USE THEREOF

Номер: US20220033778A1
Автор: Rezvani Katy, Shpall Elizabeth
Принадлежит:

Provided herein are ex vivo methods for the expansion of cord blood-derived natural killer cells and methods of their use. Examples of embodiments include stimulating mononuclear cells from cord blood in the presence of antigen presenting cells (APCs) and IL-2 and re-stimulating the cells with APCs to produce expanded NK cells. In specific embodiments, the method does not utilize human leukocyte antigen (HLA) matching. 1. An ex vivo method for the expansion of natural killer (NK) cells comprising:(a) obtaining a starting population of mononuclear cells (MNCs) from cord blood;(b) stimulating the MNCs in the presence of antigen presenting cells (APCs) and IL-2; and(c) re-stimulating the cells with APCs to produce expanded NK cells, wherein the method is performed in a bioreactor and is good manufacturing practice (GMP) compliant.2. The method of claim 1 , wherein the method further comprises depleting cells positive for CD3.3. The method of claim 2 , wherein the depleting is performed between steps (b) and (c).4. The method of claim 3 , wherein the cells are removed from the bioreactor.5. The method of claim 1 , wherein obtain the starting population of MNCs from cord blood comprises thawing cord blood in the presence of dextran claim 1 , human serum albumin (HSA) claim 1 , DNAse claim 1 , and/or magnesium chloride.6. The method of claim 1 , wherein obtain the starting population of MNCs from cord blood comprises thawing cord blood in the presence of dextran and DNase.7. The method of claim 5 , wherein the cord blood is washed in the presence of 10% dextran.8. The method of or claim 5 , wherein the cord blood is suspended in the presence of magnesium chloride.9. The method of claim 8 , wherein the magnesium chloride is at a concentration of 200 mM.10. The method of any of - claim 8 , wherein obtaining comprises performing ficoll density gradient centrifugation to obtain mononuclear cells (MNCs).11. The method of any of - claim 8 , wherein the method does not comprise ...

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Номер записи: 36
15-01-2015 дата публикации

METHODS AND COMPOSITIONS FOR INHIBITION OF IMMUNE RESPONSES

Номер: US20150017130A1
Автор: Sykes Megan, Yang Yongguang
Принадлежит:

Methods and compositions for modulating immune responses are provided herein. 1. A cell of a first species comprising a nucleotide sequence encoding a CD47 polypeptide , or fragment thereof , of a second species.2. The cell of claim 1 , wherein the first species is a non-human mammalian species.3. The cell of claim 1 , wherein the first species is a swine species.4. The cell of claim 1 , wherein the second species is human.5. The cell of claim 1 , further comprising a second nucleotide sequence encoding a second polypeptide of the second species.6. The cell of claim 1 , wherein the cell is deficient for expression of a carbohydrate modifying enzyme.7. The cell of claim 1 , which is a hematopoietic cell.8. A transgenic non-human mammal whose genome comprises a nucleotide sequence encoding a human CD47 polypeptide.9. The mammal of claim 8 , wherein the mammal is a swine.10. An organ from the transgenic mammal of .11. The organ of claim 10 , wherein the first species is a non-human mammalian species.12. The organ of claim 11 , wherein the first species is a swine species.13. The organ of claim 10 , wherein the second species is human.14. The organ of claim 10 , wherein the mammal further comprises a second nucleotide sequence encoding a polypeptide of the second mammalian species.15. The organ of claim 10 , wherein the mammal is deficient for expression of a carbohydrate modifying enzyme.17. The method of claim 16 , wherein said donor and recipient are of different species.18. The method of claim 16 , wherein said donor and recipient are of same species and expression of CD47 on the graft is upregulated. This application is a continuation of U.S. Ser. No. 11/519,667, filed Sep. 12, 2006, which claims the benefit of priority of U.S. Ser. No. 60/716,875, filed Sep. 13, 2005, the contents of which are hereby incorporated by reference in their entirety for all purposes.This invention relates to methods and compositions for modulating immune responses, and more particularly ...

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Номер записи: 37
15-01-2015 дата публикации

Virus like particle comprising pd-1 antigen or pd-1 ligand antigen

Номер: US20150017194A1
Автор: Ryuji Ueno, Wataru Akahata
Принадлежит: VLP Therapeutics Inc

The present invention provides a virus like particle comprising a virus structural protein and an antigen derived from PD-1 or a ligand of PD-1, and a composition or kit comprising thereof, its use in immune response etc.

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Номер записи: 38
18-01-2018 дата публикации

Engineered Exosomes for the Delivery of Bioactive Cargo Using Transmembrane Tetraspanins

Номер: US20180015182A1
Автор: Losacco Joseph, Lu Biao, Meyer Conary, Stickney Zachary
Принадлежит:

Engineered exosomes for the delivery of bioactive cargo are provided. The exosomes incorporate a tetraspanin transmembrane anchoring scaffold onto the membrane of the exosome. The tetraspanin transmembrane anchoring scaffold has a C-terminal attachment site in the inner-vesicle space of the exosome, a N-terminal attachment site in the inner-vesicle space or the outer-vesicle space, and/or a loop attachment site in the outer-vesicle space. Peptides can be attached to the different attachments sites in any form or combination. Tetrapanins naturally anchor on the exosome membrane, are biocompatible, and allow for robust loading and delivery of bioactive cargos in mammalian system. 1. An engineered exosome for the delivery of bioactive cargo , comprising:an exosome defining an inner-vesicle space and an outer-vesicle space, wherein the exosome incorporates a tetraspanin transmembrane anchoring scaffold onto the membrane of the exosome,wherein the tetraspanin transmembrane anchoring scaffold has a C-terminal attachment site in the inner-vesicle space,wherein the tetraspanin transmembrane anchoring scaffold has a N-terminal attachment site in the inner-vesicle space or the outer-vesicle space, andwherein the tetraspanin transmembrane anchoring scaffold has a loop attachment site in the outer-vesicle space,wherein a first peptide is attached to the C-terminal attachment site of the tetraspanin transmembrane anchoring scaffold so that the first peptide is located in the inner-vesicle space,wherein a second peptide is attached to the N-terminal attachment site of the tetraspanin transmembrane anchoring scaffold so that the second peptide is located in the inner-vesicle space or in the outer-vesicle space, andwherein a third peptide is attached to the loop attachment site of the tetraspanin transmembrane anchoring scaffold so that the third peptide is located in the outer-vesicle space.2. The engineered exosome as set forth in claim 1 , wherein the second peptide is attached ...

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Номер записи: 39
17-01-2019 дата публикации

ADHERENT CANCER CELL LINE EXPRESSING A HEMATOLOGICAL TUMOR ANTIGEN

Номер: US20190015493A1
Автор: WU Lijun
Принадлежит:

The present invention relates to a transduced cancer cell line stably expressing a leukemia tumor antigen, wherein the cancer cell line is cervical cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, lung cancer cells, or glioblastoma cells. The transduced adherent cell line of the present invention is useful for many pre-clinical applications such as real time cytotoxicity assay or to test the effects of CAR-T cells that target the tumor antigen. The present invention is exemplified by Hela cell line stably expressing CD19. 1. A method for measuring cytotoxicity of CD19-CAR T cells , comprising:seeding transduced Hela cancer cells that stably express CD19 on a plate,adding CD19-CAR T cells to the plate, andmeasuring real time cytotoxicity of the CD19-CAR T cells.2. The method of claim 1 , wherein the CAR comprises CD19 scFv claim 1 , CD28-transmembrane domain claim 1 , CD28 activation domain claim 1 , and CD3 zeta.3. The method of claim 1 , wherein the CAR further comprises a FLAG tag. This application is a continuation of U.S. application Ser. No. 15/610,419, filed May 31, 2017, which claims the priority of U.S. Provisional Application No. 62/343,976, dated Jun. 1, 2016. The above applications are incorporated herein by reference in their entireties.The Sequence Listing is concurrently submitted herewith with the specification as an ASCII formatted text file via EFS-Web with a file name of Sequence Listing.txt with a creation date of May 15, 2017, and a size of 13.0 kilobytes. The Sequence Listing filed via EFS-Web is part of the specification and is hereby incorporated in its entirety by reference herein.The present invention relates to Hela-CD19 cell line that stably express CD19 (cluster of differentiation 19), which is a marker of hematopoietic cancers.Hela cell line was derived from cervical cancer cells taken on Feb. 8, 1951 from Henrietta Lacks, who died of cancer on Oct. 4, 1951 [Ghorashian et al. 2015, 169, 463-478.] The cell ...

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Номер записи: 40
19-01-2017 дата публикации

METHOD FOR GENERATING T-CELLS COMPATIBLE FOR ALLOGENIC TRANSPLANTATION

Номер: US20170016025A1
Автор: Cabaniols Jean-Pierre, Duchateau Philippe, POIROT Laurent, Sourdive David
Принадлежит:

The present invention pertains to engineered T-cells, method for their preparation and their use as medicament, particularly for immunotherapy. The engineered T-cells of the invention are characterized in that the expression of beta 2-microglobulin (B2M) and/or class II major histocompatibility complex transactivator (CIITA) is inhibited, e.g., by using rare-cutting endonucleases able to selectively inactivating by DNA cleavage the gene encoding B2M and/or CIITA, or by using nucleic acid molecules which inhibit the expression of B2M and/or CIITA. In order to further render the T-cell non-alloreactive, at least one gene encoding a component of the T-cell receptor is inactivated, e.g., by using a rare-cutting endonucleases able to selectively inactivating by DNA cleavage the gene encoding said TCR component. In addition, expression of immunosuppressive polypeptide can be performed on those modified T-cells in order to prolong the survival of these modified T cells in host organism. Such modified T-cell is particularly suitable for allogeneic transplantations, especially because it reduces both the risk of rejection by the host's immune system and the risk of developing graft versus host disease. The invention opens the way to standard and affordable adoptive immunotherapy strategies using T-Cells for treating cancer, infections and auto-immune diseases. 1. A method for preparing an engineered T-cell comprising the steps of:a) providing a T-cell; andb) inhibiting the expression of beta 2-microglobulin (B2M) and/or class II major histocompatibility complex transactivator (CIITA) in said T-cell by using a rare-cutting endonuclease able to selectively inactivate by DNA cleavage gene encoding said B2M and/or CIITA.2. The method according to claim 1 , wherein step b) is performed by using a rare-cutting endonuclease able to selectively inactivate by DNA cleavage the gene encoding B2M.3. The method according to claim 1 , wherein step b) is performed by using a rare-cutting ...

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Номер записи: 41
21-01-2016 дата публикации

TIM RECEPTORS AS VIRUS ENTRY COFACTORS

Номер: US20160017035A1
Автор: AMARA Ali, MEERTENS Laurent
Принадлежит: Institut National de la Sante et de la Recherche Medicale (INSERM)

The present invention concerns the use of an inhibitor of an interaction between phosphatidylserine and a TIM receptor for preventing or treating a virus entry cofactors, in particular phosphatidylserine harboring virus infection such as infection.

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Номер записи: 42
18-01-2018 дата публикации

METHODS AND COMPOSITIONS FOR MODULATING TOSO ACTIVITY

Номер: US20180016320A1
Автор: Brenner Dirk, Lang Karl, Lang Philipp, Lin Gloria, Mak Tak W., Ohashi Pamela S., Tusche Michael W.
Принадлежит:

The present invention is further directed to methods and compositions for modulating the activity of the Toso protein. The invention further encompasses treatment of disorders associated with inflammation, autoimmune disorders, and cancer using compositions that include a soluble Toso protein. 150-. (canceled)51. A method of modulating Toso activity , the method comprising applying a Toso composition to a cell comprising a membrane-bound Toso receptor , wherein the Toso composition comprises at least a portion of an extracellular Toso domain , a signal sequence and an Fc domain.52. The method of claim 51 , wherein the extracellular Toso domain comprises amino acid residues 18-253 of SEQ ID NO: 7.53. The method of claim 51 , wherein the extracellular Toso domain is at least 95% identical to SEQ ID NO: 8.54. The method of claim 51 , wherein the Toso composition is a protein comprising an amino acid sequence according to SEQ ID NO: 5.55. The method of claim 51 , wherein the signal sequence is an IL-2 signal sequence.56. The method of claim 51 , wherein the Fc domain comprises one or more mutations that diminish or ablate antibody-dependent and complement-dependent cytotoxicity. The present application is a Continuation of U.S. application Ser. No. 14/539,879, filed Nov. 12, 2014, which is a Divisional of U.S. application Ser. No. 14/539,872, filed Nov. 12, 2014, which is a Continuation of U.S. application Ser. No. 13/831,031, filed Mar. 14, 2013, which claims the benefit of priority to U.S. Provisional Application No. 61/612,183, filed Mar. 16, 2012, U.S. Provisional Application No. 61/646,143, filed May 11, 2012, and U.S. Provisional Application No. 61/731,428, filed Nov. 29, 2012, the contents of which are expressly incorporated herein by reference in their entirety for all purposes.Toso or Faim3 (Fas Apoptotic inducing molecule 3) is a single membrane spanning cell surface receptor originally characterized through a retroviral overexpression screen in Jurkat cells, ...

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Номер записи: 43
18-01-2018 дата публикации

SIGNALLING SYSTEM

Номер: US20180016335A1
Автор: Cordoba Shaun, Pulé Martin
Принадлежит:

The present invention relates to a chimeric antigen-receptor (CAR) signalling system comprising; (i) a targeting component comprising an antigen-binding domain, a transmembrane domain and a first heterodimerization domain; and (ii) an intracellular signalling component comprising a signalling domain and a second heterodimerization domain; wherein spontaneous heterodimerization between the first and second heterodimerization domains causes the targeting component and signalling component to form a functional CAR complex. 2. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise leucine zipper domains.3. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise DDD1 and AD1 domains.4. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise Barnase and Barnstar domains.5. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise human pancreatic RNAse and S-peptide domains.619-. (canceled)22. (canceled)23. A vector comprising a nucleic acid construct according to .24. The vector according to which is a retroviral vector or a lentiviral vector or a transposon.25. The cell which comprises a CAR signalling system according to .2627-. (canceled)28. The cell according to claim 25 , which is a T cell or NK cell.29. A pharmaceutical composition comprising a plurality of cells according to .30. (canceled)31. A method for treating or preventing a disease claim 29 , comprising the step of administering a pharmaceutical composition according to to a subject.33. (canceled)34. The method according to claim 31 , wherein the disease is cancer.3536-. (canceled)38. The method according to claim 37 , wherein the cell is from a sample isolated from a subject. The present invention relates to an antigen receptor signalling system.Traditionally, antigen-specific T- ...

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Номер записи: 44
16-01-2020 дата публикации

Cell

Номер: US20200016203A1
Автор: Cordoba Shaun, Kong Khai, Pulé Martin
Принадлежит:

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain. 1. A T cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface , each CAR comprising:(i) an antigen-binding domain;(ii) a spacer(iii) a trans-membrane domain; and(iv) an endodomainwherein the antigen binding domains of the first and second CARs bind to different antigens, and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-on inhibitory endodomain.211-. (canceled)12. A nucleic acid sequence encoding both the first and second chimeric antigen receptors (CARs) as defined in .13. A nucleic acid sequence according to claim 12 , which has the following structure:AgB1-spacer1-TM1-endo1-coexpr-AbB2-spacer2-TM2-endo2 in whichAgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR;spacer 1 is a nucleic acid sequence encoding the spacer of the first CAR;TM1 is a a nucleic acid sequence encoding the transmembrane domain of the first CAR;endo 1 is a nucleic acid sequence encoding the endodomain of the first CAR;coexpr is a nucleic acid sequence enabling co-expression of both CARsAgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;spacer 2 is a nucleic acid sequence encoding the spacer of the second CAR;TM2 is a a nucleic acid sequence encoding the transmembrane domain of the second CAR;endo 2 is a nucleic acid sequence encoding the ...

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Номер записи: 45
16-01-2020 дата публикации

Cell

Номер: US20200016204A1
Автор: Khai KONG, Martin PULÉ, Shaun CORDOBA
Принадлежит: UCL BUSINESS LTD

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, wherein the spacer of the first CAR is different to the spacer of the second CAR and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain.

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Номер записи: 46
16-01-2020 дата публикации

TREATMENT OF INFECTION BY HUMAN ENTEROVIRUS D68

Номер: US20200016243A1
Автор: Moss Ronald B.
Принадлежит:

The present disclosure provides compositions and methods for treating an infection by EV-D68. In particular, the present disclosure provides methods that entail administering agents having an anchoring domain that anchors the compound to the surface of a target cell, and a sialidase domain that can act extracellularly to inhibit infection of a target cell by EV-D68. 1. A method of treating infection by EV-D68 in a patient , the method comprising administering to the patient an effective amount of an agent having sialidase activity.223.-. (canceled) Human enterovirus D68 (EV-D68) (species, Human enterovirus D; genus, Enterovirus; family, Picornaviridae) can cause severe respiratory tract infections. It was rarely identified in patients in the United States prior to about 2005. However, since the late 2000s, the number of reported EV-D68 cases increased dramatically in in various countries. Some EV-D68 infections are characterized by severe disease, requiring intensive care and non-invasive ventilatory support. A 2014 EV-D68 outbreak particularly affected children with a history of asthma or reactive airway disease; and exacerbation of pre-existing asthma or reactive airway disease, similar to that associated with rhinovirus (RV) infection was noted in a high proportion of cases, though some patients with no history of asthma also had asthma-like symptoms (Midglcy et al., 201463:798-799).The present disclosure provides compositions and methods for treating EV-D68 infection and disorders associated with EV-D68 infection. Specifically, it provides compounds which can act extracellularly to reduce (e.g., reduce the risk of) or prevent infection of a cell by EV-D68 and method of treatment employing such compounds. Some preferred embodiments of the disclosure include therapeutic compounds having an anchoring domain that facilitates association of the compound with the surface of a target cell and a sialidase domain that can act extracellularly to reduce or prevent ...

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Номер записи: 47
17-01-2019 дата публикации

TUMOR-SPECIFIC IFNA SECRETION BY CAR T-CELLS TO REPROGRAM THE SOLID TUMOR MICROENVIRONMENT

Номер: US20190016776A1
Автор: Jensen Michael C., Johnson Adam
Принадлежит:

The present application relates to fusion proteins, chimeric antigen bearing cells expressing fusion proteins and compositions comprising chimeric antigen bearing cells expressing fusion proteins. The application further relates to methods of using the fusion proteins, cells and compositions for modulating an immune response. 1. A nucleic acid encoding a fusion protein , the nucleic acid comprising:a first sequence, wherein the first sequence encodes a protein that modulates an immune response;a second sequence, wherein the second sequence encodes a spacer, such as an amino acid spacer e.g., a plurality of glycines; anda third sequence, wherein the third sequence encodes an interferon.286-. (canceled) The present application claims the benefit of priority to U.S. Provisional Patent Application No. 62/278,648, filed Jan. 14, 2016. The entire disclosure of the aforementioned application is expressly incorporated by reference in its entirety.The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 2017_01_10_SQ_LISTING_SCRI_109WO.TXT, created Jan. 10, 2017, which is 25 kb in size. The information is the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.Disclosed herein are compositions and methods relating to a dual-active, secretable fusion protein that can be used in chimeric antigen receptor (CAR) therapy for a subject. Additionally, methods for intrinsic production and secretion of a PD-1:IFNα2a fusion protein in CAR T-cells to support T-cell activity, promote inflammatory cytokine production and decrease immunosuppression within the solid tumor microenvironment, are also provided. These methods and compositions can improve the therapeutic efficacy of CAR T-cell therapy targeted against solid tumors by providing regulatory inputs for multiple immune cell subsets found in the tumor microenvironment.The tumor microenvironment (TME) is the ...

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Номер записи: 48
17-01-2019 дата публикации

T CELL RECEPTORS RECOGNIZING HLA-A1- OR HLA-CW7-RESTRICTED MAGE

Номер: US20190016777A1
Автор: Feldman Steven A., Morgan Richard A., Robbins Paul F., Rosenberg Steven A., Zhu Shiqui
Принадлежит: The United States of America,as represented by the Secretary,Department of Health and Human Services

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or b) MAGE-A12 in the context of HLA-Cw7. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention. 1. An isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or b) MAGE-A12 in the context of HLA-Cw7.2. The isolated or purified TCR of having antigenic specificity for a) a MAGE-A3 epitope comprising EVDPIGHLY (SEQ ID NO: 2) or b) a MAGE-A12 epitope comprising VRIGHLYIL (SEQ ID NO: 4).3. The isolated or purified TCR of claim 2 , comprising the amino acid sequences of SEQ ID NOs: 16-21 claim 2 , 26-31 claim 2 , or 36-41.4. The isolated or purified TCR of claim 3 , comprising the amino acid sequences of SEQ ID NOs: 22-23 claim 3 , 32-33 claim 3 , or 42-43.5. The isolated or purified TCR of claim 4 , comprising the amino acid sequences of SEQ ID NOs: 24-25 claim 4 , 34-35 claim 4 , or 44-45.6. An isolated or purified polypeptide comprising a functional portion of the TCR of claim 1 , wherein the functional portion comprises the amino acid sequences of SEQ ID NOs: 16-21 claim 1 , 26-31 claim 1 , or 36-41.7. The isolated or purified polypeptide of claim 6 , wherein the portion comprises the amino acid sequences of SEQ ID NOs: 22-23 claim 6 , 32-33 claim 6 , or 42-43.8. The isolated or purified polypeptide of claim 7 , wherein the portion comprises the amino acid sequences of SEQ ID NOs: 24-25 claim 7 , 34-35 ...

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Номер записи: 49
17-01-2019 дата публикации

ENHANCED EXPRESSION OF HUMAN OR HUMANIZED IMMUNOGLOBULIN IN NON-HUMAN TRANSGENIC ANIMALS

Номер: US20190017021A1
Автор: Buelow Roland
Принадлежит:

The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Igα and/or Igβ sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Igα and/or Igβ sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Igα and/or Igβ results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies. 16-. (canceled)7. A method for producing human or humanized antibodies in a non-human animal , comprising the steps of:(a) introducing and expressing a transgene construct encoding either a native human Igα subunit or a chimeric Igα subunit, and/or a transgene construct encoding either a native human Igβ subunit or a chimeric Igβ subunit into the non-human animal;(b) introducing and expressing a transgene construct encoding a human or humanized immunoglobulin locus into the non-human animal;(c) subjecting the animal to an antigenic stimulus; and(d) isolating human or humanized antibodies from the animal.8. The method according to claim 7 , wherein the antibody is a monoclonal antibody.9. The method according to claim 7 , wherein the antibody is a fragment of a monoclonal antibody.10. The method according to claim 9 , wherein the antibody fragment is fused to a heterologous amino acid sequence.111. An isolated human or humanized antibody produced with the method according to claim . This is a non-provisional application filed under 37 CFR 1.53(b), claiming priority under U.S.C. Section 119(e) to U.S. Provisional Patent Application Ser. No. 60/841,980 filed Sep. 1, 2006.This invention relates to a method to improve the expression of human(ized) immunoglobulin in non-human transgenic animals by promoting normal B-cell development and by sustaining the expression of human(ized) ...

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Номер записи: 50
28-01-2016 дата публикации

MODIFIED FC FUSION PROTEINS

Номер: US20160024179A1
Автор: Colon Grace, Warner Thomas G.
Принадлежит:

Preparations of modified Fc fusion peptides that exhibit metabolically complete or near-complete oligosaccharide structures are provided. Also provided are methods for preparation of the modified Fc fusion peptides. These preparations exhibit enhanced serum half-life and are useful for treatment of a variety of diseases. 1. A Fc fusion protein , comprising an immunoglobulin Fc region linked to a biologically active polypeptide comprising one or more oligosaccharide , whereini. more than 10% of all oligosaccharides on the biologically active polypeptide terminate in sialic acid; andii. at least one of the oligosaccharides linked to the biologically active polypeptide comprises a biantennary glycan structure terminating in at least 3 sialic acid molecules, or a triantennary glycan structure terminating in at least 4 sialic acid molecules, or a tetraantennary glycan structure terminating in at least 5 sialic molecules.2. The Fc fusion protein of claim 1 , wherein at least 5% claim 1 , 10% claim 1 , 15% claim 1 , 20% of the oligosaccharides linked to the biologically active polypeptide comprise a biantennary glycan structure terminating in at least 3 sialic acid molecules.3. The Fc fusion protein of claim 1 , wherein at least 5% claim 1 , 10% claim 1 , 15% claim 1 , 20% of the oligosaccharides linked to the biologically active polypeptide comprise a triantennary glycan structure terminating in at least 4 sialic acid molecules.4. The Fc fusion protein of claim 1 , wherein at least 5% claim 1 , 10% claim 1 , 15% claim 1 , 20% of the oligosaccharides linked to the biologically active polypeptide comprise a tetraantennary glycan structure terminating in at least 5 sialic molecules.5. The Fc fusion protein of claim 1 , wherein at least one of the oligosaccharides linked to the biologically active polypeptide in the Fc fusion comprises a biantennary glycan structure terminating in at least 3 or 4 sialic acid molecules.6. The Fc fusion protein of claim 1 , wherein more than 20 ...

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Номер записи: 51
26-01-2017 дата публикации

Medical uses of crtam agonists

Номер: US20170022286A1
Автор: Holbrook Kohrt
Принадлежит: Leland Stanford Junior University

Methods and compositions relating to use of CRTAM agonists are provided. In some embodiments, the present invention provides methods and compositions relating to use of CRTAM in the treatment of cancer, including enhancing the efficacy of antibody therapy directed to cancer cells.

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Номер записи: 52
17-04-2014 дата публикации

SOLUBLE HYBRID FCGAMMA RECEPTORS AND RELATED METHODS

Номер: US20140107034A1
Автор: Birks Carl W., Ellsworth Jeff L., FOX BRIAN A., RIXON Mark W.
Принадлежит: ZYMOGENETICS, INC.

Disclosed are soluble hybrid Fcγ receptor (FcγR) polypeptide compositions and related methods of using such polypeptides to treat IgG-mediated and immune complex-mediated inflammation. Also disclosed are related compositions and methods for producing the soluble hybrid FcγR polypeptides. 1. An isolated , soluble polypeptide comprising an amino acid sequence having at least 90% sequence identity with a polypeptide region selected from the group consisting ofamino acid residues 36-301 of SEQ ID NO:40;amino acid residues 43-310 of SEQ ID NO:42;amino acid residues 21-286 of SEQ ID NO:44; oramino acid residues 21-286 of SEQ ID NO:46;wherein said polypeptide is capable of specifically binding the Fc region of IgG.2. The polypeptide of claim 1 , wherein said polypeptide has at least 95% sequence identity with the polypeptide region.3. The polypeptide of claim 1 , wherein the polypeptide comprisesamino acid residues 36-301 of SEQ ID NO:40;amino acid residues 43-310 of SEQ ID NO:42;amino acid residues 21-286 of SEQ ID NO:44; oramino acid residues 21-286 of SEQ ID NO:46.4. The polypeptide of claim 1 , further comprising a secretory signal sequence.5. An isolated nucleic acid molecule encoding a polypeptide as in any one of to .6. The nucleic acid molecule of claim 5 , wherein the nucleic acid molecule comprisesnucleotides 106-903 of SEQ ID NO:39;nucleotides 127-930 of SEQ ID NO:41;nucleotides 61-858 of SEQ ID NO:43; ornucleotides 61-858 of SEQ ID NO:45.7. An expression vector comprising the following operably linked elements:a) a transcription promoter,{'claim-ref': [{'@idref': 'CLM-00001', 'claims 1'}, {'@idref': 'CLM-00004', '4'}], 'b) a DNA segment encoding a polypeptide as in any one of to ; and'}c) a transcription terminator.8. The expression vector of claim 7 , wherein the DNA segment comprisesnucleotides 106-903 of SEQ ID NO:39;nucleotides 127-930 of SEQ JD NO:41;nucleotides 61-858 of SEQ ID NO:43; ornucleotides 61-858 of SEQ ID NO:45.9. The expression vector of or ...

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Номер записи: 53
25-01-2018 дата публикации

TARGETING CYTOTOXIC CELLS WITH CHIMERIC RECEPTORS FOR ADOPTIVE IMMUNOTHERAPY

Номер: US20180022795A1
Автор: Milone Michael, Wang Enxiu
Принадлежит:

The present invention provides compositions and methods for regulating the specificity and activity of T cells. In one embodiment, the invention provides a type of chimeric antigen receptor (CAR) wherein the CAR is termed a “KIR-CAR” which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells. In one embodiment, the NK receptor includes but is not limited to a naturally occurring activating and inhibitory receptor of NK cells known as a killer cell immunoglobulin-like receptor (KIR). 1253-. (canceled)254. A nucleic acid comprising a sequence encoding an activating killer cell immunoglobulin-like receptor chimeric antigen receptor (actKIR-CAR) , wherein the actKIR-CAR comprises:an extra-cellular antigen binding domain from an antibody molecule or a non-antibody scaffold;an activating killer cell immunoglobulin-like receptor (actKIR) transmembrane domain; anda cytoplasmic domain.255. The nucleic acid of claim 254 , wherein the actKIR transmembrane domain can interact with the transmembrane domain of a DAP12 polypeptide.256. The nucleic acid of claim 254 , wherein the actKIR transmembrane domain comprises a positively charged moiety.257. The nucleic acid of claim 254 , wherein the cytoplasmic domain is a KIR-cytoplasmic domain.258. The nucleic acid of claim 254 , wherein the antigen binding domain from an antibody molecule comprises a scFv.259. The nucleic acid of claim 254 , wherein the actKIR-CAR further comprises an extracellular hinge domain.260. The nucleic acid of claim 254 , wherein the actKIR-CAR further comprises an extracellular hinge domain that:(i) is other than a KIR hinge domain;(ii) is derived from a natural molecule;(iii) comprises a non-naturally occurring polypeptide sequence;(iv) is from human CD8-alpha subunit;(v) is of less than 50, 20, or 10 amino acids in length, or(vi) has fewer amino acids than a KIR2DS2 hinge domain.261. The nucleic acid of claim 254 , wherein the actKIR-CAR comprises an actKIR ...

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Номер записи: 54
25-01-2018 дата публикации

COMPOSITIONS AND METHODS FOR TUMOR TRANSDUCTION

Номер: US20180022821A1
Автор: Lobb Roy, Rennert Paul
Принадлежит:

The invention relates to cancer therapeutics, in particular, the system of making cancer cells more susceptible to effector cells by introduction of cellular therapy targets into the cancer cells. 132-. (canceled)33. An adenoviral vector , comprising a nucleotide sequence encoding a fusion protein comprising (a) an antibody , or antigen-binding fragment thereof , that binds a tumor antigen; and (b) a polypeptide target for a cellular therapeutic , antibody , or antibody-drug conjugate.34. The vector of claim 33 , wherein the polypeptide target is a B cell antigen.35. The vector of claim 34 , wherein the B cell antigen is CD19 or CD22.36. The vector of claim 33 , wherein the tumor antigen is HER-2/neu claim 33 , c-met claim 33 , EGFR claim 33 , Ga733\EpCAM claim 33 , CD20 claim 33 , ROR1 claim 33 , or BCMA.37. The vector of claim 33 , wherein the antigen-binding fragment is an Fab claim 33 , scFv claim 33 , Fv claim 33 , or VHH.38. The vector of claim 33 , wherein the cellular therapeutic is a CAR-T cell or CAR-NK cell.39. A method of treating a subject having a tumor claim 33 , comprising administering to the subject the adenoviral vector of .40. An oncolytic viral vector claim 33 , comprising a nucleotide sequence encoding a fusion protein comprising (a) an antibody claim 33 , or antigen-binding fragment thereof claim 33 , that binds a tumor antigen; and (b) a polypeptide target for a cellular therapeutic claim 33 , antibody claim 33 , or antibody-drug conjugate.41. The vector of claim 40 , wherein the polypeptide target is a B cell antigen.42. The vector of claim 41 , wherein the B cell antigen is CD19 or CD22.43. The vector of claim 40 , wherein the tumor antigen is HER-2/neu claim 40 , c-met claim 40 , EGFR claim 40 , Ga733\EpCAM claim 40 , CD20 claim 40 , ROR1 claim 40 , or BCMA.44. The vector of claim 40 , wherein the antigen-binding fragment is an Fab claim 40 , scFv claim 40 , Fv claim 40 , or VHH.45. The vector of claim 40 , wherein the cellular therapeutic ...

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Номер записи: 55
23-01-2020 дата публикации

A GENETICALLY MODIFIED MOUSE EXPRESSING HUMAN APOE4 AND MOUSE TREM2 P.R47H AND METHODS OF USE THEREOF

Номер: US20200022343A1
Автор: Carter Gregory, Howell Gareth, Lamb Bruce, Sasner Michael
Принадлежит:

Genetically modified mice characterized by one or more symptoms or signs associated with expression of human APOE4p and mouse Trem2p and relevant to non-familial late-onset Alzheimer's disease are provided wherein the genome of the mouse includes: 1) a DNA sequence encoding a human APOE4 protein (APOE4p) operably linked to a promoter; and 2) a DNA sequence encoding a mouse Trem2 protein having a mutation p,R47H (Trem2p) operably linked to a promoter, such that the mouse expresses human APOE4p and mouse Trem2p. Methods ace provided for screening for a compound for use in the treatment of Alzheimer's disease using such genetically modified mice. 1. A genetically modified mouse characterized by one or more symptoms or signs associated with expression of human APOE4p and mouse Trem2p and relevant to non-familial late-onset Alzheimer's disease , the genome of the mouse comprising: 1) a DNA sequence encoding a human APOE4 protein (APOE4p) operably linked to a promoter; and 2) a DNA sequence encoding a mouse Trem2 protein having a mutation p.R47H (Trem2p) operably linked to a promoter , wherein the mouse expresses human APOE4p and mouse Trem2p.2. The genetically modified mouse of claim 1 , therein the APOE4p comprises an amino acid sequence of: SEQ ID NO: 1 claim 1 , or the APOE4p is encoded by the complement of a nucleic acid which hybridizes to SEQ ID NO:2 under highly stringent hybridization conditions.3. The genetically modified mouse of claim 1 , wherein the mouse Trem2p comprises an amino acid sequence of: SEQ ID NO:3 claim 1 , or the mouse Trem2p is encoded by the complement of a nucleic acid which hybridizes to SEQ ID NO:4 under highly stringent hybridization conditions.4. The genetically modified mouse of claim 1 , wherein the genetically modified mouse is a B6(SJL)-ApoeTrem2/J mouse whose genome comprises: 1) a DNA sequence encoding human APOE4 protein (APOE4p) operably linked to a promoter;and 2) a DNA sequence encoding mouse Trem2 protein having a mutation p. ...

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Номер записи: 56
10-02-2022 дата публикации

A GROUP OF CHIMERIC ANTIGEN RECEPTORS (CARS)

Номер: US20220041687A1
Автор: LEHNER Manfred, SALZER Benjamin, TRAXLMAYR Michael
Принадлежит:

Disclosed is a group of chimeric antigen receptors (CARs) having two, three or four CAR molecules, 2. The group of CARs according to claim 1 , wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 1 mM and 150 nM claim 1 , preferably between 1 mM and 200 nM claim 1 , more preferably between 1 mM and 300 nM claim 1 , especially between 1 mM and 400 nM; andwherein the affinity of each individual antigen binding moiety of another polypeptide to its target antigen or alternatively the affinity of this other polypeptide to the binding site of its respective CAR molecule is between 1 mM and 150 nM, preferably between 1 mM and 200 nM, more preferably between 1 mM and 300 nM, especially between 1 mM and 400 nM.3. The group of CARs according to claim 1 , wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 500 μM and 100 nM claim 1 , preferably between 250 μM and 100 nM claim 1 , more preferably between 125 μM and 100 nM claim 1 , especially between 50 μM and 100 nM claim 1 , andwherein the affinity of each individual antigen binding moiety of another polypeptide to its target antigen or alternatively the affinity of this other polypeptide to the binding site of its respective CAR molecule is between 500 μM and 100 nM, preferably between 250 μM and 100 nM, more preferably between 125 μM and 100 nM, especially between 50 μM and 100 nM.4. The group of CARs according to claim 1 , wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 500 μM and 150 nM claim 1 , preferably between 250 μM and 200 nM claim 1 , more preferably between 125 μM and 300 nM claim 1 , especially between 50 μM and 400 nM; andwherein the affinity of each individual antigen binding moiety of another polypeptide to its target antigen or alternatively the affinity of this other polypeptide to ...

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Номер записи: 57
10-02-2022 дата публикации

METHODS OF REDUCING LIVER PD-1-EXPRESSING CD8+ T CELLS USING PD-1 FC FUSION PROTEINS THAT BIND FC RECEPTORS

Номер: US20220041726A1
Автор: Ahmed Rafi, FREEMAN Gordon J., Hashimoto Masao, Jin Hyun T., Sharpe Arlene H.
Принадлежит:

The present invention relates to methods of reducing liver PD-1-expressing CD8+ T cells using PD-1 Fc fusion proteins that bind Fc receptors, as well as diagnostic, prognostic, therapeutic methods and compositions related thereto. 1. A method of reducing CD8+ T cells expressing PD-1 in the liver of a subject comprising administering to the subject a therapeutically effective amount of an Fc fusion protein that specifically binds to PD-1 and binds to at least one Fc receptor , optionally wherein the PD-1 is listed in Table 1 , is mouse PD-1 , or is human PD-1.23-. (canceled)4. The method of claim 1 , wherein the Fc fusion protein inhibits or blocks the activity of PD-1 on the CD8+ T cells expressing PD-1.5. The method of claim 1 , wherein the at least one Fc receptor is an activating human FcγR claim 1 , optionally selected from the group consisting of human FcγRI claim 1 , human FcγRIIa claim 1 , human FcγRIIc claim 1 , human FcγRIIIa claim 1 , and human FcγRIIIb.6. The method of claim 5 , wherein i the human FcγRIIa is an H131 allotype human FcγRIIa or an R131 allotype human FcγRIIa or ii) the human FcγRIIIa is a V158 allotype human FcγRIIIa or an F158 allotype human FcγRIIa.7. (canceled)8. The method of claim 1 , wherein the at least one Fc receptor is an inhibitory human FcγR claim 1 , optionally wherein the inhibitory human FcγR is human FcγRIIb.9. The method of claim 1 , wherein the at least one Fc receptor is an activating mouse FcγR claim 1 , optionally selected from the group consisting of mouse FcγRI claim 1 , mouse FcγRII claim 1 , and mouse FcγRIV.10. The method of claim 1 , wherein the at least one Fc receptor is an inhibitory mouse FcγR claim 1 , optionally wherein the inhibitory mouse FcγR is mouse FcγRIIb.11. The method of claim 1 , whereina) the Fc fusion protein mediates antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), or a combination thereof;{'sub': 'A', 'sup ...

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Номер записи: 58
23-01-2020 дата публикации

COMPOSITIONS AND METHODS FOR CAR T CELL THERAPY

Номер: US20200023009A1
Автор: CHU Haiyan, II Leroy W., LEAMON Christopher Paul, LEE Yong Gu, Low Philip Stewart, LU Yingjuan J., Wheeler
Принадлежит:

The present disclosure relates to methods of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells and a small molecule linked to a targeting moiety by a linker. The disclosure also relates to compositions for use in such methods. 12.-. (canceled)3. A method of treatment of a cancer , the method comprisingi) administering to a patient a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker;ii) administering to the patient a CAR T cell composition wherein the CAR T cell composition comprises CAR T cells and wherein the CAR T cells comprise a CAR directed to the targeting moiety; andiii) administering to the patient a folate, a conjugate comprising a folate wherein the conjugate comprising a folate does not comprise a targeting moiety, or an agent that inhibits activation of the CAR T cells.46.-. (canceled)7. A method of treatment of a cancer , the method comprisingi) administering to a patient a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, wherein at least a first dose and a second dose of the compound, or the pharmaceutically acceptable salt thereof, are administered to the patient, wherein the first dose and the second dose are different, wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is about 2-fold to about 15000-fold greater in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof; andii) administering to the patient a CAR T cell composition comprising CAR T cells wherein the CAR T cells comprise a CAR directed to the targeting moiety.8. A method of treatment of a cancer , the method comprisingi) administering to a patient a first dose of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a ...

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Номер записи: 59
28-01-2021 дата публикации

CELLULAR IMMUNOTHERAPY COMPOSITIONS AND USES THEREOF

Номер: US20210023135A1
Автор: COREY Daniel Mark
Принадлежит:

The present disclosure relates to cellular immunotherapy compositions comprising a combination of immune cells or cellular subsets modified with chimeric engulfment receptors and chimeric antigen receptors/or T cell receptor binding proteins, and methods of using such cellular immunotherapy compositions. 1. A combination cellular immunotherapy composition comprising: an extracellular domain comprising a binding domain that binds to a first target antigen,', 'an engulfment signaling domain, and', 'a transmembrane domain positioned between and connecting the extracellular domain and the engulfment signaling domain; and, '(a) a first composition comprising a CD4+ T cell comprising a first chimeric engulfment receptor (CER) comprising an extracellular domain comprising a binding domain that binds to a second target antigen,', 'an engulfment signaling domain, and', 'a transmembrane domain positioned between and connecting the extracellular domain and the engulfment signaling domain., '(b) a second composition comprising a CD8+ T cell comprising a second CER comprising2. A combination cellular immunotherapy composition comprising: an extracellular domain comprising a binding domain that binds to a first target antigen,', 'an engulfment signaling domain; and', 'a transmembrane domain positioned between and connecting the extracellular domain and the engulfment signaling domain; and, '(a) a first composition comprising a CD4+ T cell comprising a chimeric engulfment receptor (CER) comprising an extracellular domain comprising a binding domain that binds to a second target antigen,', 'an intracellular signaling domain, and', 'a transmembrane domain positioned between and connecting the extracellular domain and the intracellular signaling domain., '(b) a second composition comprising a CD8+ T cell comprising a chimeric antigen receptor (CAR) comprising3. A combination cellular immunotherapy composition comprising: an extracellular domain comprising a binding domain that binds ...

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Номер записи: 60
24-01-2019 дата публикации

Methods of Sequencing, Determining, Pairing, and Validating Therapeutic Agents and Disease Specific Antigens

Номер: US20190024145A1
Автор: Briggs Adrian Wrangham, Clouser Christopher Ryan, Goldfless Stephen Jacob, Timberlake Sonia, V Francois, Vigneault
Принадлежит: AbVitro LLC

Provided herein are methods and composition for immune repertoire sequencing and single cell barcoding. The methods and compositions can be used to pair any two sequences originating from a single cell, such as heavy and light chain antibody sequences, for antibody discovery, disease and immune diagnostics, and low error sequencing. 1. A method comprising:(a) sequencing a polynucleotide encoding an immunoglobulin (Ig) or a T-cell receptor (TCR) polypeptide from at least one tumor infiltrating lymphocyte (TIL) from a biological sample from a subject and a polynucleotide encoding an Ig or a TCR polypeptide from at least one non-TIL cell from the biological sample from the subject, thereby obtaining sequence information; and(b) selecting an Ig or TCR polynucleotide sequence from a TIL of the at least one TIL and at least one non-TIL cell based on the sequence information.2. A method comprising:(a) sequencing a polynucleotide encoding an immunoglobulin (Ig) or a T-cell receptor (TCR) polypeptide from at least one tumor-infiltrating lymphocyte (TIL) from a biological sample from a subject and a polynucleotide encoding an Ig or a TCR polypeptide from at least one non-TIL cell from the biological sample from the subject, thereby obtaining sequence information;(b) comparing the sequence information to sequence information obtained from a corresponding normal adjacent tissue sample; and(c) selecting an Ig or TCR polynucleotide sequence from a TIL of the at least one TIL and at least one non-TIL cell based on the comparing.3. A method comprising:(a) sequencing a polynucleotide encoding an immunoglobulin (Ig) or a T-cell receptor (TCR) polypeptide from at least one tumor-infiltrating lymphocyte (TIL) from a biological sample from a first subject and a polynucleotide encoding an Ig or a TCR polypeptide from at least one non-TIL cell from the biological sample from the first subject, thereby obtaining sequence information;(b) comparing the sequence information to sequence ...

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Номер записи: 61
23-01-2020 дата публикации

Proteins binding psma, nkg2d and cd16

Номер: US20200024353A1
Автор: Ann F. CHEUNG, Bianka Prinz, Bradley M. LUNDE, Gregory P. CHANG, William Haney
Принадлежит: Dragonfly Therapeutics Inc

Multi-specific binding proteins that bind PSMA, the NKG2D receptor, and CD 16 are described, as well as pharmaceutical compositions and therapeutic methods useful for the treatment of cancer.

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Номер записи: 62
28-01-2021 дата публикации

NKG2D CHIMERIC ANTIGEN RECEPTORS

Номер: US20210024608A1
Автор: Davila Marco
Принадлежит:

Disclosed are compositions and methods for targeted treatment of infections and cancers expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill transformed and infected cells. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an immunotherapy in a subject with an infection or cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. 1. A chimeric antigen receptor (CAR) polypeptide , comprising a NKG2D ectodomain , a transmembrane domain , and either an intracellular signaling domain but not a co-stimulatory signaling region , or a co-stimulatory signaling region but not an intracellular signaling domain.2. The polypeptide of claim 1 , wherein the NKG2D ectodomain comprises an amino acid sequence having at least 65% claim 1 , 70% claim 1 , 71% claim 1 , 72% claim 1 , 73% claim 1 , 74% claim 1 , 75% claim 1 , 76% claim 1 , 77% claim 1 , 78% claim 1 , 79% claim 1 , 80% claim 1 , 81% claim 1 , 82% claim 1 , 83% claim 1 , 84% claim 1 , 85% claim 1 , 86% claim 1 , 87% claim 1 , 88% claim 1 , 89% claim 1 , 90% claim 1 , 91% claim 1 , 92% claim 1 , 93% claim 1 , 94% claim 1 , 95% claim 1 , 96% claim 1 , 97% claim 1 , 98% claim 1 , 99% claim 1 , or 100% sequence identity SEQ ID NO:1 claim 1 , or a fragment thereof of at least 100 claim 1 , 110 claim 1 , 120 claim 1 , 130 claim 1 , 135 claim 1 , 136 claim 1 , 137 claim 1 , 138 claim 1 , 139 claim 1 , 140 claim 1 , 141 claim 1 , 142 claim 1 , or 143 amino acids that can bind induced-self proteins.3. The polypeptide of claim 1 , wherein the costimulatory signaling region comprises the cytoplasmic domain of a costimulatory molecule selected from the group consisting of CD27 claim 1 , CD28 claim 1 , 4-1BB claim 1 , OX40 claim 1 , CD30 ...

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Номер записи: 63
28-01-2021 дата публикации

Guidance and navigation control proteins and method of making and using thereof

Номер: US20210024630A1
Автор: Anne-Marie Rousseau, Bill Brady, Blair RENSHAW, Brian Kovacevich, Camilla WANG, David JELLYMAN, Dong Xia, Hui Huang, Katrina BYKOVA, Ole Olsen, Yi Zhu, Yu Liang, Zeren Gao
Принадлежит: Sichuan Bail! Pharmaceutical Co Ltd, Sichuan Baili Pharmaceutical Co Ltd, Systimmune Inc

The application provides guidance and navigation control (GNC) proteins. In one embodiment, the guidance and navigation control (GNC) protein, comprising a binding domain for a T cell activating receptor, a binding domain for a tumor associated antigen, a bind domain for an immune checkpoint receptor, and a binding domain for a T cell co-stimulating receptor. The binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor. In one embodiment, the binding domain for the T cell activating receptor is adjacent to the binding domain for the tumor associated antigen (TAA).

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Номер записи: 64
02-02-2017 дата публикации

Human SIRPa Transgenic Animals and Their Methods of Use

Номер: US20170027140A1
Автор: Elizabeth Eynon, Markus Manz, Richard A. Flavell, Till Strowig, William Philbrick
Принадлежит: HOWARD HUGHES MEDICAL INSTITUTE, YALE UNIVERSITY

The invention relates generally to compositions and methods of using transgenic non-human animals expressing human SIRPα that are engrafted with a human hematopoietic system. In various embodiments, the human hematopoietic system engrafted, human SIRPα transgenic non-human animals of the invention are useful as systems for the in vivo evaluation of the growth and differentiation of hematopoietic and immune cells, for the in vivo assessment of an immune response, for the in vivo evaluation of vaccines and vaccination regimens, for in vivo production and collection of immune mediators, including human antibodies, and for use in testing the effect of agents that modulate hematopoietic and immune cell function.

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Номер записи: 65
01-02-2018 дата публикации

Chimeric antigen receptor combination therapy for treating tumors

Номер: US20180028633A1
Автор: Lan Bo Chen
Принадлежит: Individual

A method for treating a tumor in a subject by administering at least three of the following treatment modalities: (i) an antibody, (ii) T cells bearing a first chimeric antigen receptor (CAR), (iii) NK cells bearing a second CAR, and (iv) NKT cells bearing a third CAR. The antibody binds specifically to stage-specific embryonic antigen 4 and each CAR contains a scFv that also binds specifically to SSEA4.

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Номер записи: 66
02-02-2017 дата публикации

HUMAN TIM-3 FUSION PROTEIN CAPABLE OF BLOCKING TIM-3 SIGNALING PATHWAY

Номер: US20170029485A1
Автор: CHEN Guojiang, FENG Jiannan, HAN Gencheng, HOU Chunmei, JIANG Xingwei, Li Yan, SHEN Beifen, WANG Renxi, Xiao He, YU Jiahui, Zhao Zhi
Принадлежит:

The present invention provides a human Tim-3-Ig fusion protein which can block Tim-3 signal pathway, and said Ig fusion protein comprises Tim-3 protein, human Ig fragment, and the linking sequence therebetween. In the present invention, a human Tim-3-Ig gene is obtained by an artificial synthesis process; an expression vector containing the Tim-3-Ig gene is constructed; and the prepared Ig fusion protein is tested in an expression verification experiment, a binding activity experiment, a blocking activity experiment in different cell lines, and in vivo experiments in mice. The human Tim-3-Ig fusion protein prepared in the present invention can be used to treat immunological diseases caused by high expression of Tim-3. 112-. (canceled)13. A Tim-3-Ig fusion protein , wherein the amino acid sequence of the Tim-3-Ig fusion protein is set forth in SEQ ID NO: 1.14. The Tim-3-Ig fusion protein according to claim 13 , wherein the nucleotide sequence encoding the Tim-3-Ig fusion protein is set forth in SEQ ID NO: 2.15. A vector comprising the nucleotide sequence which encodes a Tim-3-Ig fusion protein and is set forth in SEQ ID NO: 2.16. A pharmaceutical composition for increasing the expression of immunocytokines and/or inhibiting a tumor claim 13 , comprising the Tim-3-Ig fusion protein according to and a pharmaceutically acceptable carrier.17. The pharmaceutical composition according to claim 16 , comprising 10-40 mg/ml of the Tim-3-Ig fusion protein claim 16 , 10-100 mg/ml of a protectant claim 16 , 3-10 mmol of a buffer claim 16 , 0.05-0.2 mg/ml of a surfactant claim 16 , and 2-9 mg/ml of an isotonic regulator. The present invention relates to a fusion protein, and specifically to a human Tim-3-Ig fusion protein and a preparation containing thereof. The present invention also relates to use of the human Tim-3-Ig fusion protein for treating immunological diseases.Tim-3 is a member of the T-cell immunoglobulin domain and Mucin domain protein (Tim) family in structure. Tim ...

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Номер записи: 67
01-02-2018 дата публикации

SIRP ALPHA-ANTIBODY FUSION PROTEINS

Номер: US20180030142A1
Автор: Griffin Emily Piccione, Majeti Ravindra
Принадлежит:

SIRPabodies comprise an immunoglobulin variable region, which may specifically bind a tumor antigen, viral antigen, etc., fused to a sequence comprising a binding domain of SIRPα. The binding domain of SIRPα comprises at least the N-terminal Ig-like domain of SIRPα, and may further comprise additional SIRPα sequences. The SIRPabodies find use in therapeutic methods that benefit from the combined activity of blocking CD47 activity, and antibody targeting, e.g. in the treatment of cancer, etc. In some specific embodiments, the SIRPabody comprises anti-CD20 activity and a SIRP binding domain; anti-CD99 and a SIRP binding domain; or anti-TIM3 activity and a SIRP α binding domain. 1. An isolated polypeptide comprising:an immunoglobulin variable region fused to a sequence comprising a binding domain of SIRPα.2. The polypeptide of claim 1 , comprising:{'sub': 'L', 'a first and a second polypeptide chain, which first polypeptide chain comprises (i) a first domain comprising a binding region of a light chain variable domain of an immunoglobulin (V) specific for a first epitope; and'}{'sub': 'H', 'a second polypeptide comprising (i) a first domain comprising a binding region of a heavy chain variable region domain of an immunoglobulin (V) specific for a first epitope; and (ii) a second domain comprising the N-terminal Ig-like domain of SIRPα.'}3. The polypeptide of claim 1 , comprising:{'sub': 'L', 'a first and a second polypeptide chain, which first polypeptide chain comprises (i) a first domain comprising a binding region of a light chain variable domain of an immunoglobulin (V) specific for a first epitope; and (ii) a second domain comprising the N-terminal Ig-like domain of SIRPα; and'}{'sub': 'H', 'a second polypeptide comprising (i) a first domain comprising a binding region of a heavy chain variable region domain of an immunoglobulin (V) specific for a first epitope.'}4. The polypeptide of claim 1 , wherein the first polypeptide and the second polypeptide further ...

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Номер записи: 68
17-02-2022 дата публикации

POLYPEPTIDES AND POLYNUCLEOTIDES, AND USES THEREOF FOR TREATMENT OF IMMUNE RELATED DISORDERS AND CANCER

Номер: US20220048972A1
Автор: NOVIK Amit, Shemesh Ronen, TOPORIK Amir
Принадлежит:

This invention relates to LY6G6F, VSIG10, TMEM25 and LSR proteins, which are suitable targets for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders, and drug development. This invention further relates to soluble LY6G6F, VSIG10, TMEM25 and LSR molecules, extracellular domains of LY6G6F, VSIG10, TMEM25 and LSR and conjugates, which are suitable drugs for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders. This invention further relates to antibodies and antigen binding fragments and conjugates containing same, and/or alternative scaffolds, specific for LY6G6F, VSIG10, TMEM25 or LSR molecules, which are suitable drugs for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders. 1. A method for treating a subject in need thereof for cancer , the method comprising administering to the subject a monoclonal or polyclonal antibody or an antigen binding fragment thereof comprising an antigen binding site that binds specifically to an isolated polypeptide consisting essentially of an amino acid sequence as set forth in any one of SEQ ID NOs: 3 , 4 or 60.2. The method of claim 1 , wherein the treatment is combined with another moiety or therapy useful for treating cancer.3. The method of claim 2 , wherein the therapy is radiation therapy claim 2 , antibody therapy claim 2 , chemotherapy claim 2 , photodynamic therapy claim 2 , adoptive T cell therapy claim 2 , Treg depletion claim 2 , surgery or combination therapy with conventional drugs.4. The method of claim 2 , wherein the moiety is immunosuppressants claim 2 , cytotoxic drugs claim 2 , tumor vaccines claim 2 , antibodies peptides claim 2 , peptibodies claim 2 , small molecules claim 2 , chemotherapeutic agents or immunological modifiers.5. The method of claim 4 , wherein the chemotherapeutic agent is cytotoxic or cytostatic agents.6. The method of claim 5 , wherein the cytotoxic or cytostatic agent is ...

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Номер записи: 69
30-01-2020 дата публикации

COMPOSITIONS AND METHODS FOR INHIBITION OF LINEAGE SPECIFIC PROTEINS

Номер: US20200030381A1
Автор: BOLEN Joseph, Lydeard John, Radovic-Moreno Aleksandar Filip
Принадлежит: VOR BIOPHARMA, INC

Disclosed herein are compositions, methods, and kits for use in treating hematopoietic malignancies, the compositions, methods, and kits comprise a cytotoxic agent targeting cells expressing a lineage-specific cell-surface protein and a population of hematopoietic cells that express the lineage-specific cell-surface protein, the hematopoietic cells being manipulated such that they do not bind the cytotoxic agent. 1. A method of treating a hematopoietic malignancy , comprising administering to a subject in need thereof:(i) an effective amount of a cytotoxic agent targeting cells expressing a lineage-specific cell-surface protein, wherein optionally the cytotoxic agent comprises an antigen-binding fragment that specifically binds an epitope of the lineage-specific cell-surface protein; and(ii) a population of hematopoietic cells, wherein the hematopoietic cells are manipulated such that they or descendants thereof have reduced binding to the cytotoxic agent.2. The method of claim 1 , wherein the hematopoietic cells or the descendants thereof express the lineage-specific cell-surface protein and are manipulated genetically such that the lineage-specific cell-surface protein lacks the epitope to which the cytotoxic agent binds.3. The method of claim 2 , wherein the lineage-specific cell-surface protein expressed on the hematopoietic cell or the descendants thereof comprises a deletion of the epitope or alteration of one or more amino acid residues in the epitope to which the antigen-binding fragment in the cytotoxic agent binds.4. The method of claim 1 , wherein the hematopoietic cells express the lineage-specific cell surface protein and are manipulated by contacting the hematopoietic cells with a blocking agent that comprises the antigen-binding fragment claim 1 , and wherein the blocking agent binds the lineage-specific cell-surface protein and blocks its binding to the cytotoxic agent.5. The method of claim 4 , wherein the hematopoietic cells are incubated ex vivo ...

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Номер записи: 70
17-02-2022 дата публикации

COMPOSITIONS AND METHODS FOR THE TREATMENT AND/OR PREVENTION OF HER2+ CANCERS

Номер: US20220049015A1
Автор: Hartman Zachary, Lyerly Herbert
Принадлежит: Duke University

The present disclosure provides compositions and methods for the treatment of HER2 cancers in a subject. The present disclosure provides a combination therapy of a HER2 antibody and a CD47 antagonist. The method activate an anti-tumor response that comprises activating the antibody dependent cellular phagocytosis (ADCP) within the subject. 1. A method for treating a HER2/neu positive cancer in a subject in need thereof , the method comprising administering to the subject a therapeutically effective amount of a HER2 antibody comprising an IgG Fc portion capable of binding Fcγ-receptor (FCGR) and activating the antibody dependent cellular phagocytosis (ADCP) and a CD47 antagonist such that the cancer is treated in the subject.2. The method according to claim 1 , wherein the HER2 antibody is selected from the group consisting of trastuzumab claim 1 , trastuzumab-dsk claim 1 , MYL-1401O claim 1 , ado-trastuzumab emtansine claim 1 , pertuzumab and combinations thereof3. The method according to claim 2 , wherein the HER2 antibody is trastuzumab.4. The method of claim 1 , wherein the HER2 antibody has a high activating FcγR binding to inhibitory FcγR binding (A/I ratio) of greater than 1.5. The method of claim 1 , wherein the HER2 antibody has a human IgG1 Fc portion capable of activating the antibody dependent cellular phagocytosis (ADCP).6. The method of claim 1 , wherein the CD47 antagonist is selected from the group consisting of MIAP301 claim 1 , MIAP410 claim 1 , TTI-621 claim 1 , CV1 claim 1 , Hu5F9-G4 claim 1 , CC-90002 claim 1 , B6H12 claim 1 , 2D3 and combinations thereof.7. The method of claim 6 , wherein the CD47 antagonist is MIAP410.8. The method of in which the CD47 antagonist is administered prior to the HER2 antibody.9. The method of claim 1 , wherein the CD47 antagonist is administered concurrently with the HER2 antibody.10. The method of claim 1 , wherein the subject comprises a human.11. method of claim 1 , wherein the cancer comprises breast cancer.12. ...

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Номер записи: 71
17-02-2022 дата публикации

Methods of treating sensitized patients with hypoimmunogenic cells, and associated methods and compositions

Номер: US20220049226A1
Автор: Charles E. MURRY, Sonja SCHREPFER, Steve HARR
Принадлежит: Sana Biotechnology Inc

Disclosed herein are hypoimmunogenic cells for administering to a sensitized patient. In some instances, the patient is sensitized from a previous pregnancy or a previous transplant. In some embodiments, the cells exogenously express CD47 proteins and exhibit reduced expression of MHC class I proteins, MHC class II proteins, or both.

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Номер записи: 72
31-01-2019 дата публикации

Affinity maturated t cell receptors and use thereof

Номер: US20190031733A1
Автор: Esther Tzehoval, Rachel Lea Eisenbach, Yosi GOZLAN
Принадлежит: Yeda Research and Development Co Ltd

The present invention relates to methods and systems for increasing the affinity of a T cell receptor (TCR) to its ligand by subjecting the TCR gene to somatic hypermutation. The present invention further relates to use of affinity maturated TCRs to create T cells reactive against a selected antigen.

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Номер записи: 73
30-01-2020 дата публикации

THERAPEUTIC USE OF ANTI-CS1 ANTIBODIES

Номер: US20200031929A1
Автор: Landolfi Nicholas F., Liu Gao, Tso J. Yun, Williams Marna
Принадлежит:

The present invention is directed to antagonists of CS1 that bind to and neutralize at least one biological activity of CS1. The invention also includes a pharmaceutical composition comprising such antibodies or antigen-binding fragments thereof. The present invention also provides for a method of preventing or treating disease states, including autoimmune disorders and cancer, in a subject in need thereof, comprising administering into said subject an effective amount of such antagonists. 1. An antibody or an antigen-binding fragment thereof , wherein said antibody binds to CS1 and inhibits immunoglobulin secretion.2. The antibody or the antigen-binding fragment according to claim 1 , wherein said antibody inhibits the proliferation of leukocytes.3. The antibody or the antigen-binding fragment according to claim 1 , wherein said antibody inhibits the proliferation of cancer cells.4. The antibody or the antigen-binding fragment according to claim 1 , wherein said antibody triggers cytotoxic effects on cells expressing CS1 or enhances cytotoxicity mediated by immune cells.5. The antibody or antigen binding fragment of claim 4 , wherein said antibody triggers ADCC-mediated cytotoxicity of cells expressing CS1.6. The antibody or the antigen-binding fragment according to claim 1 , wherein said antibody binds to substantially the same eptitope as the antibody produced by a hybridoma cell line having ATCC accession number PTA-5091 or a Luc63 antibody.7. The antibody or antigen-binding fragment according to claim 1 , wherein said antibody is produced by a hybridoma cell line having ATCC accession number PTA-5091.8. The antibody or the antigen-binding fragment according to claim 1 , wherein said antibody is produced by a hybridoma cell line expressing Luc63 antibody.9. The antibody according to claim 1 , wherein said antibody is a monoclonal antibody.10. The antibody according to claim 9 , wherein said monoclonal antibody is a chimeric antibody claim 9 , a humanized ...

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Номер записи: 74
04-02-2021 дата публикации

Vista-ig for treatment of autoimmune, allergic and inflammatory disorders

Номер: US20210032317A1
Автор: Elizabeth Nowak, Isabelle LeMercier, Janet Lines, Randolph J. Noelle, Sabrina Ceeraz
Принадлежит: Dartmouth College, KINGS COLLEGE LONDON

The present invention relates to a fusion proteins comprising regulatory T cell protein, VISTA (V-domain Immunoglobulin Suppressor of T cell Activation (PD-L3) and an immunoglobulin protein (Ig). The invention also provides the use of VISTA polypeptides, multimeric VISTA polypeptides, VISTA-conjugates (e.g., VISTA-Ig), and VISTA antagonists for the treatment of autoimmune disease, allergy, and inflammatory conditions.

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Номер записи: 75
11-02-2016 дата публикации

High affinity pd-1 agents and methods of use

Номер: US20160039903A1
Автор: Aaron Michael RING, Aashish Manglik, Andrew KRUSE, Irving L. Weissman, Melissa N. MCCRACKEN, Roy Louis MAUTE, Sydney GORDON
Принадлежит: Leland Stanford Junior University

High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.

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Номер записи: 76
09-02-2017 дата публикации

Polypeptides and polynucleotides, and uses thereof as a drug target for producing drugs and biologics

Номер: US20170037141A1
Автор: Amir Toporik, Amit Novik, Anat Cohen-Dayag, Avi Rosenberg, Cynthia Koifman, Dalit Landesman-Milo, Eve Montia, Galit Rotman, Liat Dassa, Marina Bubis, Merav Beiman, Ofer Levy, Sergey Nemzer, Shira Walach, Shirley SAMEACH- GREENWALD, Tania Pergam, Yaron Kinar, Zurit Levine
Принадлежит: Compugen Ltd

This invention relates to a novel target for production of immune and non-immune based therapeutics and for disease diagnosis. More particularly, the invention provides therapeutic antibodies against VSIG1, ILDR1, LOC253012, AI216611, C1ORF32 or FXYD3 antigens, which are predicted co-stimulatory family members and which are differentially expressed in cancers including, lung cancer, ovarian cancer, and colon cancer, and diagnostic and therapeutic usages. The use of these antibodies for modulating B7 costimulation and related therapies such as the treatment of autoimmunity are also provided. This invention further relates to the discovery of extracellular domains of VSIG1 and its variants, FXYD3 and its variants, ILDR1 and its variants, LOC253012 and its variants, AI216611 and its variants, and C1ORF32 and its variants awhich are suitable targets for immunotherapy, cancer therapy, and drug development.

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Номер записи: 77
08-02-2018 дата публикации

USE OF THE CD2 SIGNALING DOMAIN IN SECOND-GENERATION CHIMERIC ANTIGEN RECEPTORS

Номер: US20180037625A1
Автор: JR. Avery D., June Carl H., Posey, Scholler John
Принадлежит:

The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell expressing a CAR having an antigen binding domain, a transmembrane domain, a CD2 signaling domain, and a CD3 zeta signaling domain. The invention also includes incorporating CD2 into the CAR to alter the cytokine production of CAR-T cells in both negative and positive directions. 19.-. (canceled)10. A cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR) , the CAR comprising an antigen binding domain , a transmembrane domain , a costimulatory signaling region , and a CD3 zeta signaling domain , wherein the costimulatory signaling domain comprises the CD2 signaling domain.11. The cell of claim 10 , wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 1.12. The cell of claim 10 , wherein the antigen binding domain is an antibody or an antigen-binding fragment thereof.13. The cell of claim 10 , wherein the antigen binding domain binds to a tumor antigen.14. The cell of claim 10 , wherein the costimulatory signaling region further comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27 claim 10 , CD28 claim 10 , 4-1BB claim 10 , OX40 claim 10 , CD30 claim 10 , CD40 claim 10 , PD-1 claim 10 , ICOS claim 10 , lymphocyte function-associated antigen-1 (LFA-1) claim 10 , CD7 claim 10 , LIGHT claim 10 , NKG2C claim 10 , B7-H3 claim 10 , a ligand that specifically binds with CD83 claim 10 , and any combination thereof.15. The cell of claim 14 , wherein the cell is selected from the group consisting of a T cell claim 14 , a Natural Killer (NK) cell claim 14 , a cytotoxic T lymphocyte (CTL) claim 14 , and a regulatory T cell.16. The cell of claim 10 , wherein the cell exhibits an anti-tumor immunity when the antigen binding domain binds to its corresponding antigen.1743.-. (canceled) This application is a divisional ...

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Номер записи: 78
07-02-2019 дата публикации

Cell

Номер: US20190038672A1
Автор: Cordoba Shaun, Kong Khai, Pulé Martin
Принадлежит:

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, and wherein each of the first and second CARs is an activating CAR comprising an activating endodomain. 1. A T cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface , each CAR comprising:(i) an antigen-binding domain;(ii) a spacer(iii) a trans-membrane domain; and(iv) an endodomain;wherein the first CAR binds CD19 and the second CAR binds CD20.24-. (canceled)5. A T cell according to which comprises more than two CARs such that it is specifically stimulated by a cell claim 1 , such as a target cell claim 1 , bearing a distinct pattern of more than two antigens.6. A nucleic acid sequence encoding first and second chimeric antigen receptors (CARs) each CAR comprising:(i) an antigen-binding domain;(ii) a spacer(iii) a trans-membrane domain; and(iv) an endodomain;wherein the first CAR binds CD19 and the second CAR binds CD20.7. A nucleic acid sequence according to claim 6 , which has the following structure:AgB1-spacer1-TM1-endo1-coexpr-AbB2-spacer2-TM2-endo2in whichAgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR;spacer 1 is a nucleic acid sequence encoding the spacer of the first CAR;TM1 is a a nucleic acid sequence encoding the transmembrane domain of the first CAR;endo 1 is a nucleic acid sequence encoding the endodomain of the first CAR;coexpr is a nucleic acid sequence enabling co-expression of both CARsAgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;spacer 2 is a nucleic acid sequence encoding the spacer of the second CAR;TM2 is a a nucleic acid sequence encoding the transmembrane domain of the second CAR; ...

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Номер записи: 79
24-02-2022 дата публикации

D-DOMAIN CONTAINING POLYPEPTIDES AND USES THEREOF

Номер: US20220056105A1
Автор: Hilbert David M., SWERS Jeffrey S.
Принадлежит:

D domain (DD) containing polypeptides (DDpp) that specifically bind targets of interest (e.g., BCMA, CD123, CS1, HER2, AFP, and AFP p26) are provided, as are nucleic acids encoding the DDpp, vectors containing the nucleic acids and host cells containing the nucleic acids and vectors. DDpp such as DDpp fusion proteins, are also provided as are methods of making and using the DDpp. Such uses include, but are not limited to diagnostic and therapeutic applications. 144-. (canceled)45. A protein comprising a D Domain (DD) target binding domain wherein the DD is a member selected from the group consisting of:(a) a DD that specifically binds BCMA and comprises the amino acid sequence of SEQ ID NO: 11-305, or 306;(b) a DD that specifically binds CD123 and comprises the amino acid sequence of SEQ ID NO: 307-739, or 740;(c) a DD that specifically binds AFP and comprises the amino acid sequence of SEQ ID NO: 741-874, or 886-895;(d) a DD that specifically binds AFP p26 and comprises the amino acid sequence of SEQ ID NO: 741-874, or 886-895;(e) a DD that specifically binds CS1 and comprises the amino acid sequence of SEQ ID NO: 896-909, or 910; and(f) a DD that specifically binds HER2 and comprises the amino acid sequence of SEQ ID NO: 911-949, or 950.46. The protein of wherein the DD is fused to a heterologous polypeptide.47. The protein of claim 46 , wherein the heterologous polypeptide comprises(a) a full-length antibody or an antibody fragment;(b) an Fc region;(c) the extracellular domain, or a fragment of an extracellular domain, of a receptor selected from the group consisting of: BCMA, CD123, CS1, and CD19;(d) a transmembrane domain;(e) a membrane associating domain;(f) human serum albumin or a fragment thereof;(g) AFP or a fragment thereof;(h) AFP p26 or a fragment thereof; and/or(i) the extracellular domain of a receptor or a fragment thereof.48. The protein of claim 45 , which is labeled and/or conjugated to a therapeutic or cytotoxic agent.49. A chimeric antigen ...

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Номер записи: 80
12-02-2015 дата публикации

Treatment methods using adenovirus

Номер: US20150044280A1
Автор: Andrea Leubitz, Erez Feige, Eyal Breitbart, Richard PENSON
Принадлежит: Vascular Biogenics Ltd

The invention provides methods of reducing or decreasing a size of a tumor or eliminating a tumor or inhibiting, decreasing, or reducing neo-vascularization or angiogenesis in a tumor in a patient by administering an adenovirus comprising a nucleic acid construct comprising a FAS-chimera gene operably linked to an endothelial cell-specific promoter. Also provided is a homogeneous population of an adenovirus comprising a FAS-chimera gene operably linked to an endothelial cell-specific promoter and its uses thereof.

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Номер записи: 81
06-02-2020 дата публикации

Medicine

Номер: US20200038508A1
Автор: Koji Tamada, Shun DOI, Tomoya Miyakawa
Принадлежит: Cytlimic Inc

The present invention provides a medicine comprising a Toll-like receptor agonist, LAG-3 protein, a variant or derivative thereof.

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Номер записи: 82
18-02-2021 дата публикации

GENETICALLY MODIFIED NON-HUMAN ANIMAL WITH HUMAN OR CHIMERIC LAG3

Номер: US20210045366A1
Автор: Bai Yang, Guo Chaoshe, Guo Yanan, Huang Rui, Shen Yuelei, Yao Jiawei, ZHANG MEILING, Zhao Lei
Принадлежит:

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) LAG3, and methods of use thereof. 1. A genetically-modified , non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a chimeric LAG3 , wherein the sequence comprises humanized LAG-3 exons 2-7 , and an endogenous LAG-3 exon 8.2. The animal of claim 1 , wherein the sequence encoding the chimeric LAG3 is operably linked to an endogenous regulatory element at the endogenous LAG3 gene locus in the at least one chromosome.3. The animal of claim 1 , wherein the chimeric LAG3 comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 44.4. The animal of claim 1 , wherein the chimeric LAG3 comprises an amino acid sequence that is identical to SEQ ID NO: 44.5. The animal of claim 1 , wherein the chimeric LAG3 consists of an amino acid sequence that is identical to SEQ ID NO: 44.6. The animal of claim 1 , wherein the chimeric LAG3 comprises a sequence that is at least 80% identical to amino acids 25-465 of SEQ ID NO: 4.7. The animal of claim 1 , wherein the animal is a rodent.8. The animal of claim 1 , wherein the animal is a mouse.9. The animal of claim 1 , wherein the animal does not express endogenous LAG3.10. The animal of claim 1 , wherein the animal has one or more cells expressing the chimeric LAG3.1112.-. (canceled)13. A genetically-modified claim 1 , non-human animal claim 1 , wherein the genome of the animal comprises a replacement of a nucleotide sequence comprising a contiguous sequence starting at exon 2 and ending at exon 7 of endogenous LAG3 with a nucleotide sequence comprising a contiguous sequence starting at exon 2 and ending at exon 7 of human LAG3 at an endogenous LAG3 gene locus.14. The animal of claim 13 , wherein the contiguous sequence of endogenous LAG3 starts from within exon 2 and ends within exon 7 claim 13 , wherein the contiguous sequence of human LAG3 starts from ...

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Номер записи: 83
06-02-2020 дата публикации

Ligands Modified by Circular Permutation as Agonists and Antagonists

Номер: US20200040053A1
Автор: Alvarez Juan C.
Принадлежит:

The present invention provides fusion polypeptides comprising polypeptide ligands that are modified by circular permutation and fused to at least one polypeptide fusion partner wherein such fusion polypeptides have new, improved or enhanced biological functions or activities. Such improvements include, but are not limited to, increased binding affinity, increased activity, increased agonist activity (super agonist), antagonist activity, increased accessibility, increased flexibility of the active site, increased stability, broader and/or changed substrate specificity, and combinations thereof. 115-. (canceled)16. A fusion polypeptide comprising a first polypeptide fusion partner linked to a modified ligand corresponding to all or a portion of a native ligand of a target receptor , wherein the modified ligand has been circularly permuted to create a new N-terminus and a new C-terminus as compared to the native ligand , wherein the new C-terminus and the new N-terminus of the modified ligand do not disrupt any binding domain of the modified ligand for the target receptor , wherein the modified ligand is circularly permuted IL-2 , the fusion partner is IL-2Rα and the target receptor is IL-2Rβγ , wherein the fusion polypeptide is optionally further fused to the Fc region of an antibody.17. The fusion polypeptide of claim 16 , wherein the modified ligand is a circularly permuted IL-2 having a C145S mutation.18. A pharmaceutical composition comprising the fusion polypeptide of .19. A pharmaceutical composition comprising the fusion polypeptide of .20. A method of selectively agonizing IL-2Rβγ on a cell comprising contacting the cell with a fusion polypeptide of .21. The method of claim 20 , wherein the fusion polypeptide is contacted with the cell extracorporeally.22. A method of selectively agonizing IL-2Rβγ on a cell comprising contacting the cell with a fusion polypeptide of .23. The method of claim 22 , wherein the fusion polypeptide is contacted with the cell ...

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Номер записи: 84
06-02-2020 дата публикации

SECRETABLE VARIANT IMMUNOMODULATORY PROTEINS AND ENGINEERED CELL THERAPY

Номер: US20200040059A1
Автор: KORNACKER Michael, SWANSON Ryan
Принадлежит: Alpine Immune Sciences, Inc.

Provided are immunomodulatory proteins, nucleic acids encoding such immunomodulatory proteins, cells engineered to express the immunomodulatory proteins and infections agents containing nucleic acid encoding the immunomodulatory proteins. In some embodiments, the immunomodulatory proteins are secretable. In some embodiments, the immunomodulatory proteins are transmembrane proteins that are surface expressed. The immunomodulatory proteins, engineered cells and infectious agents provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided. 1. An engineered immune cell comprising a nucleic acid molecule that encodes an immunomodulatory protein , wherein:the immunomodulatory protein comprises at least one non-immunoglobulin affinity-modified immunoglobulin superfamily (IgSF) domain comprising one or more amino acid substitutions in a wild-type IgSF domain of an IgSF family member, wherein the at least one affinity-modified IgSF domain specifically binds at least one cell surface cognate binding partner of the wild-type IgSF domain; andthe engineered immune cell expresses and secretes the immunomodulatory protein.2. The engineered immune cell of claim 1 , wherein the immunomodulatory protein does not comprise a transmembrane domain.3. The engineered immune cell of or claim 1 , wherein the nucleic acid molecule comprises a sequence encoding a secretory signal peptide operably linked to the sequence encoding the immunomodulatory protein.4. The engineered immune cell of claim 3 , wherein the signal peptide is the native signal peptide from the corresponding wild-type IgSF member.5. The engineered immune cell of claim 3 , wherein the signal peptide is a non-native signal sequence.6. The engineered immune cell of or claim 3 , wherein the signal peptide is an IgG-kappa signal peptide claim 3 , an IL-2 signal peptide claim 3 , or a CD33 signal peptide.7. The engineered immune cell ...

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Номер записи: 85
16-02-2017 дата публикации

NKT-LIKE CELL SUBPOPULATION AND METHOD OF USING THE SAME IN THE TREATMENT OF TUMOR

Номер: US20170042939A1
Автор: Zhang Minghui
Принадлежит: TSINGHUA UNIVERSITY

The disclosure discloses a kind of new NKT-like cell subpopulation, a therapeutical composition comprising the NKT-like cell subpopulation, and the medical use thereof. The disclosure also provides a preparation method of the NKT-like cell subpopulation. The disclosed NKT-like cell subpopulation has a strong antitumor effect, and can be adoptive transferred into a subject to treat the tumor in the subject after in vitro cultured and amplified. 1. An isolated NKT-like cell subpopulation , comprising NKT-like cells expressing CD8 , CD3 and TCRαβ , wherein the NKT-like cell subpopulation is isolated from a mammal subject.2. The NKT-like cell subpopulation according to claim 1 , comprising 50% or more claim 1 , preferably 60% or more claim 1 , more preferably 70% or more claim 1 , most preferably 80% or more of the NKT-like cells expressing CD8 claim 1 , CD3 and TCRαβ.3. The NKT-like cell subpopulation according to claim 1 , wherein the NKT-like cells further express CD56 claim 1 , but not Vα24 TCR.4. The NKT-like cell subpopulation according to claim 1 , wherein the NKT-like cells further express CD161c claim 1 , but not Vα14 TCR.5. The NKT-like cell subpopulation according to claim 1 , wherein the mammal is a species selected from the group consisting of bovidae claim 1 , equidae claim 1 , felidae claim 1 , canidae claim 1 , leporidae claim 1 , suidae claim 1 , camelidae claim 1 , rodent and primate claim 1 , preferably being a cattle claim 1 , a horse claim 1 , a dog claim 1 , a goat claim 1 , a sheep claim 1 , a pig claim 1 , a camel claim 1 , a rat claim 1 , a mouse claim 1 , a monkey or a human.6. A therapeutical composition comprising mammal NKT-like cells expressing CD8 claim 1 , CD3 and TCRαβ as a main active ingredient claim 1 , and a pharmaceutical acceptable carrier claim 1 , diluent claim 1 , excipient claim 1 , and/or additive.7. The composition according to claim 6 , wherein the NKT-like cells further express CD56 claim 6 , but not Vα24 TCR.8. The ...

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Номер записи: 86
16-02-2017 дата публикации

USE OF CTLA4 COMPOUND FOR ACHIEVING DRUG-FREE REMISSION IN SUBJECTS WITH EARLY RA

Номер: US20170042972A1
Автор: KARYEKAR Chetan
Принадлежит:

The present invention is directed to methods and compositions for achieving drug-free remission in subjects with early RA by administering to a subject in need thereof an effective amount of soluble CTLA4 molecule until Disease Activity Score Calculator for Rheumatoid Arthritis (DAS)-defined remission is achieved and then withdrawing the RA therapy. 2. The method of further comprising an amino acid sequence which alters the solubility or affinity of the CTLA4 molecule.3. The method of claim 2 , wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin.4. The method of claim 3 , wherein the immunoglobulin is an immunoglobulin constant region or portion thereof.5. The method of claim 4 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.6. The method of claim 4 , wherein the immunoglobulin constant region or portion thereof comprises a hinge claim 4 , CH2 and CH3 regions of a human or monkey immunoglobulin molecule.7. The method of claim 5 , wherein the immunoglobulin constant region or portion thereof comprises a hinge claim 5 , CH2 and CH3 regions of a human or monkey immunoglobulin molecule.8. A method for achieving drug free remission in subjects with early rheumatoid arthritis comprisingi) administering to the subject an effective amount of CTLA4 molecule or pharmaceutical composition thereof, comprising an amino acid sequence beginning with methionine at position 27 or alanine at position 26 and ending with lysine at position 383 of SEQ ID NO:2 until DAS-defined remission is achieved, andii) withdrawing all RA therapy.9. The method of or claim 5 , wherein DAS-defined remission is characterized as DAS28 (C-reactive protein[CRP]) less than 2.6 after 12 months of treatment.10. The method of or claim 5 , wherein the CTLA4 pharmaceutical composition is a subcutaneous formulation administered at 125 mg/week subcutaneously.11. The method of or claim 5 , wherein early RA is ...

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Номер записи: 87
15-02-2018 дата публикации

INHIBITORY CHIMERIC ANTIGEN RECEPTORS

Номер: US20180044399A1
Автор: Juillerat Alexandre, Pertel Thomas Charles, POIROT Laurent, Potluri Shobha Chowdary, RAJPAL ARVIND, Sasu Barbra Johnson, STONE Donna Marie
Принадлежит:

The invention relates to an inhibitory chimeric antigen receptor (N-CAR) comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain, and, an intracellular domain wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TXYXXX, wherein Xis an amino acid Xis an amino acid Xis an amino acid and Xis V or 1. An inhibitory chimeric antigen receptor (N-CAR) comprisingan extracellular domain comprising an antigen binding domain,a transmembrane domainan intracellular domain{'sub': 1', '2', '3', '4, 'wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TXYXXX,'}wherein{'sub': '1', 'Xis an amino acid'}{'sub': '2', 'Xis an amino acid'}{'sub': '3', 'Xis an amino acid and'}{'sub': '4', 'Xis V or I.'}2. The N-CAR according to claim 1 , wherein the intracellular domain is not the intracellular domain of human PD-1 claim 1 , human CD244 or human BTLA.3. The N-CAR according to claim 1 , wherein the intracellular domain comprises the sequence{'sup': n', 'm', 'p, '((L1-ITIM-L2)-(L3-ITSM-L4)), wherein'}n is 0, 1 or an integer greater than 1;m is 1 or an integer greater than 1;p is 1 or an integer greater than 1; (a) a naturally occurring N-terminal flanking region of ITIM only intracellular domains selected from the sequences shown in Table 3 or a fragment thereof;', '(b) a naturally occurring N-terminal flanking region of ITIM.*ITSM intracellular selected from the sequences shown in Table 1 or a fragment thereof;', '(c) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in Table 2 or a fragment thereof, wherein said intracellular domain is N-terminally flanking to a sequence in (b) above, or a fragment thereof; and', '(d) a non-naturally occurring sequence comprising between 1 and 500 amino acids;, 'L1 is absent or ...

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Номер записи: 88
15-02-2018 дата публикации

IMMUNOMODULATORY FUSION PROTEINS AND USES THEREOF

Номер: US20180044404A1
Автор: Greenberg Philip D., Oda Shannon K., Schmitt Thomas M.
Принадлежит:

The present disclosure relates to immunomodulatory fusion proteins containing an extracellular binding domain and an intracellular signaling domain, wherein binding of a target can generate a modulatory signal in a host cell, such as a T cell. The present disclosure also relates to uses of immune cells expressing such immunomodulatory fusion proteins to treat certain diseases, such as cancer or infectious disease. 1. A fusion protein , comprising (a) an extracellular component comprised of a binding domain that specifically binds a target , (b) an intracellular component comprised of an intracellular signaling domain , and (c) a hydrophobic component connecting the extracellular and intracellular components ,wherein the extracellular portion of a complex formed by specific binding of the fusion protein to the target (fusion protein::target complex) is of a size, or spans a distance, of (i) up to about a distance between two cell membranes of an immunological synapse, (ii) up to about or substantially the same as a distance spanned by the extracellular portion of a complex between a T cell receptor (TCR) and an MHC-peptide complex specifically bound by the TCR, (iii) up to about or substantially the same as a distance spanned by the extracellular portion of a complex between a natural molecule comprising the binding domain and its cognate binding partner; (iii) less than or up to about 40 nm, 25 nm, 20 nm, 15 nm, or 14 nm; or (iv) any combination thereof.2. The fusion protein according to claim 1 , wherein the fusion protein::target complex localizes to a supramolecular activation cluster (SMAC).3. The fusion protein according to or claim 1 , wherein the fusion protein::target complex localizes to a central region supramolecular activation cluster (cSMAC).4. The fusion protein according to or claim 1 , wherein the SMAC has a width of a T cell receptor (TCR) associated with an antigen::human leukocyte antigen (HLA) complex.5. The fusion protein according to any one of ...

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Номер записи: 89
19-02-2015 дата публикации

HUMAN SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (sRAGE), METHODS OF PREPARING HUMAN sRAGE, AND TREATMENT METHODS USING sRAGE

Номер: US20150051136A1
Автор: Lakatta Edward G., LIN Li, Park Sungha, Talan Mark I., Wei Wen, Xiao Rui-Ping
Принадлежит:

The present disclosure provides a method for recombinant production of human sRAGE in mammalian cells, as well as a human sRAGE having a mammalian post-translational modification and compositions thereof. The present disclosure also provides a method of treating a vascular disease, injury, or inflammation in a mammal by administering to a mammal with a vascular disease, injury, or inflammation a composition comprising human sRAGE having a mammalian post-translational modification, thereby treating the vascular disease, injury, or inflammation in the mammal. 1. A method of treating a vascular disease , injury or inflammation in a mammal , comprising administering to the mammal an isolated human soluble receptor for advanced glycation end products (sRAGE) polypeptide , thereby treating the vascular disease , injury , or inflammation in the mammal.2. The method of claim 1 , wherein the mammalian post-translational modification comprises a modification selected from the group consisting of mammalian glycosylation claim 1 , mammalian phosphorylation claim 1 , mammalian sulfation claim 1 , mammalian carboxylation claim 1 , mammalian hydroxylation claim 1 , mammalian acetylation claim 1 , mammalian myristoylation claim 1 , mammalian farnesylation claim 1 , mammalian ADP ribosylation claim 1 , mammalian disulfide formation claim 1 , and mammalian SUMOylation.3. (canceled)4. The method of claim 1 , wherein the mammalian post-translational modification comprises a mammalian N-glycan profile.5. The method of claim 1 , wherein the mammal has a vascular disease claim 1 , and the vascular disease comprises atherosclerosis or restenosis.6. The method of claim 1 , wherein the mammal has a vascular injury claim 1 , and the vascular injury comprises acute myocardial infarction claim 1 , angioplasty or traumatic injury.7. The method of claim 1 , wherein the mammal has vascular inflammation.8. The method of claim 1 , wherein the sRAGE polypeptide is administered within about 1 hour ...

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Номер записи: 90
19-02-2015 дата публикации

Chimeric antigen receptors targeting b-cell maturation antigen

Номер: US20150051266A1
Автор: James Noble KOCHENDERFER
Принадлежит: US Department of Health and Human Services

The invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The invention also provides host cells, such as T-cells or natural killer (NK) cells, expressing the CAR and methods for destroying multiple myeloma cells.

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Номер записи: 91
25-02-2016 дата публикации

Non-human animals having a humanized signal-regulatory protein gene

Номер: US20160050896A1
Автор: Andrew J. Murphy, Bindu Varghese, Cagan Gurer, O. Gavin Thurston
Принадлежит: Regeneron Pharmaceuticals Inc

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus.

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Номер записи: 92
14-02-2019 дата публикации

Compositions and Methods for Recombinant CXADR Expression

Номер: US20190046570A1
Автор: NIAZI Kayvan, RABIZADEH Shahrooz, Soon-Shiong Patrick
Принадлежит:

Recombinant expression of CXADR in a cell, and especially an immune competent cell is employed to enable or improve gene delivery to the cell by an adenovirus. In particularly preferred aspects, the immune competent cell is a an NK cell, a T-cell, a B-cell, a macrophage, or a dendritic cell, and the gene delivery comprises a recombinant nucleic acid encoding a disease-specific antigen, such as a patient specific neoepitope or a tumor associated antigen. 1. A method of modifying an immune competent cell , comprising:introducing into the immune competent cell a recombinant nucleic acid encoding CXADR to produce a modified immune competent cell, wherein the immune competent cell is an NK cell, a T-cell, a B-cell, a macrophage, or a dendritic cell;cultivating the modified immune competent cell to a desired quantity in a first medium under conditions to express the CXADR; andreplacing the first medium with a second medium suitable for administration of the modified immune competent cell to a mammal.24-. (canceled)5. The method of claim 1 , wherein the recombinant nucleic acid encoding CXADR is under the control of a hypoxia inducible promoter.6. The method of further comprising a step of infecting the modified immune competent cell with a recombinant adenovirus.7. The method of wherein the recombinant adenovirus has an E2b deletion and includes a recombinant nucleic acid that encodes at least one of a neoepitope claim 6 , a co-stimulatory molecule claim 6 , a cytokine claim 6 , and a checkpoint inhibitor.8. The method of further comprising a step of administering the modified immune competent cell to a patient claim 6 , and wherein the step of infecting is performed in vivo after administration of the modified immune competent cell to the patient claim 6 , or further comprising a step of administering the modified immune competent cell to a patient claim 6 , wherein the step of infecting is performed in vitro before administration of the modified immune competent cell to ...

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Номер записи: 93
03-03-2022 дата публикации

EXPRESSION OF NOVEL CELL TAGS

Номер: US20220064609A1
Автор: Emtage Peter, SHAH Rutul, YARLAGADDA Ramya
Принадлежит: PRECIGEN, INC.

Disclosed herein are polynucleotides encoding cell tags for use in immunotherapeutic applications, and systems comprising polynucleotide cell tags for regulating the activity of a cell. The compositions, methods and systems described herein provide tools for regulating activity of genetically engineered cells in a subject. 1138-. (canceled)139. A method of regulating activity of a genetically engineered cell in a subject comprising providing to the subject a genetically engineered cell encoding a cell surface polypeptide and a trans-membrane dimerization domain , wherein: the trans-membrane dimerization domain induces dimerization of the cell surface polypeptide; and the cell surface polypeptide binds a predetermined antibody or a variant or fragment thereof.140. The method of claim 139 , wherein the cell surface polypeptide comprises at least one of a HER1 polypeptide claim 139 , a LNGFR polypeptide claim 139 , a CD20 polypeptide claim 139 , a CD52 polypeptide claim 139 , or a variant or fragment thereof.141. The method of claim 139 , wherein the trans-membrane dimerization domain comprises a glycophorin A transmembrane domain or fragment or variant thereof claim 139 , a glycophorin A-integrin β3 chimeric transmembrane domain or fragment or variant thereof claim 139 , a CD3 zeta transmembrane domain claim 139 , or a CD28 transmembrane domain or fragment or variant thereof.142. The method of claim 140 , wherein the cell surface polypeptide comprises at least a HER1 polypeptide claim 140 , or a variant or fragment thereof.143. The method of claim 139 , wherein the genetically engineered cell further comprises a Sleeping Beauty transposase.144. The method of claim 139 , wherein the genetically engineered cell further expresses at least one of a chimeric antigen receptor (CAR) claim 139 , a T-cell receptor (TCR) claim 139 , and a recombinant cytokine.145. A method of regulating activity of a genetically engineered cell in a subject comprising providing to the subject a ...

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Номер записи: 94
25-02-2021 дата публикации

TREATMENT OF INFECTION BY HUMAN ENTEROVIRUS D68

Номер: US20210052708A1
Автор: Moss Ronald B.
Принадлежит:

The present disclosure provides compositions and methods for treating an infection by EV-D68. In particular, the present disclosure provides methods that entail administering agents having an anchoring domain that anchors the compound to the surface of a target cell, and a sialidase domain that can act extracellularly to inhibit infection of a target cell by EV-D68. 1. A method of treating infection by EV-D68 in a patient , the method comprising administering to the patient an effective amount of DAS 181.223.-. (canceled) Human enterovirus D68 (EV-D68) (species, Human enterovirus D; genus, Enterovirus; family, Picornaviridae) can cause severe respiratory tract infections. It was rarely identified in patients in the United States prior to about 2005. However, since the late 2000s, the number of reported EV-D68 cases increased dramatically in in various countries. Some EV-D68 infections are characterized by severe disease, requiring intensive care and non-invasive ventilatory support. A 2014 EV-D68 outbreak particularly affected children with a history of asthma or reactive airway disease; and exacerbation of pre-existing asthma or reactive airway disease, similar to that associated with rhinovirus (RV) infection was noted in a high proportion of cases, though some patients with no history of asthma also had asthma-like symptoms (Midgley et al., 201463:798-799).The present disclosure provides compositions and methods for treating EV-D68 infection and disorders associated with EV-D68 infection. Specifically, it provides compounds which can act extracellularly to reduce (e.g., reduce the risk of) or prevent infection of a cell by EV-D68 and method of treatment employing such compounds. Some preferred embodiments of the disclosure include therapeutic compounds having an anchoring domain that facilitates association of the compound with the surface of a target cell and a sialidase domain that can act extracellularly to reduce or prevent infection of the target cell by a ...

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Номер записи: 95
14-02-2019 дата публикации

PSEUDOTYPED ONCOLYTIC VIRAL DELIVERY OF THERAPEUTIC POLYPEPTIDES

Номер: US20190048082A1
Автор: EVNIN Luke
Принадлежит:

Described herein are pseudotyped oncolytic viruses comprising nucleic acids encoding an engager molecule. In some embodiments, the pseudotyped oncolytic viruses comprises nucleic acids encoding an engager molecule and one or more therapeutic molecules. Pharmaceutical compositions containing the pseudotyped oncolytic virus and methods of treating cancer using the pseudotyped oncolytic viruses are further provided herein. 112.-. (canceled)13. An oncolytic herpes simplex virus (HSV) comprising a recombinant nucleic acid comprising:i) a first nucleic acid sequence encoding a polypeptide comprising a first domain specific for an antigen expressed on an effector cell and a second domain that binds to an antigen expressed on a target cell, wherein the antigen expressed on the effector cell is CD3 and wherein the antigen expressed on the target cell is PDL1 or CD47; andii) a second nucleic acid sequence encoding an immune modulator polypeptide selected from the group consisting of a cytokine, a costimulatory molecule, an immune checkpoint polypeptide, an anti-angiogenesis factor, and a matrix metalloprotease (MMP).14. The oncolytic HSV of claim 13 , wherein the first and second nucleic acid sequences are expressed from a single promoter sequence present in the recombinant nucleic acid.15. The oncolytic HSV of claim 13 , wherein the first and second nucleic acids have a size of 7.2-38 kb.16. The oncolytic HSV of claim 13 , wherein the HSV is HSV-1.17. The oncolytic HSV of claim 13 , wherein the immune modulator polypeptide is a cytokine selected from IL-15 claim 13 , IL-12 claim 13 , and CXCL10.18. The oncolytic HSV of claim 13 , wherein one or more the HSV glycoproteins are modified to alter the trophism of the oncolytic HSV.19. An oncolytic herpes simplex virus (HSV) comprising a recombinant nucleic acid comprising:i) a first nucleic acid sequence encoding a polypeptide comprising a first domain specific for an antigen expressed on an effector cell and a second domain that ...

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Номер записи: 96
25-02-2016 дата публикации

HIGH AFFINITY PD-1 AGENTS AND METHODS OF USE

Номер: US20160052990A1
Автор: Gordon Sydney, Kruse Andrew, Manglik Aashish, Maute Roy Louis, McCracken Melissa N., Ring Aaron Michael, Weissman Irving L.
Принадлежит:

High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2. 1. A high affinity PD-1 mimic polypeptide , wherein the polypeptide is a variant of a wild-type PD1 sequence , which:(a) lacks the PD-1 transmembrane domain, and(b) comprises one or more amino acid changes relative to a corresponding sequence of the wild type PD-1 polypeptide, wherein the one or more amino acid changes increases the affinity of the polypeptide for PD-L1 as compared to the affinity for PD-L1 of the corresponding wild type PD-1 polypeptide.2. The high affinity PD-1 mimic polypeptide of claim 1 , wherein the PD-1 mimic polypeptide has a Kof 1×10M or less for PD-L1.3. The high affinity PD-1 mimic polypeptide of claim 1 , wherein the one or more amino acid changes is located at an amino acid position of PD-1 that contacts PD-L1.4. The high affinity PD-1 mimic polypeptide of claim 3 , wherein the one or more amino acid changes is located at an amino acid position claim 3 , relative to the PD-1 protein fragment set forth in SEQ ID NO: 2 claim 3 , selected from: V39 claim 3 , N41 claim 3 , Y43 claim 3 , M45 claim 3 , S48 claim 3 , N49 claim 3 , Q50 claim 3 , T51 claim 3 , D52 claim 3 , K53 claim 3 , A56 claim 3 , Q63 claim 3 , G65 claim 3 , Q66 claim 3 , L97 claim 3 , S102 claim 3 , L103 claim 3 , A104 claim 3 , P105 claim 3 , K106 claim 3 , and A107; or the corresponding amino acid position relative to another wild type PD-1 protein.5. The high affinity PD-1 mimic polypeptide of claim 1 , wherein the one or more amino acid changes is ...

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Номер записи: 97
22-02-2018 дата публикации

Dendrimer Conjugates for Coating Cells

Номер: US20180050111A1
Автор: Daftarian Pirouz, Daunert Sylvia, Deo Sapna, LIU Zhao-Jun, Velazquez Omaida
Принадлежит:

The present invention provides dendrimer conjugates. The present invention provides a composition comprising a dendrimer conjugate and a cell, such as a cell covered with dendrimer conjugates, in which dendrimer conjugates home the cell to a target tissue. 140.-. (canceled)41. A method for promoting ocular tissue repair in a subject in need thereof comprising administering to the subject a composition comprising a conjugate comprising a dendrimer conjugated to a cell adhesion molecule (CAM) , wherein the CAM is an immunoglobulin superfamily CAM (IgSF CAM) , addressin , integrin , cadherin or selectin.42. The method of claim 41 , wherein the composition further comprises a cell claim 41 , wherein the cell is coated with the conjugate.43. The method of claim 42 , wherein the cell is a bone-marrow-derived mononuclear cell (BMC).44. The method of claim 41 , wherein the CAM is selectin.45. The method of claim 41 , wherein the dendrimer is a poly(amidoamine) (PAMAM) dendrimer.46. The method of claim 45 , wherein the PAMAM dendrimer is of generation 2 to 10.47. The method of claim 45 , wherein the PAMAM dendrimer is of generation 5.48. The method of claim 41 , wherein the composition further comprises a pharmaceutically acceptable carrier.49. The method of claim 41 , wherein the composition is administered intraocularly claim 41 , intravenously claim 41 , subcutaneously claim 41 , intraperitoneally or topically.50. The method of claim 41 , wherein the composition is administered by grafting or transplantation.51. The method of claim 41 , wherein the composition is a gel claim 41 , matrix or liquid.52. The method of claim 41 , wherein the ocular tissue repair comprises neovascularization.53. The method of claim 41 , wherein the ocular tissue is corneal tissue.54. The method of claim 49 , wherein the intraocular administration comprises intravitreal claim 49 , subconjunctival or subtenon injection. This application claims priority to and the benefit of U.S. Provisional ...

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Номер записи: 98
25-02-2021 дата публикации

AFFINITY LIGANDS FOR ANTIBODY FC REGION

Номер: US20210054042A1
Автор: Bratkovic Tomaz, Kruljec Nika, Lunder Mojca, Molek Peter
Принадлежит:

The present invention relates to ligand that may be a peptide compound as well as peptoid or retro-inverso analogues thereof with binding affinity for the Fc region of immunoglobulins. The invention further relates to the application of such peptides and variants thereof for purification of immunoglobulins on the basis of affinity chromatography, non-covalent antibody labelling, antibody detection or immobilization of antibodies to solid support. 142.-. (canceled)44. The ligand of claim 43 , wherein Xis not present.45. The ligand of claim 43 , wherein Xis present.46. The ligand of claim 45 , wherein Xis G.47. The ligand of claim 43 , wherein Xis not present.48. The ligand of claim 43 , wherein Xis present.49. The ligand of claim 48 , wherein Xis S claim 48 , T claim 48 , C claim 48 , N or K.50. The ligand of claim 43 , wherein Xis Y claim 43 , W or F.51. The ligand of claim 43 , wherein Xis W claim 43 , Y or F.52. The ligand of claim 43 , wherein Xis Y claim 43 , W or F.53. The ligand of claim 43 , wherein Xis A claim 43 , D claim 43 , E claim 43 , N claim 43 , Q or K.54. The ligand of claim 43 , wherein Xis V claim 43 , A claim 43 , K claim 43 , C claim 43 , I claim 43 , L or M.55. The ligand of claim 43 , wherein Xis W claim 43 , Y or F.56. The ligand of claim 43 , wherein Xis F claim 43 , W or Y.57. The ligand of claim 43 , wherein the ligand comprises an amino acid sequence having at least 60% claim 43 , such as at least 70% claim 43 , sequence identity with any one of the amino acid sequences SEQ ID NO: 2 to SEQ ID NO: 173.58. The ligand of claim 43 , wherein the ligand consists of any one of the amino acid sequences SEQ ID NO: 2 to SEQ ID NO: 173.59. A retro-inverso analogue or peptidomimetic of the ligand of .60. A solid phase support claim 43 , on which the ligand of is immobilized.61. A method for purifying immunoglobulins or Fc region-containing proteins thereof in a sample claim 43 , comprising the steps a) to c):{'claim-ref': {'@idref': 'CLM-00043', ' ...

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Номер записи: 99
25-02-2021 дата публикации

MODULATION OF SLAMF6 SPLICE VARIANTS FOR CANCER THERAPY

Номер: US20210054043A1
Автор: HAJAJ Emma, Lotem Michal, MISHAN EISENBERG Galit
Принадлежит:

The invention relates to cancer immunotherapy, particularly to improved therapeutic modalities involving specifically modulating the expression and/or activity of SLAMF6 splice variants. More specifically, embodiments of the invention provide compositions and methods for cancer therapy, including adoptive T cell transfer therapies, cell vaccines and/or polypeptide- based medicaments. In various embodiments, compositions and methods providing selective augmentation of SLAMF6 variant 3 (SLAMF6) N expression or activity on T cells and/or tumor cells are provided. 143-. (canceled)44. A therapeutic cell composition comprising a cell population engineered to express preferentially SLAMF6.45. The composition of claim 44 , selected from the group consisting of: an adoptive transfer T cell composition claim 44 , a tumor cell vaccine claim 44 , and a dendritic cell (DC) vaccine.46. The composition of claim 45 , wherein the cell population is a human T cell population.47. The composition of claim 45 , wherein the cell population is a human melanoma cell population and the cell vaccine is a tumor cell vaccine.48. The composition of claim 45 , wherein the cell population has been engineered to selectively down-regulate SLAMF6expression.49. The composition of claim 45 , wherein the cell population has been engineered to selectively up-regulate SLAMF6expression.50. The composition of claim 45 , wherein the cell population has been engineered to express SLAMF6exogenously.51. A method for treating cancer in a human subject in need thereof claim 45 , comprising administering to the subject T cells engineered to express preferentially SLAMF6 claim 45 , or a cell vaccine comprising a cell population engineered to express preferentially SLAMF6.52. The method of claim 51 , wherein the T cells have been engineered to selectively up-regulate SLAMF6expression and/or to selectively down-regulate SLAMF6expression.53. The method of claim 51 , comprising administering to the subject T cells ...

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Номер записи: 100