КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИЗБИРАТЕЛЬНОЙ ЭКСПРЕССИИ БЕЛКА

Изобретение относится к области биотехнологии, конкретно к получению слитых белков, и может быть использовано в медицине для лечения рака в присутствии стабилизирующего соединения. Рекомбинантным путем получают слитые белки, содержащие домен условной экспрессии, домен, содержащий интересующий белок, и расщепляемый протеазой домен, разделяющий эти два домена. Изобретение позволяет получить слитые белки, отличающиеся контролируемой экспрессией в зависимости от присутствия стабилизирующего соединения в среде. 9 н. и 59 з.п. ф-лы, 47 ил., 24 табл., 29 пр.

КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИММУНОТЕРАПИИ

Настоящее изобретение относится к иммунологии. Предложена Т-клетка, содержащая химерный рецептор антигена (CAR) и химерный костимулирующий рецептор (CCR), а также способ получения такой клетки. Описаны способы индукции гибели клеток опухоли, лечения и предотвращения неоплазмы, фармацевтическая композиция и набор для иммунотерапии. Связывание CCR с антигеном обеспечивает доставку костимулирующего сигнала к Т-клетке, что обеспечивает более высокую степень цитолитической активности. 7 н. и 44 з.п. ф-лы, 6 ил., 1 табл., 1 пр.

ЛЕЧЕНИЕ РАКА С ПОМОЩЬЮ ГУМАНИЗИРОВАННОГО АНТИ-CD19 ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА

Настоящее изобретение относится к области иммунологии. Предложены выделенная молекула нуклеиновой кислоты, кодирующая анти-CD19 химерный антигенный рецептор, выделенная молекула анти-CD19 химерный антигенный рецептор, а также гуманизированный анти-CD19-связывающий домен. Кроме того, рассмотрен вектор, клетки, способ получения клетки, способ получения популяции клеток, способ создания противоопухолевого иммунитета и способ лечения. Также описаны выделенные молекулы нуклеиновой кислоты, кодирующие анти-CD19 CAR. Данное изобретение может найти дальнейшее применение в терапии различных пролиферативных заболеваний, ассоциированных с экспрессией CD19, в частности рака. 15 н. и 68 з.п. ф-лы, 12 ил., 6 табл., 6 пр.

МЕЧЕНЫЕ ХИМЕРНЫЕ ЭФФЕКТОРНЫЕ МОЛЕКУЛЫ И ИХ РЕЦЕПТОРЫ

Группа изобретений относится к гибридным белкам, содержащим кассету с Strep-меткой и к меченым химерным эффекторным молекулам, меченым химерным молекулам антигенных рецепторов, рекомбинантным клеткам-хозяевам, продуцирующим такие гибридные белки. Одноцепочечный гибридный белок для активации и стимулирования пролиферации Т-клеток содержит трансмембранный домен, расположенный между внеклеточным компонентом и внутриклеточным компонентом, содержащим эффекторный домен. Внеклеточный компонент содержит домен связывания, который специфически связывает мишень, множество меток и соединительную область, содержащую шарнир. Множество меток содержит от двух до пяти меток и по меньшей мере две из множества меток содержат Strep-метку. Рекомбинантные клетки-хозяева, продуцирующие такие гибридные белки, можно идентифицировать, отделить, отсортировать, вызвать пролиферацию, отследить, устранить и/или использовать в качестве терапевтического средства в адоптивной иммунотерапии. Изобретения позволяют в значительной ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР (CAR) ПРОТИВ CD123 ДЛЯ ИСПОЛЬЗОВАНИЯ В ЛЕЧЕНИИ ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ

Настоящее изобретение относится к иммунологии. Предложены CD123-связывающий домен, содержащий его химерный антигенный рецептор (CAR) и кодирующая рецептор нуклеиновая кислота. Также рассмотрены вектор экспрессии, экспрессирующая CAR клетка и популяция таких клеток, способы их получения. Кроме того, описаны способы обеспечения противоопухолевого иммунитета, лечения млекопитающего, профилактики CD19-отрицательного рецидива, уменьшения или истощения экспрессирующих CD123 CAR клеток после терапии CAR, а также способ воздействия на индивидуум клетками по настоящему изобретению с целью подготовки к трансплантации. Данное изобретение может найти дальнейшее применение в терапии CD123-ассоциированных заболеваний. 14 н. и 87 з.п. ф-лы, 75 ил., 17 табл., 2 пр.

ОПУХОЛЕСПЕЦИФИЧНОЕ АНТИТЕЛО ПРОТИВ EGFR И ЕГО ПРИМЕНЕНИЕ

Изобретение относится к области биотехнологии. Описана группа изобретений, включающая антитело, специфически распознающее экспрессируемый опухолевыми клетками EGFRvIII или сверхэкспрессируемый EGFR, нуклеиновую кислоту, кодирующую вышеуказанное антитело, вектор экспрессии, клетку-хозяин, применение антитела для получения направленно действующего лекарственного средства, специфически направленного на опухолевые клетки, применение антитела для получения конъюгата антитела с лекарственным средством, специфически направленного на опухолевые клетки, применение антитела для получения многофункционального антитела, специфически направленного на опухолевые клетки, применение антитела для получения средства для диагностики опухолей, применение антитела для получения иммунной клетки, модифицированной химерным антигенным рецептором, иммуноконъюгат (варианты), применение иммуноконъюгата для получения средства против опухолей, применение иммуноконъюгата для получения средства для диагностики опухолей ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР

Настоящее изобретение относится к иммунологии. Предложен химерный антигенный рецептор (CAR), который содержит дисиалоганглиозид (GD2)-связывающий домен. Кроме того, представлены нуклеиновая кислота, кодирующая CAR по изобретению; вектор экспрессии; Т-клетки и способ получения Т-клетки. Также описаны фармацевтическая композиция, способ лечения злокачественной опухоли и применение T-клетки в получении лекарственного средства для лечения злокачественной опухоли. Предложенный CAR обеспечивает увеличенное продуцирование INF-γ, пролиферацию CAR-T-клеток и уничтожение клеток нейробластомы по сравнению с CAR на основе антитела 14g2a. Данное изобретение может найти дальнейшее применение в терапии. 9 н. и 17 з.п. ф-лы, 15 ил., 10 пр.

ИММУНОМОДУЛИРУЮЩИЕ СЛИТЫЕ БЕЛКИ И ПУТИ ИХ ПРИМЕНЕНИЯ

Изобретение относится к области биотехнологии, конкретно к слитому белку, связывающемуся с CD47 для передачи костимулирующего сигнала CD28 Т-клетке, и может быть использовано в медицине. Слитый белок, состоящий из CD47-связывающей части SIRPα, трансмембранной части CD28 и сигнального домена костимулирующей молекулы CD28, может быть использован для создания Т-клеток для эффективной иммунотерапии рака, экспрессирующего CD47. 9 н. и 42 з.п. ф-лы, 13 ил., 13 пр.

ЛЕЧЕНИЕ РАКА С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО АНТИГЕНСПЕЦИФИЧЕСКОГО РЕЦЕПТОРА НА ОСНОВЕ ГУМАНИЗИРОВАННОГО АНТИТЕЛА ПРОТИВ EGFRvIII

Настоящее изобретение относится к иммунологии. Предложен связывающий домен против EGFRvIII, содержащий его химерный антигенный рецептор, кодирующие нуклеиновые кислоты, вектор, клетка, а также применения указанных изобретений в производстве лекарственного средства, способы создания клетки и получения популяции клеток, способ обеспечения иммунитета, способ лечения. Данное изобретение может найти дальнейшее применение в терапии с использованием адоптивного переноса клеток. 22 н. и 81 з.п. ф-лы, 18 ил., 9 пр., 2 табл.

КОМПОЗИЦИИ АНТИТЕЛ К ROR1 И СООТВЕТСТВУЮЩИЕ СПОСОБЫ

Группа изобретений относится к иммунологии и терапии заболеваний или состояний, ассоциированных с повышенной экспрессией человеческого ROR1. Предложены антитела, которые специфически распознают человеческий ROR1, конъюгаты антитело-лекарственное средство (ADCs), химерные антигенные рецепторы (CARs), композиции на их основе и их применения. Антитело или антигенсвязывающий фрагмент антитела включает последовательности CDRs тяжелой и легкой цепей, показанные в (1) SEQ ID NO:27-29 и SEQ ID NO:66-68; (2) SEQ ID NO:30-32 и SEQ ID NO:69-71; (3) SEQ ID NO:33-35 и SEQ ID NO:72-74; (4) SEQ ID NO:36-38 и SEQ ID NO:75-77; (5) SEQ ID NO:39-41 и SEQ ID NO:78-80; (6) SEQ ID NO:42-44 и SEQ ID NO:81-83; (7) SEQ ID NO:45-47 и SEQ ID NO:84-86; (8) SEQ ID NO:48-50 и SEQ ID NO:87-89; (9) SEQ ID NO:51-53 и SEQ ID NO:90-92; (10) SEQ ID NO:54-56 и SEQ ID NO:93-95; (11) SEQ ID NO:57-59 и SEQ ID NO:96-98; (12) SEQ ID NO:60-62 и SEQ ID NO:99-101; или (13) SEQ ID NO:63-65 и SEQ ID NO:102-104. Предложенные анти-ROR1 ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР (CAR) С АНТИГЕНСВЯЗЫВАЮЩИМИ ДОМЕНАМИ К КОНСТАНТНОЙ ОБЛАСТИ β Т-КЛЕТОЧНОГО РЕЦЕПТОРА

Настоящее изобретение относится к области иммунологии. Предложены применение цитолитической Т-клетки, цитолитическая Т-клетка, CAR. Также рассмотрены молекула нуклеиновой кислоты, вектор экспрессии, способ получения клетки, способ лечения Т-клеточной лимфомы или лейкемии. Данное изобретение может найти дальнейшее применение в терапии онкологических заболеваний, связанных со злокачественными Т-клетками. 7 н. и 11 з.п. ф-лы, 29 ил., 6 табл., 13 пр.

ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ОБЛАДАЮЩАЯ ПРОТИВООПУХОЛЕВЫМ ЭФФЕКТОМ, И СПОСОБ СНИЖЕНИЯ ИНГИБИРУЮЩЕГО ЭФФЕКТА PD-L1 НА Т-КЛЕТКИ ЧЕЛОВЕКА

Группа изобретений относится к медицине и касается фармацевтической композиции, обладающей противоопухолевым эффектом, содержащей эффективное количество популяций Т-клеток человека, где Т-клетки человека включают изолированную нуклеотидную последовательность, содержащую нуклеотидную последовательность, кодирующую модифицированный белок запрограммированной смерти клетки 1 (PD-1) и нуклеотидную последовательность, кодирующую химерный антигенный рецептор (CAR), где модифицированный PD-1 и CAR экспрессируются в виде генных продуктов, которые являются отдельными полипептидами, и где модифицированный PD-1 является доминантно-негативным PD-1. Группа изобретений также касается способа снижения ингибирующего эффекта PD-L1 на Т-клетки человека, включающего введение первой нуклеотидной последовательности и второй нуклеотидной последовательности в Т-клетки человека. Где первая нуклеотидная последовательность кодирует модифицированный PD-1, который является доминантно-негативным PD-1, и вторая нуклеотидная ...

Терапевтические средства

Настоящее изобретение относится к области иммунологии. Предложена иммунореактивная клетка для лечения рака, экспрессирующая химерный антигенный рецептор второго поколения и химерный костимулирующий рецептор. Кроме того, рассмотрен способ получения иммунореактивной клетки, комбинация нуклеиновых кислот, вектор, комбинация векторов, способ стимуляции иммунного ответа. Данное изобретение может найти дальнейшее применение в терапии различных видов рака. 6 н. и 14 з.п. ф-лы, 25 ил., 4 пр.

КОМПОЗИЦИЯ, ВКЛЮЧАЮЩАЯ СМЕСЬ ИЗОФОРМ CD95-Fc

... 1. Композиция, включающая смесь изоформ слитых белков, каждый слитый белок, включающий, по меньшей мере, внеклеточный домен CD95 или его функциональный фрагмент и, по меньшей мере, Fc-домен или его функциональный фрагмент, распределенные в рамках pI-диапазона 4,0-8,5.2. Композиция по п. 1, в которой домен Fc представляет собой домен Fc человека.3. Композиция по п. 1, в которой слитый белок представляет собой APG101, полипептид, имеющий, по меньшей мере, 70% идентичности с APG101, и/или функциональный фрагмент APG101.4. Композиция по п. 1, в которой pI-диапазон равен 4,5-7,8, предпочтительно 5,0-7,5.5. Композиция по п. 1, включающая 0,0-5,0 мол.% высокомолекулярных форм слитого белка, таких как димеры и/или агрегаты.6. Композиция по п. 1, включающая высокие количества сиаловых кислот.7. Композиция по п. 3, включающая укороченные с N-конца слитые белки, такие как -17, -21 и/или -26 слитые белки,8. Композиция по п. 1 в которой домен Fc или его функциональный фрагмент гликозилирован по N-связи ...

СПОСОБЫ ОПРЕДЕЛЕНИЯ ДОЗИРОВКИ CART-КЛЕТОК

МУЛЬТИСПЕЦИФИЧЕСКИЕ АНТИГЕНСВЯЗЫВАЮЩИЕ КОНСТРУКЦИИ, НАЦЕЛИВАЮЩИЕ ИММУНОТЕРАПЕВТИЧЕСКИЕ СРЕДСТВА

ВАРИАНТЫ, КОМПОЗИЦИИ И МЕТОДЫ ПРИМЕНЕНИЯ ХОМИНГ-ЭНДОНУКЛЕАЗЫ PD-1

ЛЕЧЕНИЕ РАКА С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА CLL-1

ДОСТАВКА ТЕРАПЕВТИЧЕСКИХ ПОЛИПЕПТИДОВ ПОСРЕДСТВОМ ПСЕВДОТИПИРОВАННЫХ ОНКОЛОГИЧЕСКИХ ВИРУСОВ

СПОСОБЫ, НАБОРЫ И УСТРОЙСТВО ДЛЯ РАЗМНОЖЕНИЯ ПОПУЛЯЦИИ КЛЕТОК

СПОСОБ МОДУЛЯЦИИ АКТИВНОСТИ CAR-ИНДУЦИРОВАННЫХ ИММУННЫХ КЛЕТОК

СВЕТОЧУВСТВИТЕЛЬНЫЙ ХИМЕРНЫЙ БЕЛОК GPCR

... 1. Фармацевтическая композиция, содержащая химерный белок GPCR для медикаментозной терапии для улучшения зрения, пригодная для включения светового сигнала в сигнальный каскад белка mGluR6 в ON-биполярных клетках внутреннего слоя сетчатки, который содержит домены, полученные из двух членов белкового семейства рецепторов, сопряженных с G-белками (GPCR), отличающаяся тем, что первым из двух членов является бистабильный светочувствительный GPCR, который является источником доменов, опосредующих фотоактивацию и содержащих аминокислотные остатки, образующие основание Шиффа, которое ковалентно связывает хромофор, а вторым из двух членов семейства GPCR является mGluR6, который является источником по меньшей мере одного внутриклеточного домена, способного связываться с белком сигнального каскада mGluR6 Galpha(o).2. Фармацевтическая композиция по п.1, где химерный белок GPCR содержит внутриклеточные петли 2 (IL2) и 3 (IL3) и C-конец (СТ) белка mGluR6.3. Фармацевтическая композиция по п.1 или 2, где ...

ИНСЕРЦИЯ ТАРГЕТНОГО ГЕНА ДЛЯ УЛУЧШЕННОЙ КЛЕТОЧНОЙ ИММУНОТЕРАПИИ

ИММУННЫЕ ЭФФЕКТОРНЫЕ КЛЕТКИ С ОТРЕДАКТИРОВАННЫМ ГЕНОМОМ

ПОЛУЧЕНИЕ АНТИГЕНСПЕЦИФИЧЕСКИХ T-КЛЕТОК

ЛЕЧЕНИЕ ЗЛОКАЧЕСТВЕННОЙ ОПУХОЛИ С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО РЕЦЕПТОРА АНТИГЕНА ПРОТИВ CD19

ДВОЙНОЙ ВЕКТОР ДЛЯ ПОДАВЛЕНИЯ ВИРУСА ИММУНОДЕФИЦИТА ЧЕЛОВЕКА

МОДИФИКАЦИЯ Т-КЛЕТОК

КОМПОЗИЦИИ, ИЗДЕЛИЯ И СПОСОБЫ, СВЯЗАННЫЕ С ДОЗИРОВАНИЕМ В КЛЕТОЧНОЙ ТЕРАПИИ

СКОНСТРУИРОВАННЫЕ УНИВЕРСАЛЬНЫЕ ИММУННЫЕ КЛЕТКИ С АНТИ-CD22 ХИМЕРНЫМ АНТИГЕННЫМ РЕЦЕПТОРОМ

ХИМЕРНЫЕ РЕЦЕПТОРЫ АНТИГЕНА, НАЦЕЛЕННЫЕ НА PSCA

ПОЛИПЕПТИДЫ ТРАНСПОЗАЗЫ И ИХ ПРИМЕНЕНИЕ

ЛЕЧЕНИЕ РАКА С ПОМОЩЬЮ ГУМАНИЗИРОВАННОГО АНТИ-CD19 ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА

СЛИТНЫЕ ФЕРМЕНТЫ

... 1. Рекомбинантный белок, обладающий активностью N-ацетилглюкозаминилтрансферазы, при этом рекомбинантный белок катализирует перенос N-ацетилглюкозамина на концевой остаток Manα3 и катализирует перенос N-ацетилглюкозамина на концевой остаток Manα6 акцепторного гликана, и при этом рекомбинантный белок содержит каталитический домен, по меньшей мере, из двух разных ферментов.2. Рекомбинантный белок по п.1, в котором рекомбинантный белок представляет собой слитый белок, содержащий каталитический домен N-ацетилглюкозаминилтрансферазы I и каталитический домен N-ацетилглюкозаминилтрансферазы II.3. Рекомбинантный белок по п.2, в котором каталитический домен N-ацетилглюкозаминилтрансферазы I и каталитический домен N-ацетилглюкозаминилтрансферазы II происходят из ферментов человека.4. Рекомбинантный белок по п.3, в котором каталитический домен N-ацетилглюкозаминилтрансферазы I содержит последовательность, которая по меньшей мере, на 70%, по меньшей мере, на 75%, по меньшей мере, на 80%, по меньшей ...

МАт-НАПРАВЛЯЕМЫЕ ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРНЫЕ СИСТЕМЫ ДЛЯ СОРТИРОВКИ/ИСТОЩЕНИЯ СКОНСТРУИРОВАННЫХ ИММУННЫХ КЛЕТОК

СКОНСТРУИРОВАННЫЕ ИММУННЫЕ КЛЕТКИ С НОКАУТОМ РЕЦЕПТОРА Т-КЛЕТОК, СНАБЖЕННЫЕ ХИМЕРНЫМИ АНТИГЕННЫМИ РЕЦЕПТОРАМИ, СВЯЗЫВАЮЩИМИСЯ С CD123, ДЛЯ ЛЕЧЕНИЯ РЕЦЕДИВИРУЮЩЕГО/УСТОЙЧИВОГО ОСТРОГО МИЕЛОИДНОГО ЛЕЙКОЗА ИЛИ НОВООБРАЗОВАНИЯ ИЗ БЛАСТНЫХ ПЛАЗМОЦИТОИДНЫХ ДЕНДРИТНЫХ КЛЕТОК

ПОЛУЧЕНИЕ АНТИГЕНСПЕЦИФИЧЕСКИХ T-КЛЕТОК

ДОСТАВКА ТЕРАПЕВТИЧЕСКИХ ПОЛИПЕПТИДОВ ПОСРЕДСТВОМ ПСЕВДОТИПИРОВАННЫХ ОНКОЛИТИЧЕСКИХ ВИРУСОВ

АНТИГЕНСВЯЗЫВАЮЩИЙ БЕЛОК, РАСПОЗНАЮЩИЙ ПРОИСХОДЯЩИЙ ИЗ MAGE-A4-ПЕПТИД

ВВЕДЕНИЕ СКОНСТРУИРОВАННЫХ Т-КЛЕТОК ДЛЯ ЛЕЧЕНИЯ РАКА ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ

ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРЫ, СПЕЦИФИЧНЫЕ В ОТНОШЕНИИ РЕЦЕПТОРА ТИМУСНОГО СТРОМАЛЬНОГО ЛИМФОПОЭТИНА, И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

КОМБИНИРОВАННАЯ ТЕРАПИЯ ДЛЯ ЛЕЧЕНИЯ СВЯЗАННЫХ С BCMA РАКОВЫХ ЗАБОЛЕВАНИЙ И АУТОИММУННЫХ РАССТРОЙСТВ

КОМПОЗИЦИИ АНТИТЕЛ К ВИЧ И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

Rekombinante Impfstoffe und deren Verwendung

Fusionsmolekül, das ein Antigen, eine Transmembranregion und die cytoplasmatische Region einer Kette eines MHC-Moleküls umfasst.

Protein coated polymeric substrate

Lentiviral vectors

Viral vectors and methods for the prevention or treatment of cancer

Anti-placenta-chondroitin-sulfate chimeric antigen receptor and application thereof

The present invention provides an anti-placenta chondroitin sulfate (pl-CS) chimeric antigen receptor and application thereof. The chimeric antigen receptor mainly comprises anti-pl-CS antigen recognition region, a hinge region, a transmembrane region and intracellular region, wherein the anti-pl-CS antigen recognition region is any one of a plasmodium protein VAR2CSA, a part of peptide segment of plasmodium protein VAR2CSA or a pl-CS antibody; and the part of peptide segment of the plasmodium protein VAR2CSA is a peptide segment with the number of amino acid greater than 500 in the plasmodium protein VAR2CSA.

T Cell Receptors

Chimeric protein

Gamma delta T cells and uses thereof

Chimeric antigen receptor

Engineered regulatory t cell

Surface decoration of extracellular vesicles

Therapeutic agents

Cell

Chimeric antigen receptors with CD2 activation

Disclosed are chimeric antigen receptors comprising a CD2 co-stimulatory domain that retain function against CD58- and CD58low tumor cells, and CD2 co-stimulatory receptors that promote CAR function against CD58- and CD58low tumor cells.

Chimeric Viruses presenting nonnative surface proteins and uses thereof

Immunogenic liposome compositions

Immunogenic liposome compositions

Chimeric Viruses presenting non-native surface proteins and uses thereof

Chimeric Viruses presenting nonnative surface proteins and uses thereof

Immunogenic liposome compositions.

The present invention provides an immunogenic liposome composition comprising vesicle-forming lipids and an antigenic construct comprising one or more antigenic determinants and a hydrophobic domain.

Use of chimeric antigen receptormodified T-cells to treat cancer

Immunogenic liposome compositions.

Recombinant DNA coding for signal peptide; selective interacting polypeptide and membrane anchoring sequence.

Chimeric Viruses presenting nonnative surface proteins and uses thereof

Use of chimeric antigen receptormodified T-cells to treat cancer

Use of chimeric antigen receptormodified T-cells to treat cancer

Immunogenic liposome compositions

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

ADJUSTED TRANSKRIPTION FROM PURPOSEFUL GENES AND OTHER BIOLOGICAL EVENTS

EXENDIN FUSIONSPROTEINE ONE

PROCEDURE FOR THE PRODUCTION OF A CONNECTION IN A EUKARYOTI CELL

STRESS PROTEINS AND YOUR USE

NEW CYTOKINE

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

VIRUS-SIMILAR PARTICLES, PREPARATION AND USE IN SCREENING AND FUNCTIONAL ONE GENE OMAN IDIOM

Rtef-1 variants and uses thereof

Disclosed are variant RTEF-1 polypeptides having an RTEF-1 amino acid sequence with one or more internal deletions, wherein the polypeptides reduce VEGF promoter activity. Some of the RTEF-1 polypeptides include an amino acid sequence that is at least 80% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17, but does not comprise the contiguous amino acids of SEQ ID NOs:8, 9, 11, or 12. Also disclosed are nucleic acids encoding the variant RTEF-1 polypeptides of the present invention. Pharmaceutical compositions that include the polypeptides and nucleic acids of the present invention are also disclosed. Methods of inducing cell contact inhibition, regulating organ size, and reducing intracellular YAP activity are also set forth, as well as methods of treating hyperproliferative diseases such as cancer using the pharmaceutical compositions of the present invention.

Compositions and methods for identifying enzyme and transport protein inhibitors

The invention is directed to compositions, e.g., cell-based and multiplexed platforms, to screen for small molecule drugs that inhibit enzymes such as proteases, e.g., viral proteases, e.g., HIV proteases; and methods for making and using these compositions. The invention provides compositions and methods for identifying compositions, e.g., drug molecules, that can inhibit proteases, e.g., viral proteases such as HIV proteases. In alternative embodiments, the invention provides cell-based platforms or assays to screen for compositions, e.g., small molecules or drugs, that inhibit or modify the activity of enzymes such as calcium-dependent protein convertases involved in HIV envelope protein processing, including cleavage of the HIV gp160 envelope precursor, resulting in gp120 and gp41 envelope products. In one embodiment, the invention provides a cell-based or multiplexed platform for monitoring the activity of enzymes, e.g., proteases such as viral proteases.

Recombinant envelope protein of human immunodeficiency virus (hiv) and vaccine containing the same

The present invention provides a recombinant HIV Env antigenic protein, a virus-like particle and a recombinant HIV virus. The present invention further provides a vaccine comprising the recombinant HIV Env antigenic protein, the virus-like particle or recombinant HIV virus.

Method for Producing Nucleases of a Gram Negative Bacterium While Using a Gram Positive Expression Host

A method for producing a nuclease of a gram negative bacterium or a nuclease preparation containing a nuclease of a gram negative bacterium including expression of the nuclease in a gram positive bacterium and subsequent secretion of the nuclease, as well as a nuclease or a nuclease preparation that can be obtained by this method.

Proteins for use in human and animal staphyococcus infections

The present invention relates to a polypeptide termed ply_pitti26 comprising the sequence as depicted in SEQ ID NO:1 as well as variants of this polypeptide. Furthermore, the present invention relates to nucleic acids and vectors encoding for said polypeptide and variants thereof as well as host cells comprising these nucleic acids and/or vectors. Finally, the present invention relates to the uses of said polypeptide, variants thereof, nucleic acid sequences, vectors and host cells, in particular for the treatment or prophylaxis of a subject infected by or exposed to Staphylococci.

Decorin compositions and use thereof

The present invention relates to improved decorin compositions and methods of their production.

Isolated laminin-421

The present disclosure provides isolated laminin-421, methods for making recombinant laminin-421, and host cells that express recombinant laminin-421. The present disclosure also provides nucleic acid sequences encoding full length human laminin β2 chain, expression vectors and host cells thereof.

Compositions and Methods for Self-Adjuvanting Vaccines against Microbes and Tumors

The present invention is drawn to compositions and methods to enhance an immune response in order to prevent or treat infections or hyperproliferative diseases such as cancer. More particularly, the composition is an immuno stimulator intracellular signaling peptide fused directly or indirectly to a peptide that leads to multimerization into complexes of three or more units, where the intracelluar signaling peptide must be present in a complex of three or more units in order to stimulate an immune response. Inserting this fusion construct into viruses like HIV-1 or introducing it into dendritic cells or tumor cells is predicted to lead to a positive therapeutic effect in humans, non-human mammals, birds, and fish.

Methods of cell culture for adoptive cell therapy

An improved method of culturing cells for cell therapy applications that includes growing desired cells in the presence of antigen-presenting cells and/or feeder cells and with medium volume to surface area ratio of up to 1 ml/cm 2 if the growth surface is not comprised of gas permeable material and up to 2 ml/cm 2 if the growth surface is comprised of gas permeable material. The desired cells are at a surface density of less than 0.5×10 6 cells/cm 2 at the onset of a production cycle, and the surface density of the desired cells plus the surface density of the antigen presenting cells and/or feeder cells are at least about 1.25×10 5 cells/cm 2 .

Light-activated fusion proteins and uses therefor

The invention, in some aspects relates to synthetic, light-activated fusion proteins and their encoding polynucleotide molecules. In some aspects the invention additionally includes expression of the light-activated fusion proteins in cells and their use in methods such as therapeutic methods and candidate compound screening methods.

Bacterial surface display and screening of thioether-bridge-containing peptides

The invention relates to bacterial cell surface display of post-translationally modified heterologous proteins. Provided is an isolated nucleic acid construct encoding a proteinaceous substance comprising, from the N-terminus to the C-terminus, at least (a) an N-terminal a lantibiotic leader sequence; (b) an amino acid sequence of interest to be post-translationally modified to a dehydroresidue- or thioether-bridge containing polypeptide; (c) a hydrophilic cell-wall spanning domain; (d) a sortase recognition motif; (e) a hydrophobic membrane spanning domain and (f) a C-terminal charged membrane anchoring domain. Also provided is a Gram-positive host cell expressing the construct, as well as a library of host cells.

Recombinant bacteriophage and methods for their use

Recombinant P4 bacteriophage containing modified tail fibers having a base plate attachment region (BPAR) from a P2 bacteriophage gene H product and a heterologous receptor binding domain (RBD) are disclosed. Methods for the use of the recombinant P4 bacteriophage, such as to detect the presence of a target bacterium in a sample, are also described.

Method for the treatment of obesity

The present invention relates to therapeutic compositions for treating or preventing obesity and obesity-related disorders in a subject using immunotherapy to target and eliminate adipocytes.

Chimeric receptors with 4-1bb stimulatory signaling domain

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

Methods for Producing Yeast-Based Vaccines

The invention provides methods for culturing yeast at a neutral pH level. Yeast cultured under neutral pH conditions exhibit desirable characteristics useful for biological purposes, such as the development of vaccines, prophylactics and therapeutics. The invention also provides for compositions and kits comprising yeast grown using the methodologies disclosed herein.

Preparation of anti-peg antibody expressing cell and application thereof

The present invention provides a method for preparing an isolated eukaryotic cell which presents an anti-polyethylene glycol (PEG) antibody on a cell membrane. The present invention also provides a method for a quantitative analysis of a polyethylene glycol (PEG) by said anti-PEG antibody expressing cell. The cell-based quantitative analysis of the present prevention could sensitively quantify free PEG and PEG-modified macromolecules (proteins, nanoparticles and liposomes) as sensitive as nano-gram level.

Proteins for use in human and animal staphylococcus infections

The present invention relates to a polypeptide termed ply_pitti26 comprising the sequence as depicted in SEQ ID NO:1 as well as variants of this polypeptide. Furthermore, the present invention relates to nucleic acids and vectors encoding for said polypeptide and variants thereof as well as host cells comprising these nucleic acids and/or vectors. Finally, the present invention relates to the uses of said polypeptide, variants thereof, nucleic acid sequences, vectors and host cells, in particular for the treatment or prophylaxis of a subject infected by or exposed to Staphylococci.

Methods and compositions for generating an immune response by inducing cd40 and pattern recognition receptor adapters

Provided are methods for activating an antigen-presenting cell and eliciting an immune response by inducing an inducible pattern recognition receptor adapter, or adapter fragment, and CD40 activity. Also provided are nucleic acid compositions comprising sequences coding for chimeric proteins that include an inducible CD40 peptide and an inducible pattern recognition receptor adapter or adapter fragment.

Fatty alcohol forming acyl reductases (fars) and methods of use thereof

The present disclosure provides methods useful for producing fatty alcohol compositions from recombinant host cells. The disclosure further provides variant fatty acyl-CoA reductase (FAR) enzymes, polynucleotides encoding the variant FAR enzymes, and vectors and host cells comprising the same.

Novel constructs for chimeric antigen receptors

The present disclosure pertains to immune cells comprising chimeric antigen receptors (CARs) and methods of using immune cells comprising CARs.

Modified Cell Expressing Therapeutic Agent and Uses thereof

Compositions and methods for enhancing T cell response which increases the efficacy of CAR T cell therapy for treating cancer are described. Embodiments include a modified cell comprising an isolated nucleic acid comprising a first nucleic acid and a second nucleic acid, the first nucleic acid encoding a chimeric antigen receptor (CAR), the second nucleic acid encoding a therapeutic agent comprising at least one of IFN-, IL-2, IL-6, IL-7, IL-15, IL-17, and IL-23. The modified cell expresses and secretes the therapeutic agent. 119-. (canceled)20. A pharmaceutical composition comprising modified T cells , wherein the modified T cells comprise chimeric antigen receptor (CAR) and an exogenous polynucleotide encoding one or more proteins , the one or more proteins comprising IFNγ.21. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises SEQ ID NO: 469 and a polynucleotide encoding SEQ ID NO: 328.22. The pharmaceutical composition of claim 20 , wherein the modified T cells express and secrete the one or more proteins in response to activation of the modified T cells claim 20 , hypoxia claim 20 , or a combination thereof.23. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide is present in the modified T cell in a recombinant DNA construct claim 20 , in an mRNA claim 20 , or in a viral vector.24. The pharmaceutical composition of claim 20 , wherein the one or more proteins further comprise IL-6.25. The pharmaceutical composition of claim 24 , wherein the exogenous polynucleotide comprises a polynucleotide encoding SEQ ID NOS: 287 and a polynucleotide encoding SEQ ID NO: 328.26. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises a promoter comprising a binding site for a transcription modulator that modulates the expression and/or secretion of the one or more proteins in the modified T cells.27. The pharmaceutical composition of claim 26 , wherein the transcription ...

RESTIMULATION OF CRYOPRESERVED TUMOR INFILTRATING LYMPHOCYTES

The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation. 1. A method for treating a subject with a cancer comprising administering expanded tumor infiltrating lymphocytes (TILs) comprising:(a) performing a first expansion by (i) thawing cryopreserved dissociated tumor materials comprising a first population of TILs obtained from a tumor that was resected from the subject, and (ii) culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs;(b) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, and wherein the second expansion is performed for about 7 to 14 days in order to obtain the third population of TILs;(c) harvesting the third population of TILs obtained from step (b);(d) transferring the harvested third population of TILs from step (c) into an infusion bag;(e) cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process; and(f) administering a therapeutically effective dosage of the third population of TILs to the subject.2. The method according to claim 1 , wherein the dissociated tumor materials comprise a tumor digest.3. The method according to claim 1 , wherein obtaining the dissociated tumor materials comprises fragmenting the tumor resected from the subject into one or more tumor fragments.4. The method according to claim 1 , wherein obtaining the dissociated tumor materials comprises mechanically disrupting the tumor resected from the subject.5. The method according to claim 1 , wherein ...

IL-13 RECEPTOR ALPHA 2 (IL13RA2) CHIMERIC ANTIGEN RECEPTOR FOR TUMOR SPECIFIC T CELL IMMUNOTHERAPY

Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of the IL-13 alpha 2 (IL13Ra2) receptor, cells containing such CARs, and methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors. 1. A nucleic acid encoding a chimeric antigen receptor , the chimeric antigen receptor comprising:a ligand binding domain that binds to and/or interacts with an IL-13 alpha 2 (IL13Rα2) receptor;a polypeptide spacer between the ligand binding domain and a transmembrane domain;the transmembrane domain; andintracellular signaling region.266-. (canceled) This application claims priority to U.S. Prov. App. No. 62/643,055 filed Mar. 14, 2018 entitled “IL-13 RECEPTOR ALPHA 2 (IL3RA2) CHIMERIC ANTIGEN RECEPTOR FOR TUMOR SPECIFIC T CELL IMMUNOTHERAPY” which is hereby 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 SCRI169WOSEQLIST, created Mar. 12, 2019, which is approximately 62 Kb in size. The information in the electronic format of the Sequence Listing is hereby expressly incorporated by reference in its entirety.Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of an IL-13 alpha 2 (IL13Ra2) receptor, to cells containing such CARs, and to methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors.Despite significant advances in the understanding of brain cancer, during the last decade, the mortality rate has remained consistent and new innovative therapies are urgently needed. To date, T cell immunotherapy has emerged as a promising cancer therapy supported by remarkable clinical data reporting complete remission in patients with B cell malignancies after ...

Chimeric antigen receptor and its use

In a first aspect, the present invention relates to a recombinant polypeptide containing a domain comprising at least two antibody units whereby the first antibody unit is an an anti-CD30 single chain antibody unit while the second antibody unit is a antibody unit being specific for an antigen present on the surface of a pre-determined target cell. In particular, the present invention relates to a recombinant polypeptide containing at least the following domains starting from the N-terminus to the C-terminus: a first domain containing an anti-CD30 single chain anti-body unit, in particular, HRS3 scFv of SEQ ID No. 2 or homologs thereof having at least 70% identity with SEQ ID No. 2 binding specifically to CD30, and an antibody unit said antibody unit being specific for an antigen present on the surface of a predetermined target cell, in particular, being specific for a tumor-associated antigen; optionally a spacer domain; a trans-membrane domain; and a cytoplasmatic signalling domain. In a further aspect, the present invention relates to a nucleic acid molecule encoding the polypeptide according to the present invention, as well as vectors and cells containing the same. Moreover, lymphocytes are provided, in particular T-cells like CD8′ or a CD4* T-cell expressing on its surface chimeric antigen receptors containing an anti-CD30 single chain antibody unit and an antibody unit whereby said antibody unit being specific for an antigen present on the surface of a predetermined target cell. Immune cells modified with the polypeptide show improved functions, in particular in the treatment of cancer, in particular CD30− cancer. That is, the cells are for use in adapted cell therapy for treating cancer in a subject in need thereof.

Homodimer-type bispecific antibody targeting cd19 and cd3, and preparation method therefor and application thereof

Provided is a tetravalent, homodimer-type bispecific antibody molecule that targets both immune effector cell antigen CD3 and tumor-related antigen CD19. The bispecific antibody molecule comprises first and second single-chain Fv and Fc fragments in sequence from the N-terminus to the C-terminus, wherein the first single-chain Fv can specifically bind to CD19, the second single-chain Fv can specifically bind to CD3, the first and second single-chains Fv are connected by means of a linker peptide, the second single-chain Fv and Fc fragments are directly connected to each other or connected by means of a linker peptide; and the Fc fragment does not have effector functions such as CDC, ADCC, and ADCP. The bispecific antibody can significantly inhibit or kill tumor cells, and has toxic and side effects that may be caused by excessive activation of effector cells; in addition, such bispecific antibody is of homodimer type, without the problem of heavy chain and light chain mismatch; the purification step is simple and efficient, the expression is high, and the physical and chemical properties as well as in vivo stability of the antibody are significantly improved.

Anti-hsp70 specific chimeric antigen receptors (cars) for cancer immunotherapy

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from an anti-HSP70 monoclonal antibody, conferring specific immunity against HSP70 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating in particular leukemia.

NOVEL CONSTRUCTS FOR CHIMERIC ANTIGEN RECEPTORS

The present disclosure pertains to immune cells comprising chimeric antigen receptors (CARs) and methods of using immune cells comprising CARs. 180-. (canceled)81. A method of modifying a macrophage or monocyte comprising delivering to the macrophage or monocyte: (a) an extracellular domain,', '(b) a transmembrane domain, and', '(c) an intracellular domain, and, '(i) a viral vector comprising one or more nucleic acid sequences encoding a chimeric antigen receptor (CAR) comprising(ii) at least one Vpx protein,thereby producing a modified macrophage or monocyte that exhibits increased CAR expression relative to a macrophage or monocyte comprising a CAR delivered by a viral vector and not delivered at least one Vpx protein.82. The method of claim 81 , wherein the viral vector comprises or is a lentiviral vector.83. The method of claim 81 , wherein the modified macrophage or monocyte exhibits increased CAR expression of about 40% or greater relative to a macrophage or monocyte not delivered at least one Vpx protein.84. The method of claim 81 , wherein the modified macrophage or monocyte exhibits CAR expression for an extended time period of at least 5 days relative to an unmodified macrophage or monocyte.85. The method of claim 81 , wherein the modified macrophage or monocyte does not exhibit an M1 phenotype relative to a macrophage or monocyte not delivered at least one Vpx protein.86. The method of claim 85 , wherein the modified macrophage or monocyte does not exhibit increased expression of one or more markers of M1 phenotype relative to a macrophage or monocyte not delivered at least one Vpx protein.87. The method of claim 86 , wherein the one or more markers of M1 phenotype comprise or are one or more of CD86 claim 86 , CD80 claim 86 , MHC II claim 86 , IL-1R claim 86 , TLR2 claim 86 , TLR4 claim 86 , iNOS claim 86 , SOCS3 claim 86 , CD83 claim 86 , PD-L1 claim 86 , CD69 claim 86 , MHC I claim 86 , CD64 claim 86 , CD32 claim 86 , CD16 claim 86 , IL1R claim 86 , a ...

Therapeutic Biologic for Treatment of Hepatocellular Carcinoma

The invention provides, inter alia, conjugates comprising a coagulating agent conjugated to an antibody, where the antibody specifically binds an extracellular domain epitope of a mammalian PLVAP protein. These agents specifically target HCC tumors and treat the HCC. The invention also provides methods of using these conjugates, such as methods of treating HCC by administering the conjugates provided by the invention or compositions provided by the invention, such as pharmaceutical compositions.

Cell lines expressing inserted secretable reporter genes at multiple stages of differentiation

A composition of matter comprises one or more cell lines configured to inducibly differentiate to at least a first stage of differentiation and a second, subsequent stage of differentiation. Each of the one or more cell lines are genetically edited to express one or more first stage inserted secretable reporter genes placed under control of promoters for genes canonically expressed during the first stage of differentiation. The cell lines are further genetically edited to express one or more second stage inserted secretable reporter genes placed under control of promoters for genes canonically expressed during the second stage of differentiation, but not during the first stage of differentiation, wherein the one or more second stage inserted secretable reporter genes are different than the one or more first stage inserted secretable reporter genes.

DENDRITIC CELL COMPOSITION

The present invention contemplates dendritic cell compositions. The dentritic cell compositions employ MHC class-II targeting signals fused to an antigen or fragment thereof to obtain MHC II presentation of the antigen or fragment thereof. In particular, the invention refers to a dendritic cell vaccine comprising dendritic cells expressing a MHC class-II targeting signal fused to an antigen or fragment thereof. Dendritic cell vaccines for the stimulation of an immune response against melanoma-associated antigen are also described. 1. Dendritic cell composition comprising dendritic cells expressing at least one fusion protein comprisingat least one antigen or a fragment thereof,an endoplasmatic reticulum (ER)-translocation signal sequence preceding the N-terminus of the antigen, anda transmembrane and cytoplasmic domain comprising an endosomal/lysosomal targeting sequence following the C-terminus of the antigen.2. Dendritic cell composition according to claim 1 ,wherein the dendritic cell composition further comprises dendritic cells expressing at least one antigen or a fragment thereof wherein the antigen is not fused to a targeting signal sequences that promotes the MHC II presentation of the antigen or fragment thereof.3. Dendritic cell composition according to or claim 1 , wherein the targeting signal sequence that promotes the MHC II presentation is at least one selected from the group consisting ofan endoplasmatic reticulum (ER)-translocation signal sequence preceding the N-terminus of the antigen, anda transmembrane and cytoplasmic domain comprising an endosomal/lysosomal targeting sequence following the C-terminus of the antigen.4. Dendritic cell composition according to any one of the preceding claims claim 1 , wherein the fusion protein and the antigen are transiently or stably expressed claim 1 , preferably stably expressed.5. Dendritic cell composition according to claim 4 , wherein the transient expression is carried out by introducing ivt-RNA.6. ...

Compositions and Methods for Treating Cancer

The invention provides compositions and methods for treating ovarian cancer. Specifically, the invention relates to administering a genetically modified T cell having α-folate receptor (FRα) binding domain and 4-1BB (CD137) costimulatory domain to treat ovarian cancer. 1. An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR) , wherein the isolated nucleic acid sequence comprises a nucleic acid sequence encoding an α-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 23.2. The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a CD3 zeta signaling domain.3. The isolated nucleic acid sequence of claim 2 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.4. The isolated nucleic acid sequence of claim 2 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence of SEQ ID NO: 7.5. The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a transmembrane domain.6. An isolated chimeric antigen receptor (CAR) claim 1 , wherein the CAR comprises an anti-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 23.7. The isolated CAR of claim 6 , wherein the CAR further comprises a CD3 zeta signaling domain.8. The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.9. The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence of SEQ ID NO: 7.10. The isolated CAR of claim 6 , wherein the CAR further comprises a transmembrane domain.11. A method for providing anti-tumor immunity in a subject claim 6 , the method comprising:{'claim-ref': {'@idref': 'CLM-00006', 'claim 6'}, 'administering to the subject an effective amount of a T cell comprising the CAR of , thereby providing anti-tumor immunity in the subject.'}12. The method of claim 11 , wherein the CAR further comprises a 4-1BB ...

Peptides and nanoparticles for intracellular delivery of molecules

The present invention pertains to peptides and peptide-containing complexes/nanoparticles that are useful for stabilizing and delivering cargo molecules such as nucleic acids.

Methods and compositions for generating an immune response by inducing cd40 and pattern recognition receptor adapters

Provided are methods for activating an antigen-presenting cell and eliciting an immune response by inducing an inducible pattern recognition receptor adapter, or adapter fragment, and CD40 activity. Also provided are nucleic acid compositions comprising sequences coding for chimeric proteins that include an inducible CD40 peptide and an inducible pattern recognition receptor adapter or adapter fragment.

CONSTRUCTION OF CHIMERIC ANTIGEN RECEPTOR TARGETING CD20 ANTIGEN AND ACTIVITY IDENTIFICATION OF ENGINEERED T CELLS THEREOF

Provided are a chimeric antigen receptor targeting CD20 antigen and a preparation method thereof. The extracellular antigen binding domain of the chimeric antigen receptor includes an antibody heavy chain variable region shown in SEQ ID NO: 7 or 9 or 33 and an antibody light chain variable region shown in SEQ ID NO: 11 or 13 or 35, and is capable of killing tumor cells. 1. A chimeric antigen receptor (CAR) wherein the CAR has an antigen binding domain which comprises an antibody heavy chain variable region as shown in SEQ ID NO: 7 or 9 or 33 and an antibody light chain variable region as shown in SEQ ID NO: 11 or 13 or 35.2. The chimeric antigen receptor of claim 1 , whose antigen binding domain is as follows:{'br': None, 'sub': H', 'L, 'V-V'}{'sub': H', 'L, 'wherein Vis an antibody heavy chain variable region; Vis an antibody light chain variable region; and “-” is a linker peptide or a peptide bond.'}3. The chimeric antigen receptor of claim 2 , wherein the amino acid sequence of Vis as shown in SEQ ID NO: 7 claim 2 , and the amino acid sequence of Vis as shown in SEQ ID NO: 11; or{'sub': H', 'L, 'the amino acid sequence of Vis as shown in SEQ ID NO: 9, and the amino acid sequence of Vis as shown in SEQ ID NO: 13, or'}{'sub': H', 'L, 'the amino acid sequence of Vis as shown in SEQ ID NO: 33, and the amino acid sequence of Vis as shown in SEQ ID NO: 35.'}4. A nucleic acid molecule encoding the chimeric antigen receptor (CAR) of .5. The nucleic acid molecule of claim 4 , which comprises a nucleic acid sequence encoding hinge region selected from the group consisting of:(a) a polynucleotide encoding a polypeptide as shown in SEQ ID NO: 17 or 19;(b) a polynucleotide having a sequence as shown in SEQ ID NO: 18 or 20;(c) a polynucleotide having a nucleotide sequence with ≥90% (preferably ≥95%) homologous to the sequence of SEQ ID NO: 18 or 20 and encoding the amino acid sequence of SEQ ID NO: 17 or 19;(d) a polynucleotide complementary to the polynucleotide of any of (a ...

CD33 SPECIFIC CHIMERIC ANTIGEN RECEPTORS

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% ...

Cll1-specific multi-chain chimeric antigen receptor

The present invention relates to a new generation of chimeric antigen receptors (CAR) referred to as multi-chain CARs, which are made specific to the antigen CLL1. Such CARs aim to redirect immune cell specificity and reactivity toward malignant cells expressing the tumor antigen CLL1. The alpha, beta and gamma polypeptides composing these CARs are designed to assemble in juxtamembrane position, which forms flexible architecture closer to natural receptors, that confers optimal signal transduction. The invention encompasses the polynucleotides, vectors encoding said multi-chain CAR and the isolated cells expressing them at their surface, in particularly for their use in immunotherapy. The invention opens the way to efficient adoptive immunotherapy strategies for treating cancer, especially leukemia.

mAb-DRIVEN CHIMERIC ANTIGEN RECEPTOR SYSTEMS FOR SORTING/DEPLETING ENGINEERED IMMUNE CELLS

A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope. 1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen , wherein said extracellular binding domain comprises at least one mAb-specific epitope.2. The polypeptide according to claim 1 , wherein said mAb-specific epitope is located between the VH and VL chains.3. The polypeptide according to claim 1 , wherein said VH and VL chains claim 1 , and mAb specific-epitope are bound together by at least one linker and to the transmembrane domain of said CAR by a hinge.4. The polypeptide according to claim 3 , wherein the mAb-specific epitope is joined to the VH and VL chains by two linkers.5. The polypeptide according to claim 1 , wherein the mAb-specific epitope is an epitope to be bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such epitope.6. The polypeptide according to claim 1 , wherein the polypeptide comprises one extracellular binding domain claim 1 , wherein said extracellular binding domain further comprises a hinge claim 1 , and said polypeptide further comprisesa transmembrane domain, and,an intracellular domain.7. The polypeptide according to claim 1 , wherein the extracellular binding domain comprises 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 claim 1 , 5 claim 1 , 6 claim 1 , 7 claim 1 , 8 claim 1 , 9 or 10 mAb-specific epitopes.8. The polypeptide according to claim 1 , wherein the extracellular binding domain comprises 1 claim 1 , 2 claim 1 , 3 or claim 1 , 4 mAb-specific epitopes.9. The polypeptide according to claim 1 , wherein the extracellular binding ...

CHIMERIC TRANSMEMBRANE PROTEINS AND USES THEREOF

Provided herein are chimeric transmembrane proteins and proteins, nucleic acids encoding these chimeric transmembrane proteins or proteins, and mammalian cells containing these nucleic acids, and methods of making and using these mammalian cells. 1. A protein comprising a transmembrane domain of an alpha chain of interleukin-7 receptor , with one or more modifications , wherein the transmembrane domain with one or more modifications has a sequence of SEQ ID NO: 2 , 4 , 6 or 8.2. The protein of claim 1 , wherein the protein further comprises an intracellular domain of an alpha chain of interleukin-7 receptor.3. The protein of claim 2 , wherein the intracellular domain comprises a sequence of SEQ ID NO: 45.4. The protein of claim 1 , wherein the protein further comprises an extracellular domain of an alpha chain of interleukin-7 receptor.5. The protein of claim 4 , wherein the extracellular domain comprises a sequence of SEQ ID NO: 11.6. The protein of claim 1 , further comprisingan extracellular interleukin-15 domain; andan extracellular sushi domain from an alpha chain of interleukin-15 receptor.7. The protein of claim 6 , wherein the extracellular interleukin-15 domain comprises a sequence of SEQ ID NO: 22 or SEQ ID NO: 24.8. The protein of claim 6 , wherein the extracellular sushi domain of the alpha chain of interleukin-15 receptor comprises SEQ ID NO: 36 or SEQ ID NO: 37.9. A nucleic acid encoding a protein of .10. A vector comprising the nucleic acid of .11. The vector of claim 10 , further comprising a promoter operably linked to the nucleic acid claim 10 , and optionally claim 10 , an enhancer sequence operably linked to the nucleic acid.12. The vector of claim 10 , further comprising a sequence encoding a chimeric antigen receptor which binds specifically to a tumor antigen.13. The vector of claim 12 , wherein the tumor antigen is selected from the group consisting of: glypican-3 claim 12 , BCMA claim 12 , MAGE claim 12 , MUC16 claim 12 , CD19 claim 12 , WT- ...

CHIMERIC ANTIGEN RECEPTORS, COMPOSITIONS, AND METHODS

This disclosure describes chimeric antigen receptors for expression in a Natural Killer (NK) cell, pharmaceutical compositions that include NK cells (and/or iPSCs) modified to express a chimeric antigen receptor, and methods involving such chimeric antigen receptors. Generally, the chimeric antigen receptor includes an ectodomain that includes an antigen recognition region, a transmembrane domain linked to the ectodomain, and an endodomain linked to the transmembrane domain. The endodomain can include a signaling peptide that activates an NK cell. 1. A chimeric antigen receptor comprising:an ectodomain comprising an antigen recognition region;a transmembrane domain linked to the ectodomain; andan endodomain linked to the transmembrane domain, the endodomain comprising a signaling peptide that activates an NK cell.2. The chimeric antigen receptor of wherein the antigen recognition domain specifically binds an antigen associated with a disease.3. The chimeric antigen receptor of wherein the antigen recognition domain specifically binds a tumor antigen.4. The chimeric antigen receptor of wherein the ectodomain further comprises a signal peptide or leader sequence.5. The chimeric antigen receptor of wherein the ectodomain further comprises a spacer.6. The chimeric antigen receptor of wherein the endodomain comprises a signaling domain of and NK cell membrane-bound signaling adaptor protein.7. The chimeric antigen receptor of wherein the NK cell membrane-bound signaling adaptor protein comprises at least a portion of 2B4 (CD244) claim 6 , CD137 (41BB) claim 6 , IL21 claim 6 , DAP10 claim 6 , DAP12 claim 6 , or CD3ζ.8. The chimeric antigen receptor of wherein the transmembrane domain comprises a transmembrane region of a natural cytotoxicity receptor expressed in NK cells.9. The chimeric antigen receptor of wherein the natural cytotoxicity receptor expressed in NK cells comprises at least a portion of CD16 claim 8 , NKp44 claim 8 , NKp46 claim 8 , NKG2D claim 8 , NKp30 ...

CS1-SPECIFIC CHIMERIC ANTIGEN RECEPTOR ENGINEERED IMMUNE EFFECTOR CELLS

Disclosed herein are chimeric antigen receptors (CAR) that can specifically recognize tumor-associated antigens (TAA) on multiple myelorna (MM) cells. Also disclosed are Mullane 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 anti-tumor immunity in a subject with MM that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. 14.-. (canceled)5. A nucleic acid sequence encoding a chimeric antigen receptor (CAR) polypeptide , wherein the CAR polypeptide is defined by the formula:{'br': None, 'SP-CS1-HG-TM-CSR-ISD; or'}{'br': None, 'SP-CS1-HG-TM-ISD-CSR'}wherein “SP” represents a signal peptide,wherein “CS1” represents a CS1 antigen binding domain,wherein “HG” represents an optional hinge domain,wherein “TM” represents a transmembrane domain,wherein “CSR” represents a co-stimulatory signaling region,wherein “ISD” represents an intracellular signaling domain, andwherein “-” represents a bivalent linker.6. The nucleic acid sequence of claim 5 , wherein the CS1 antigen binding domain comprises an Fab or a single-chain variable fragment (scFv) of an antibody that specifically binds CS1.7. The nucleic acid sequence of claim 5 , wherein the intracellular signaling domain comprises a CD3 zeta (CD3ζ) signaling domain.8. The nucleic acid sequence of claim 5 , wherein the costimulatory signaling region comprises the cytoplasmic domain of a costimulatory molecule selected from the group consisting of CD28 and 4-1BB.9. A vector comprising the nucleic acid sequence of .10. A cell comprising the vector of .11. The cell of claim 10 , wherein the cell is selected from the group consisting of a T cell claim 10 , a Natural Killer (NK) cell claim 10 , and a cytotoxic T lymphocyte (CTL).12. The cell of claim 11 , wherein the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to CS1.1320.-. ( ...

SITE-SPECIFIC BIO-CONJUGATION METHODS AND COMPOSITIONS USEFUL FOR NANOPORE SYSTEMS

The present disclosure relates to relates methods and associated compositions that provide fast, efficient site-selective conjugation of a protein, such as the pore-forming protein α-hemolysin, to a biomolecule, such as a DNA polymerase, and the use of such site-selective protein-biomolecule conjugates in nanopore devices and methods. 2. The method of claim 1 , wherein the thiol reactive group A is a maleimide or a haloacetamide.4. The composition of claim 3 , wherein the thiol reactive group A is a maleimide or a haloacetamide claim 3 , wherein the halogen atom is selected from F claim 3 , Cl claim 3 , Br claim 3 , and I.5. The composition of claim 3 , wherein the click chemistry reactive groups X and Y are a pair selected from the following pairs of click chemistry reactive groups: azide and alkyne; azide and cyclooctyne; and azide and dibenzocyclooctyne-amine.8. The composition of claim 7 , wherein the thiol reactive group A is a maleimide.9. The composition of claim 7 , wherein the click chemistry reactive groups X and Y are a pair selected from the following pairs of click chemistry reactive groups: azide and alkyne; azide and cyclooctyne; and azide and dibenzocyclooctyne-amine.11. The composition of claim 10 , wherein the reactive group B comprises a SpyTag peptide and the reactive group Z comprises a SpyCatcher protein.12Streptococcus pyogenes. The composition of claim 11 , wherein the SpyTag peptide and SpyCatcher protein each comprise a fragment of an amino acid sequence of the CnaB2 domain from the fibronectin binding protein FbaB.13. The composition of claim 10 , wherein the protein is a pore-forming protein claim 10 , optionally selected from the group consisting of α-hemolysin claim 10 , β-hemolysin claim 10 , γ-hemolysin claim 10 , aerolysin claim 10 , cytolysin claim 10 , leukocidin claim 10 , melittin claim 10 , MspA porin and porin A.14. The composition of claim 10 , wherein the protein is a pore-forming protein embedded in a membrane.15. The ...

Novel generation of antigen-specific tcrs

The present invention contemplates methods for the generation of human antigen-specific T lymphocytes. The methods employ MHC class-II targeting signals fused to an antigen or fragment thereof to obtain MHC class presentation of RNA coded proteins. Accordingly, the present invention concerns expression vectors comprising MHC class-II targeting signal and at least one antigen or fragment thereof and its use for the in vitro generation of antigen-specific T lymphocytes. T cell clones and T cell receptors (TCRs) specific for tumor antigens or viral antigens are also described.

THERAPEUTIC AGENTS

An immunoresponsive cell, such as a T-cell expressing 1. An immuno-responsive cell expressing (a) a signalling region;', '(b) a co-stimulatory signalling region;', '(c) a transmembrane domain; and', '(d) a binding element that specifically interacts with a first epitope on a target antigen; and, '(i) a second generation chimeric antigen receptor comprising (e) a co-stimulatory signalling region which is different to that of (b);', '(f) a transmembrane domain; and', '(g) a binding element that specifically interacts with a second epitope on a target antigen., '(ii) a chimeric costimulatory receptor comprising'}2. The immuno-responsive cell of which is a T-cell.3. The immuno-responsive cell of wherein the signalling region (a) comprises the intracellular domain of human CD3 [zeta] chain or a variant thereof.4. The immuno-responsive cell of wherein co-stimulatory signalling regions for (b) and (e) are selected from CD28 claim 1 , CD27 ICOS claim 1 , 4-1BB claim 1 , OX40 claim 1 , CD30 claim 1 , GTR claim 1 , HVEM claim 1 , DR3 or CD40.5. The immuno-responsive cell of wherein one of (b) or (e) is CD28 and the other is 4-1BB or OX40.6. The immuno-responsive cell of wherein (b) is CD28.7. The immuno-responsive cell of wherein (e) is 4-1BB or CD27.8. The immuno-responsive cell of wherein the transmembrane domains of (c) and (f) are selected from CD8α and CD28 transmembrane domains.9. The immuno-responsive cell of wherein the first and second epitopes are associated with the same receptor or antigen.10. The immuno-responsive cell of which co-expresses a chimeric cytokine receptor.11. The immuno-responsive cell of wherein the chimeric cytokine receptor is 4αβ.12. The immuno-responsive cell of wherein at least one of binding element (d) or binding element (g) is a ligand for an ErbB dimer claim 1 , a receptor for colony stimulating factor-1 (CSF-1R) or an αβintegrin-specific binding agent.13. The immuno-responsive cell of wherein binding element (d) comprises CSF-1 and ...

NOVEL HUMANIZED ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR, ITS NUCELIC ACID SEQUENCE AND ITS PREPARATION

The present invention relates to novel humanized anti-CD19 chimeric antigen receptor containing an optimized anti-CD19 binding domain effective against the treatment of disease associated with expression of the Cluster of Differentiation 19 protein (CD19), and to a nucleic acid molecule encoding the humanized CAR. The invention also encompasses a process forth preparation of the CAR, composition containing the CAR, vectors containing the polynucleotide encoding the CAR and cells expressing the Carat their surface, in particular for their use in immunotherapy. 2. The nucleic acid molecule as claimed in claim 1 , which encodes a heavy chain complementary determining region 1 (HC CDR1) of SEQ ID No: 6 claim 1 , a heavy chain complementary determining region 2 (HC CDR2) of SEQ ID No: 8 or SEQ ID No. 9 claim 1 , a heavy chain complementary determining region 3 (HC CDR3) of SEQ ID No: 11 and a light chain complementary determining region 1 (LC CDR1) of SEQ ID No: 14 claim 1 , a light chain complementary determining region 2 (LC CDR2) of SEQ ID No: 16 claim 1 , and a light chain complementary determining region 3 (LC CDR3) of SEQ ID No: 18.3. The nucleic acid molecule as claimed in any of the preceding claims claim 1 , which encodes a heavy chain variable region (HCVR) selected from SEQ ID No: 1 claim 1 , SEQ ID No: 2 & SEQ ID No. 58 and a light chain variable region (LCVR) of SEQ ID No: 3.4. The nucleic acid molecule as claimed in claim 1 , which comprises a nucleic acid sequences encoding the HCVR and the LCVR claim 1 , wherein the nucleic acid sequence encoding the HCVR comprises the nucleotide sequence selected from SEQ ID No. 35 claim 1 , SEQ ID No. 36 & SEQ ID No.63 claim 1 , or nucleotide sequence with at least 95% identity thereof claim 1 , and the nucleic acid sequence encoding the LCVR comprises the nucleotide sequence selected from SEQ ID No. 37 claim 1 , SEQ ID No. 50 and SEQ ID No. 51 claim 1 , or nucleotide sequence with at least 95% identity thereof.5. The ...

Cd33 specific chimeric antigen receptors for cancer immunotherapy

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD33 monoclonal antibody, conferring specific immunity against CD33 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia.

TREATMENT OF CANCER USING A CD123 CHIMERIC ANTIGEN RECEPTOR

The invention provides compositions and methods for treating diseases associated with expression of CD123. The invention also relates to chimeric antigen receptor (CAR) specific to CD123, vectors encoding the same, and recombinant cells comprising the CD123 CAR. The invention also includes methods of administering a genetically modified cell expressing a CAR that comprises a CD123 binding domain. 1. An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) , wherein the CAR comprises a humanized CD123 binding domain , a transmembrane domain , and an intracellular signaling domain , and wherein said CD123 binding domain comprises a heavy chain variable domain region comprising a heavy chain complementary determining region 1 (HC CDR1) , a heavy chain complementary determining region 2 (HC CDR2) , and a heavy chain complementary determining region 3 (HC CDR3) and light chain variable domain region comprising a light chain complementary determining region 1 (LC CDR1) , a light chain complementary determining region 2 (LC CDR2) , and a light chain complementary determining region 3 (LC CDR3) , wherein:(a) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 sequences comprise the amino sequences of SEQ ID NO: 490, 495, 500, 505, 510, and 515, respectively;(b) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 sequences comprise the amino sequences of SEQ ID NO: 520, 525, 530, 535, 540, and 555, respectively;(c) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 sequences comprise the amino sequences of SEQ ID NO: 361, 389, 417, 445, 473, and 47, respectively.24.-. (canceled)5. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising:(i) the amino acid sequence of the light chain variable region of SEQ ID NO: 302-333;(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of the light chain variable region of SEQ ID ...

CD123 SPECIFIC CHIMERIC ANTIGEN RECEPTORS FOR CANCER IMMUNOTHERAPY

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD123 monoclonal antibody, conferring specific immunity against CD123 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia. 1. A chimeric antigen receptor (CAR) comprising:{'sub': H', 'L, 'an extracellular ligand binding domain comprising a heavy chain variable region (V) and a light chain variable region (V) from a monoclonal anti-CD123 antibody;'}an FcγRIIIα, CD8α, or IgG1 hinge;a CD8α or 4-1BB transmembrane domain; anda cytoplasmic domain comprising a CD3-ζ signaling domain and a co-stimulatory domain from 4-1BB2. The CAR of wherein the CAR has at least 80% sequence identity with SEQ ID NO. 42 claim 1 , SEQ ID NO. 44 claim 1 , or SEQ ID NO. 46.3. The CAR of claim 1 , wherein the Vregion comprises the following CDR sequences:SEQ ID NO. 67, SEQ ID NO. 68, and SEQ ID NO. 69.4. The CAR of claim 1 , wherein the Vregion comprises the following CDR sequences: SEQ ID NO. 70 claim 1 , SEQ ID NO. 71 claim 1 , and SEQ ID NO. 72.5. (canceled)6. The CAR of claim 1 , wherein the extracellular ligand binding domain comprises at least one of the following sequences:SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 56, SEQ ID NO. 57, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 60, SEQ ID NO. 61, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65, SEQ ID NO. 66, or a combination thereof.7. The CAR of claim 1 , comprising a CD8α hinge and a CD8α transmembrane domain.8. The CAR of claim 1 , comprising:a polypeptide having at least 80% sequence identity with a polypeptide of SEQ ID NO. 19; anda polypeptide having at least 80% sequence identity with a polypeptide of SEQ ID NO. 20.9. The CAR of claim 1 , further comprising another ...

Targeted Protein Degradation

The invention relates to a method of controlling the level of a polypeptide sequence comprising administering a polypeptide sequence fused to a ubiquitin targeting protein which comprises a minimal degron structural motif. In particular, the polypeptide sequence comprises a chimeric antigen receptor therefore the present invention is useful in methods of cell and gene therapy where the activity of the chimeric antigen receptor needs to be controlled. 1. A method of controlling the level of a polypeptide sequence comprising:a) administering a fusion protein comprising said polypeptide sequence and a ubiquitin targeting protein consisting of less than 135 amino acids in length which comprises the hairpin motif of a cereblon binding site, andb) controlling the level of the polypeptide sequence by administering a compound which mediates binding of the ubiquitin targeting protein and cereblon.2. The method of claim 1 , wherein the hairpin motif comprises a sequence selected from the group consisting of: SEQ ID NOs: 2-5 or a functional variant thereof claim 1 , wherein one or two amino acids may be substituted claim 1 , added or deleted except for the GLY residue present in each amino acid sequence.3. The method of claim 1 , wherein the hairpin motif comprises a sequence selected from the group consisting of: SEQ ID NOs: 2-5.4. The method of claim 1 , wherein the ubiquitin targeting protein is a polypeptide sequence consisting of less than 100 amino acids in length.5. The method of claim 1 , wherein the ubiquitin targeting protein comprises a lysine residue which acts as a ubiquitination site.6. The method of claim 1 , wherein the ubiquitin targeting protein comprises a sequence selected from the group consisting of: SEQ ID NOs: 6-14 and 27.7. The method of claim 1 , wherein the polypeptide sequence controlled by administering a compound which mediates binding of the ubiquitin targeting protein and cereblon is a transmembrane protein.8. The method of claim 1 , wherein the ...

Listeria-Based Compositions Comprising A Peptide Minigene Expression System And Methods Of Use Thereof

This disclosure provides compositions, including delivery vectors comprising minigene expression constructs, and methods of using the same for inducing an immune response against an antigen-expressing tumor and for treating the same, and vaccinating against the same in subjects bearing the tumors. 1Listeria. A recombinant strain comprising a minigene nucleic acid construct , said construct comprising an open reading frame encoding a chimeric protein , wherein said chimeric protein comprises:a. a bacterial secretion signal sequence,b. a ubiquitin (Ub) protein,c. a peptide,wherein said signal sequence, said ubiquitin and said peptide in a.-c. are arranged from the amino-terminus to the carboxy-terminus of said chimeric protein.2Listeria. The recombinant of claim 1 , wherein said open reading frame encoding the chimeric protein is linked to a second open reading frame by a Shine-Dalgarno ribosome binding site nucleic acid sequence claim 1 , wherein the second open reading frame encodes a second chimeric protein comprising: (a) a second bacterial secretion signal sequence; (b) a second ubiquitin (Ub) protein; and (c) a second peptide claim 1 , wherein the second signal sequence claim 1 , the second ubiquitin claim 1 , and the second peptide in (a)-(c) are arranged from the amino terminus to the carboxy terminus of the second chimeric protein.3. (canceled)4Listeria. The recombinant of claim 1 , wherein said peptide comprises one or more neoepitopes.5Listeria. The recombinant of claim 2 , wherein each open reading frame comprises a different peptide.6Listeria. The recombinant of claim 1 , wherein said minigene construct further comprises a 5′ bacterial promoter driving expression of the nucleic acid construct.7Listeria. The recombinant of claim 6 , wherein said promoter is an actA promoter claim 6 , an hly promoter claim 6 , or a p60 promoter.8Listeria. The recombinant of claim 1 , wherein said bacterial secretion signal sequence encodes an ActAsignal sequence comprising ...

TUMOR IMMUNOTHERAPY

Aspects of the present disclosure provide a platform that triggers potent and effective immunotherapy against tumors from within tumors themselves, thus overcoming limitations of existing cancer immunotherapies and tumor-detecting gene circuits. 1. An engineered genetic circuit , comprising:(a) a first nucleic acid comprising a promoter operably linked to (i) a nucleotide sequence encoding an output messenger RNA (mRNA) containing an intronic microRNA (miRNA) and (ii) a nucleotide sequence encoding at least one miRNA binding site complementary to the miRNA of (a)(i); and(b) a second nucleic acid comprising a promoter operably linked to a nucleotide sequence encoding at least one miRNA binding site complementary to the miRNA of (a)(i).2. The engineered genetic circuit of claim 1 , wherein output mRNA encodes a synthetic T cell engager (STE) or a bispecific T cell engager (BiTE).3. The engineered genetic circuit of claim 1 , wherein the output mRNA encodes an output protein that binds to a T cell surface marker.4. The engineered genetic circuit of claim 3 , wherein the T cell surface marker is CD3 claim 3 , CD4 claim 3 , CD8 or CD45.5. The engineered genetic circuit of any one of - claim 3 , wherein the output protein is an antibody or antibody fragment that binds specifically to the T cell surface antigen.6. The engineered genetic circuit of any one of - claim 3 , wherein the output mRNA encodes an anti-cancer agent.7. The engineered genetic circuit of claim 6 , wherein the anti-cancer agent is a chemokine claim 6 , a cytokine or a checkpoint inhibitor.8. The engineered genetic circuit of any one of - claim 6 , wherein the promoter of (a) and/or (b) is an inducible promoter.9. The engineered genetic circuit of claim 8 , wherein the promoter of (a) and/or (b) is a tumor-specific promoter or a cancer-promoter.10. The engineered genetic circuit of claim 9 , wherein the promoter of (a) and/or (b) is SSX1 or H2A1.11. The engineered genetic circuit of any one of - claim 9 ...

RESTIMULATION OF CRYOPRESERVED TUMOR INFILTRATING LYMPHOCYTES

The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation. 1. A population of expanded tumor infiltrating lymphocytes (TILs) , wherein the population of expanded TILs is a third population of TILs obtainable by a method comprising:(a) performing a first expansion by (i) thawing cryopreserved dissociated tumor materials comprising a first population of TILs obtained from a tumor that was resected from a subject, and (ii) culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs;(b) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, and wherein the second expansion is performed for about 7 to 14 days in order to obtain the third population of TILs; and(c) harvesting the third population of TILs obtained from step (b).2. The population of expanded TILs according to claim 1 , wherein the method further comprises a step (d) of transferring the harvested third population of TILs from step (c) into an infusion bag.3. The population of expanded TILs according to claim 2 , wherein the method further comprises a step (e) of cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process.4. The population of expanded TILs according to claim 1 , wherein the dissociated tumor materials comprise a tumor digest.5. The population of expanded TILs according to claim 1 , wherein obtaining the dissociated tumor materials comprises fragmenting the tumor resected from the subject into one or more tumor fragments.6. The ...

IMMUNOSUPPRESSIVE ANTIGEN-SPECIFIC CHIMERIC ANTIGEN RECEPTOR TREG CELLS FOR PREVENTION AND/OR TREATMENT OF AUTOIMMUNE AND ALLOIMMUNE DISORDERS

Described herein are immunoresponsive cells which are useful for their preventive and therapeutic potential against autoimmune diseases and rejections of solid organ transplants. 1. An immunoresponses cell comprising:a chimeric antigen receptor (CAR) that binds to glutamic acid decarboxylase 65 kDA (GAD65) in the cell;the CAR comprising:a) an intracellular signaling domain of a CD3ξ polypeptide and an intracellular signaling domain of CD28 hinge-transmembrane-intracellular region, andb) an extracellular polypeptide recognizing: at least a part of an amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6; or, at least one complete amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6.2. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell is selected from the group consisting of: T cells claim 1 , cytotoxic T cells claim 1 , regulatory T cells claim 1 , and combinations thereof.3. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell comprises a pancreatic beta cell-specific chimeric antigen receptor (CAR) regulatory T cell (Treg) that expresses at least one extracellular polypeptide and is capable of affecting Teff cells.4. The immunosuppressive cell of claim 1 , wherein the extracellular polypeptide is a GAD65 MAb antigen binding domain which recognizes: at least a part of an amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6; or claim 1 , at least one complete amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6.5. A pharmaceutical composition comprising an effective amount of an immunoresponsive cell of and a pharmaceutically acceptable excipient.6. The pharmaceutical composition of claim 5 , wherein the immunoresponsive cell is a T cell.7. (canceled)8. A method of lengthening survival of a subject having type 1 diabetes (T1D) claim 5 , the method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'administering to the subject an ...

FLUORESCENT FUSION POLYPEPTIDE, BIOSENSOR COMPRISING SAID POLYPEPTIDE AND USES THEREOF

The present invention refers to a fluorescent fusion polypeptide capable of changing its localization within the cell from the cell cytoplasmic membrane to the retention vesicles, upon an increase in the concentration of second messengers within the cell cytoplasm, comprising a membrane localization peptide, a second messenger transduction protein binding peptide, a reticulum retention signal and a fluorescent peptide wherein: 1. A fluorescent fusion polypeptide , wherein said fluorescent fusion polypeptide is capable of changing its localization within a cell from cytoplasmic membrane to a retention vesicle upon an increase in the concentration of a second messenger in the cytoplasm of the cell , wherein the second messenger is calcium , comprising a membrane localization peptide , a second messenger transduction protein binding peptide , a reticulum retention signal and a fluorescent peptide wherein:a. the membrane localization peptide is located at the N-terminus of the fluorescent fusion polypeptide and is physically bound to the fluorescent peptide, which, in turn, is physically bound to the second messenger transduction protein binding peptide; andb. the second messenger transduction protein binding peptide is physically bound to the reticulum retention signal, which, in turn, is located at the C-terminus of the fluorescent fusion polypeptide.2. The fluorescent fusion polypeptide of claim 1 , wherein:a. the membrane localization peptide is the extracellular domain of interleukin-2 receptor of SEQ ID NO: 17 or a variant which is at least 90% homologous to this sequence over the entire region based on amino acid identity; andb. the reticulum retention signal is the peptide selected from the group consisting of KDEL, HDEL, KKXX, KXKXX and RXR, wherein X is any amino acid.3. The fluorescent fusion polypeptide of claim 1 , wherein:a. the membrane localization peptide is the extracellular domain of interleukin-2 receptor of SEQ ID NO: 17; andb. the reticulum ...

FLUORESCENT FUSION POLYPEPTIDE, BIOSENSOR COMPRISING SAID POLYPEPTIDE AND USES THEREOF

The present invention refers to a fluorescent fusion polypeptide capable of changing its localization within the cell from the cell cytoplasmic membrane to the retention vesicles, upon an increase in the concentration of second messengers within the cell cytoplasm, comprising a membrane localization peptide, a second messenger transduction protein binding peptide, a reticulum retention signal and a fluorescent peptide wherein: 1. A fluorescent fusion polypeptide , wherein said fluorescent fusion polypeptide is capable of changing its localization within a cell from cytoplasmic membrane to a retention vesicle upon an increase in the concentration of a second messenger in the cytoplasm of the cell , wherein the second messenger is diacylglycerol , comprising a membrane localization peptide , a second messenger transduction protein binding peptide , a reticulum retention signal and a fluorescent peptide wherein:a. the membrane localization peptide is located at the N-terminus of the fluorescent fusion polypeptide and is physically bound to the fluorescent peptide, which, in turn, is physically bound to the second messenger transduction protein binding peptide; andb. the second messenger transduction protein binding peptide is physically bound to the reticulum retention signal, which, in turn, is located at the C-terminus of the fluorescent fusion polypeptide.2. The fluorescent fusion polypeptide of claim 1 , wherein:a. the membrane localization peptide is the extracellular domain of interleukin-2 receptor of SEQ ID NO: 17 or a variant which is at least 90% homologous to this sequence over the entire region based on amino acid identity; andb. the reticulum retention signal is the peptide selected from the group consisting of KDEL, HDEL, KKXX, KXKXX and RXR, wherein X is any amino acid.3. The fluorescent fusion polypeptide of claim 1 , wherein:a. the membrane localization peptide is the extracellular domain of interleukin-2 receptor of SEQ ID NO: 17; andb. the reticulum ...

GLA DOMAINS AS TARGETING AGENTS

The disclosure relates to the recombinant Gla domain proteins and their use targeting phosphatidylserine (PtdS) moieties on the surface of cells, particularly those expressing elevated levels of PtdS, such as cells undergoing apoptosis. These proteins can be linked to both diagnostic and therapeutic payloads, thereby permitting identification and treatment of cells expression elevated PtdS. 2. The method of claim 1 , wherein said cell membrane is a cardiac cell membrane claim 1 , a neuronal cell membrane claim 1 , an endothelial cell membrane claim 1 , a virus-infected cell membrane claim 1 , an apoptotic cell membrane claim 1 , a platelet membrane or a cancer cell membrane.3. The method of claim 1 , wherein said polypeptide further comprises an EGF binding domain claim 1 , a Kingle domain claim 1 , an aromatic amino acid stack domain claim 1 , a Gla domain from Factor II claim 1 , a Gla domain from Factor VII claim 1 , a Gla domain from Factor IX claim 1 , a Gla domain from Factor X claim 1 , a Gla domain from protein S claim 1 , and a Gla domain from protein C.46-. (canceled)721-. (canceled)22. The method of claim 1 , wherein said polypeptide comprises protein S Gla domain.23. The method of claim 1 , wherein said polypeptide comprises protein S Gla domain and protein S EGF domain.24. The method of claim 1 , wherein said polypeptide comprises prothrombin Gla domain.25. The method of claim 1 , wherein said polypeptide comprises prothrombin Gla domain plus prothrombin Kringle domain.26. The method of claim 1 , wherein said polypeptide comprises protein Z Gla domain.27. The method of claim 1 , wherein said polypeptide comprises protein Z Gla domain plus prothrombin Kringle domain.28. The method of claim 1 , wherein said polypeptide comprises Factor VII Gla domain.29. The method of claim 1 , wherein said polypeptide comprises Factor VII Gla domain plus prothrombin Kringle domain.30. The method of claim 1 , wherein said polypeptide further comprises an antibody Fc ...

Methods for Enhancing Efficacy of Therapeutic Immune Cells

The present invention relates to a method of using a receptor (e.g., chimeric antigen receptor—CAR) that activates an immune response upon binding a cancer cell ligand in conjunction with a target-binding molecule that targets a protein or molecule CI for removal or neutralization to generate enhanced anti-cancer immune cells. The present invention also relates to engineered immune cells having enhanced therapeutic efficacy and uses thereof. 1. An engineered immune cell that comprises a nucleic acid comprising a nucleotide sequence encoding an immune activating receptor and a nucleic acid comprising a nucleotide sequence encoding a target-binding molecule linked to a localizing domain.2. The engineered immune cell of claim 1 , wherein the engineered immune cell is an engineered T cell claim 1 , an engineered natural killer (NK) cell claim 1 , an engineered NK/T cell claim 1 , an engineered monocyte claim 1 , an engineered macrophage claim 1 , or an engineered dendritic cell.3. The engineered immune cell of claim 1 , wherein the receptor is a chimeric antigen receptor (CAR).4. The engineered immune cell of claim 1 , wherein the CAR is anti-CD19-4-1BB-CD3ζ CAR.5. The engineered immune cell of claim 1 , wherein the target-binding molecule is an antibody.6. The engineered immune cell of claim 5 , wherein the antibody is a single-chain variable fragment (scFv).7. The engineered immune cell of claim 5 , wherein the antibody binds to a factor in a CD3/T-cell receptor (TCR) complex claim 5 , a cytokine claim 5 , a human leukocyte antigen (HLA) Class I molecule claim 5 , or a receptor that downregulates immune response.8. The engineered immune cell of claim 7 , wherein the factor in a CD3/TCR complex is CD3ε claim 7 , TCRα claim 7 , TCRβ claim 7 , TCRγ claim 7 , TCRδ claim 7 , CD3δ claim 7 , CD3γ claim 7 , or CD3ζ.9. The engineered immune cell of claim 7 , wherein the HLA Class I molecule is β2-microglobulin claim 7 , α1-microglobulin claim 7 , α2-microglobulin claim 7 , or ...

CHIMERIC ANTIGEN RECEPTOR TARGETING OF TUMOR ENDOTHELIUM

Disclosed are methods, protocols, and compositions of matter related to utilization of chimeric antigen receptor (CAR) expressing cells for the targeting of tumor endothelium utilizing chimeric antigen receptor expressing stem cells. In one embodiment tumor endothelium specific antigens are utilized as targets of the antigen binding domain of a CAR, which is attached to an extracellular hinge domain, a domain that transverses the T cell membrane and an intracellular domain associated with T cell signaling. Suitable antigens for the practice of the invention include TEM-1, ROBO-4, surviving, and FasL. In other aspects of the invention antigens are identified through serological analysis of recombinant cDNA expression libraries (SEREX) using plasma from a patient immunized with placental endothelial cells. 1. A method of immunologically inhibiting neoangiogenesis comprising:a) obtaining a cell population from peripheral blood;b) transfecting said population with a chimeric antigen receptor (CAR); andc) introducing said transfected cell population into said patient.2. The method of claim 1 , wherein said blood cell population is selected from a group comprising:a) peripheral blood mononuclear cells;b) CD4 T cells;c) CD8 T cells;d) NK cells;e) NKT cells; andf) gamma delta T cells.3. The method of claim 2 , wherein said CD4 T cells are isolated by means of magnetic separation prior to transfection with CAR.4. The method of claim 2 , wherein said CD8 T cells are isolated by means of magnetic separation prior to transfection with CAR.5. The method of claim 1 , wherein said CAR is comprised of:a) an antigen binding domain;b) a transmembrane domain;c) a costimulatory signaling region; andd) a CD3 zeta signaling domain.6. The method of claim 5 , wherein said CD3 zeta chain is resistant to cleavage by caspase 3 by means of amino acid substitution.7. The method of claim 5 , wherein the antigen binding domain is an antibody or an antigen-binding fragment thereof.8. The method of ...

Expression of Chimeric Polypeptide with Variable Lymphocyte Receptors on Immune Cells and Uses for Treating Cancer

This disclosure relates to recombinant cellular expression of chimeric proteins with peptide sequences derived from lymphocyte receptors and uses for treating cancer. In certain embodiments, the disclosure relates to a recombinant vector comprising a nucleic acid that encodes a chimeric protein with a segment with a targeting moiety based on a variable lymphocyte receptor (VLR) capable of binding a tumor associated antigen and a segment with a T cell signal transduction subunit. In certain embodiments, the recombinant vectors are used in immune based cancer treatments. 1. A recombinant vector comprising a nucleic acid that encodes a chimeric polypeptide comprising a targeting sequence of variable lymphocyte receptor domain or variant thereof , a transmembrane domain , a T cell costimulatory molecule domain , and a signal-transduction component of a T-cell antigen receptor domain.2. The recombinant vector of claim 1 , wherein the variable lymphocyte receptor domain contains a polypeptide sequence of less than 250 amino acids and 4 or 5 or more segments having SEQ ID NO: 1 (XXLXLXX) wherein X may be any amino acid and L may be claim 1 , individually and independently at each occurrence claim 1 , leucine or isoleucine or one L (leucine or isoleucine) may be substituted with any amino acid.3. The recombinant vector of claim 2 , wherein the variable lymphocyte receptor has a sequence VXCXXXXLXSVPAXIPTTTXXLXXXXNXITKXXPGVFDXLXXLXXXXL XXNXLXXXPXGXFD (SEQ ID NO: 2) wherein X may be any amino acid.4. The recombinant vector of claim 2 , wherein the variable lymphocyte receptor has SEQ ID NO: 4 claim 2 , 6 claim 2 , 8 claim 2 , 10 claim 2 , or a sequence with greater than 95% identity thereto.5. The recombinant vector of claim 2 , wherein the nucleic acid has SEQ ID NO: 3 claim 2 , 5 claim 2 , 7 claim 2 , 9 claim 2 , or a sequence with greater than 95% identity thereto.6. The recombinant vector of claim 1 , wherein the costimulatory molecule is selected from CD28 claim 1 , CD80 ...

Capsular gram-positive bacteria bioconjugate vaccines

The present invention encompasses a novel S. aureus bioconjugate vaccine. More generally, the invention is directed to Gram-positive and other bioconjugate vaccines containing a protein carrier, at least one polysaccharide such as a capsular Gram-positive polysaccharide, and, optionally, an adjuvant or pharmaceutically acceptable carrier. The instant invention also includes methods of producing Gram-positive and other bioconjugate vaccines. An N-glycosylated protein is also provided that contains one or more polysaccharides such as Gram-positive polysaccharides. The invention is additionally directed to engineered prokaryotic organisms comprising nucleotide sequences encoding a glycosyltransferase of a first prokaryotic organism and a glycosyltransferase of a second prokaryotic organism. The invention further includes plasmids and prokaryotic cells transformed with plasmids encoding polysaccharides and enzymes which produce an N-glycosylated protein and/or bioconjugate vaccine. Further, the invention is directed to methods of inducing an immune response in a mammal comprising administering said bioconjugate vaccines.

Compositions and methods for producing pro-inflammatory macrophages

Constructs are provided that exploit selected portions of the TLR4 receptor to which no extracellular ligand will bind. A dimerization domain is employed to allow for regulated activation when used in conjunction with a dimerizer drug. In addition, a myristoylation domain facilitates intracellular presentation. Constructs of the invention can be used to create engineered monocytes whose TLR4 receptors can be selectively activated with administration of a dimerization agent. Engineered macrophages can be selectively induced to become pro-inflammatory, providing methods to ameliorate conditions associated with excessive pro-repair macrophages, such as cardiac fibrosis and solid tumor growth. Delivery of the engineered macrophages to sites of cardiac fibrosis can reduce the amount of fibrosis and scarring and ameliorate cardiac function. Delivery of the engineered macrophages to solid tumors can reduce tumor growth and size.

IMMUNOMODULATORY FUSION PROTEINS AND USES THEREOF

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 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; andwherein the extracellular component is or comprises a CD95 (Fas) ectodomain or a functional fragment thereof, and the intracellular component is or comprises a CD137 (4-1BB) intracellular signaling domain or a functional portion thereof2. 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 ...

NUCLEIC ACID CONSTRUCTS FOR CO-EXPRESSION OF CHIMERIC ANTIGEN RECEPTOR AND TRANSCRIPTION FACTOR, CELLS CONTAINING AND THERAPEUTIC USE THEREOF

Nucleic acid constructs, vectors, and recombinant cells harboring the nucleic acid constructs or vectors are disclosed. The nucleic acid constructs include genes encoding a chimeric antigen receptor (CAR) and/or one or more transcription factors, optionally mutated. The transcription factors include those that mediate proinflammatory cytokine expression, e.g., T-bet, STAT1, or STAT4. Methods are disclosed of co-expression of the CAR and the transcription factor in a human or non-human immune cell, preferably human T cells. Also disclosed are methods for using these cells for immunotherapy, e.g., in treating cancer, infection, autoimmunity, allergy or inflammation diseases by the administration of a prophylactically or therapeutically effective amount of one or more of the nucleic acid constructs, vectors, and/or immune cells, e.g., human CAR-T cells, described herein. 1. A nucleic acid construct or constructs comprising (i) a nucleic acid encoding a chimeric antigen receptor (CAR) and (ii) at least one other nucleic acid encoding a transcription factor or a variant thereof , wherein (i) and (ii) are on the same or different constructs.2. The construct or constructs of claim 1 , wherein the transcription factor elicits one or more of the following effects in an immune cell containing said construct or constructs:(i) enhances the expression of said CAR by said immune cell,{'sup': +', '+, 'sub': 'H', '(ii) for an immune cell that is a CD4 T cell, promotes the development of the CD4 T cell to a T1 cell,'}{'sub': 'H', "(iii) promotes the immune cell's expression of T1 cytokines such as IL-2, IFNγ or TNFα,"}{'sub': H', 'H', 'H', 'FH, '(iv) suppresses the development of these immune cells or their progeny into other (non-T1) cells such as T2, T17, or Tcells,'}{'sub': 'H', '(v) suppresses the expression of T2 cytokines such as IL-13 by said immune cell or its progeny;'}(vi) enhances the immune cell's killing of target cells expressing the antigen bound by the CAR; and/or{' ...

Effective generation of tumor-targeted t cells derived from pluripotent stem cells

The present invention relates to the field of adoptive immunotherapy. The invention provides methods for generating phenotypically defined, functional, and/or expandable T cells from pluripotent stem cells engineered through safe genetic modifications. The engineered cells may provide one or more of: 1) targeting a specific predetermined antigen expressed on the cell surface of a target cell in an HLA independent manner, 2) enhanced survival and functional potential 3) “off-the-shelf” T cells for administration to multiple recipients, eventually across immunogenic barriers, and/or 4) cytotoxic potential and anti-tumor activity.

DIMERIZING AGENT REGULATED IMMUNORECEPTOR COMPLEXES

The present disclosure provides improved compositions for adoptive T cell therapies targeting CD33 for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith. The present disclosure also relates to adoptive T cell therapies targeting CD33 and another target antigen for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith. 1. A non-natural cell comprising:(a) a first polypeptide comprising: an FRB multimerization domain polypeptide or variant thereof; a CD8α transmembrane domain or a CD4 transmembrane domain; a CD137 co-stimulatory domain; and/or a CD3ζ primary signaling domain; and(b) a second polypeptide comprising: a binding domain that binds to CD33; an FKBP multimerization domain polypeptide or variant thereof; and a CD4 transmembrane domain or a CD8α transmembrane domain;wherein a bridging factor promotes the formation of a polypeptide complex on the non-natural cell surface with the bridging factor associated with and disposed between the multimerization domains of the first and second polypeptides.2. The non-natural cell of claim 1 , wherein the FKBP multimerization domain is FKBP12.3. The non-natural cell of or claim 1 , wherein the FRB polypeptide is FRB T2098L.4. The non-natural cell of any one of to claim 1 , wherein the bridging factor is selected from the group consisting of: AP21967 claim 1 , sirolimus claim 1 , everolimus claim 1 , novolimus claim 1 , pimecrolimus claim 1 , ridaforolimus claim 1 , tacrolimus claim 1 , temsirolimus claim 1 , umirolimus claim 1 , and zotarolimus.5. The non-natural cell of any one of to claim 1 , wherein the first polypeptide comprises a CD8α transmembrane domain; a CD137 co-stimulatory domain; and a CD3ζ primary signaling domain.6. The non-natural cell ...

Cellular Libraries of Peptide Sequences (CLiPS) and Methods of Using the Same

The present invention provides compositions including peptide display scaffolds that present at least one candidate peptide and at least one detectable moiety in at least one of the N-terminal and C-terminal candidate peptide presenting domains that when expressed in a cell are accessible at a surface of the cell outermembrane. In addition, the present invention also provides kits and methods for screening a library of cells presenting the candidate peptides in peptide display scaffolds to identify a ligand for an enzyme. 146-. (canceled)47. A peptide display scaffold comprising a fusion protein comprising the formula:{'br': None, 'sub': 1', '1', '2, '[D-C]-TM-[D],'}wherein TM is a circularly permuted transmembrane protein;{'sub': '1', 'wherein Ccomprises a candidate peptide;'}{'sub': '1', 'wherein Dis a first detectable moiety and is a heterologous peptide or polypeptide;'}{'sub': '2', 'wherein Dis a second detectable moiety and is a heterologous peptide or polypeptide;'}{'sub': 1', '2, 'wherein Dand Dare not the same; and'}{'sub': 1', '2', '1, 'wherein D, D, and C, when the peptide display scaffold is expressed in a host cell, are exposed at an extracellular surface of the host cell outer membrane.'}48. The peptide display scaffold of claim 47 , wherein the fusion protein comprises at least one linker claim 47 , wherein the linker is between Cand TM or between Dand TM.49. The peptide display scaffold of claim 47 , wherein detectable moieties Dand Dare affinity tags.50. The peptide display scaffold of claim 47 , wherein when Dprovides a detectable Dsignal claim 47 , Ddoes not provide a detectable Dsignal above a background level of a detectable Dsignal.51. The peptide display scaffold of claim 47 , wherein the Ccomprises a member of a library of candidate peptide substrates for an enzyme.52. The peptide display scaffold of claim 47 , wherein the fusion protein comprises a linker between the Cand the TM and a linker between the Dand the TM.53. The peptide display ...

Compositions and methods for peptide expression and purification using a type iii secretion system

Disclosed are compositions and methods for expressing and purifying a peptide of interest using a Flagellar Type III secretion system. Disclosed are nucleic acid sequences that contain a FlgM nucleic acid sequence, a cleavage site, and a nucleic acid sequence of interest. Also disclosed are polypeptides that contain FlgM, a cleavage site and a peptide of interest. Methods of producing polypeptides that have FlgM, a cleavage site and a peptide of interest are provided.

Method and compositions for cellular immunotherapy

The present invention provides nucleic acids, vectors, host cells, methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring CD8+ central memory T cells or combinations of central memory T cells with CD4+ T cells that are genetically modified to express a chimeric receptor. In some alternatives the genetically modified host cell comprises a nucleic acid comprising a polynucleotide coding for a ligand binding domain, a poly nucleotide comprising a customized spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain. In some alternatives, the ligand binding domains binds to CD171.

Human Biosensors for Detecting ATP

This invention provides biosensors, cell models, and methods of their use for monitoring heme, oxygen or ATP. Biosensors can include targeting domains, sensing domains and reporting domains. Biosensors can be introduced into cells reprogrammed to represent experimental or pathologic cells of interest. Model cells expressing the biosensors can be contacted with putative bioactive agents to determine possible activities. 2. The sensor of wherein fluorescent reporter fluoresces in the 605 nm to 635 nm (excitation/emission) range.3. The sensor of wherein the fluorescent reporter has the sequence of SEQ. ID. NOS. 2 claim 1 , 6 or 17 claim 1 , or is at least 90% identical to one of said sequences.4. A nucleic acid construct encoding the sensor of .5. The nucleic acid construct of claim 1 , further comprising a tag sequence selected from the group consisting of: a NLS tag claim 1 , a lipid membrane tag claim 1 , an ER tag claim 1 , a golgi tag claim 1 , an endosome tag claim 1 , a mitochondrial tag claim 1 , a synapsin tag claim 1 , a cellular compartmental tag claim 1 , a synaptic vesicle tag claim 1 , and a ciliary tag.6. A cell transformed with the nucleic acid construct of .7. The cell of which is a human cell.8. The cell of which is an iPSC derived cell claim 7 , or is derived from a fibroblast or a blood cell.9. A vector including the construct of .11. An assay kit including the sensor peptide construct of .12. A process of making an assay for detecting ATP comprising:making a sensor peptide construct by combining:a binding domain which binds to ATP which comprises a sequence at least 80% identical to:MDYKDDDDKKTNWQKRIYRVKPCVICKVAPRDWWVENRHLRIYTMCKTCFSNCI NYGDDTYYGHDDWLMYTDCKEFSNTYHNLGRLPDEDRHWSASCHHHHHHMGM SGS (SEQ ID NO: 18), with a fluorescent reporter domain, wherein the fluorescent reporter is adapted to fluoresce at wavelengths in the range from 500 nm to 1400 nm; wherein the fluorescent reporter domain is adapted to change fluorescent emissions characteristics ...

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

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.

LENTIVIRAL VECTORS FOR REGULATED EXPRESSION OF A CHIMERIC ANTIGEN RECEPTOR MOLECULE

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 ...

PD-1-CD28 FUSION PROTEINS AND THEIR USE IN MEDICINE

The present invention relates to PD-1-CD28 fusion proteins, nucleic acid molecules, vectors, transduced cells carrying nucleic acid molecules or vectors of the present invention or expressing the fusion proteins of the present invention, methods and kits comprising the nucleic acid molecules, vectors and/or the fusion proteins of the present invention. The invention also provides the use of said transduced cells in a method for the treatment of particular diseases as well as a pharmaceutical composition/medicament comprising said transduced cells expressing the fusion proteins of the present invention for use in a method of treating of diseases, in particular in the medical intervention of diseases characterized by PD-L1 and/or PD-L2 expression. 1. A fusion protein comprising a PD-1 polypeptide which is operably linked via its C-terminus to the N-terminus of an intracellular domain of a CD28 polypeptide , wherein the PD-1 polypeptide comprises the extracellular domain and the transmembrane domain of PD-1.2. The fusion protein of claim 1 , wherein the PD-1 polypeptide comprises the sequence of SEQ ID NO: 16 or a sequence which has 1 to 10 substitutions claim 1 , deletions or insertions in comparison to SEQ ID NO: 16 and which is characterized by having a PD-L1 and/or PD-L2 binding activity.3. The fusion protein of claim 1 , wherein the transmembrane domain of PD-1 has the amino acid sequence of SEQ ID NO: 20.4. The fusion protein of claim 1 , wherein the CD28 polypeptide comprises a sequence derived from the intracellular domain of a CD28 polypeptide having the sequences YMNM (SEQ ID NO: 29) and/or PYAP (SEQ ID NO: 30).5. The fusion protein of claim 1 , wherein the CD28 polypeptide has the amino acid sequence of SEQ ID NO: 22.6. The fusion protein of claim 1 , wherein the fusion protein consists of SEQ ID NO: 24.7. The fusion protein of claim 6 , wherein said fusion protein has(a) a PD-1 polypeptide comprising a sequence which has 1 to 10 substitutions, deletions or ...

SYSTEM FOR PRESENTING PEPTIDES ON THE CELL SURFACE

The subject-matter of the present application concerns fusion proteins based on tetraspanin proteins, in which the extracellular loop is replaced in whole or in part by peptide sequences of a different composition and also their production and use as transport vehicle. The disclosed fusion proteins are anchored in the membrane of cells and can be used to present foreign peptides fused with them on the cell surface. 1. Fusion protein , comprising a first domain (i) , a second domain (ii) and a third domain (iii) , wherein the second domain is disposed between the first and the third domain , wherein(i) a partial sequence of a tetraspanin, which includes the transmembrane domain 1 (TM1), the small extracellular loop (SEL), the transmembrane domain 2 (TM2), the small intracellular loop (SIL) and the transmembrane domain 3 (TM3), or comprises a sequence homologous thereto with a sequence identity of at least 70% over the entire length,(ii) comprises a peptide with a predetermined amino-acid sequence, having a sequence identity of less than 70% over the entire length in respect of the large extracellular loop (LEL) of a tetraspanin and(iii) comprises a partial sequence of a tetraspanin, comprising the transmembrane domain 4 (TM4) or a sequence homologous thereto with a sequence identity of at least 70% over the entire length.2. Fusion protein according to claim 1 , wherein flexible linkers are disposed between the first and the second domain and/or between the second and the third domain.3. Fusion protein according to or claim 1 , wherein the second domain (ii) comprises furthermore one or more partial sequences of the LEL of a tetraspanin or sequences homologous thereto with a sequence identity of at least 70% over the entire length claim 1 , which are disposed C- and/or N-terminally to the peptide with the predetermined amino-acid sequence.4. Fusion protein according to claim 1 , wherein the second domain (ii) comprises furthermore one or more protease recognition ...

Conditionally Active Chimeric Antigen Receptors for Modified T-Cells

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.

CONDITIONALLY ACTIVE CHIMERIC ANTIGEN RECEPTORS FOR MODIFIED T-CELLS

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 ...

LIGHT-GATED SIGNALING MODULATION

The present invention relates to a nucleic acid molecule encoding a fusion protein, wherein the nucleic acid molecule comprises: (a) a first nucleic acid sequence encoding a first biosensor, wherein said first biosensor is a first molecule capable of interacting with a second molecule; (b) a second nucleic acid sequence encoding an effector-activating module, wherein the effector-activating module comprises a nucleic acid sequence encoding a first part of a protease, wherein said first part of the protease is capable of interacting with a second part of said protease to form an active form of said protease; (c) a third nucleic acid sequence encoding a third biosensor comprising a protease cleavage site, wherein the protease cleavage site is sterically occluded in the absence of a stimulus for said third biosensor and wherein the protease cleavage site becomes accessible in the presence of said stimulus. 1. A nucleic acid molecule encoding a fusion protein , wherein the nucleic acid molecule comprises:(a) a first nucleic acid sequence encoding a transmembrane domain linked to a first biosensor, wherein said first biosensor is a first molecule capable of interacting with a second molecule to form part of a first inducible interaction module, and wherein said first biosensor is linked to the transmembrane domain such that the first biosensor is located intracellularly upon expression of the fusion protein in a cell; (i) a first part of a protease, wherein said first part of the protease is capable of interacting with a second part of said protease to form an active form of said protease; or', '(ii) a second biosensor, wherein said second biosensor is a first molecule capable of interacting with a second molecule to form part of a second inducible interaction module;, '(b) a second nucleic acid sequence encoding an effector-activating module, wherein the effector-activating module comprises(c) a third nucleic acid sequence encoding a third biosensor comprising a ...

Compositions and Methods for Treating Cancer with Anti-CD123 Immunotherapy

Chimeric antigen receptors containing CD123 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.

METHOD

The present invention relates to immunotherapeutic approaches to treating haematological cancers. In particular the invention relates to a method for treating a haematological cancer by targeting the 5T4 antigen. As such, the invention provides a method for treating haematological cancers comprising administering to a subject a 5T4-targeting agent. The invention also provides a 5T4-specific chimeric antigen receptor (CAR) and uses thereof in treating cancers. 1. A method for treating or preventing a haematological cancer in a subject comprising administering a 5T4-targeting agent to the subject , wherein said haematological cancer is not pre-B acute lymphoblastic leukaemia (B-ALL).2. The method according to wherein said 5T4-targeting agent is an antibody or a biologically active fragment thereof.3. The method according to wherein said antibody is a monoclonal antibody or a biologically active fragment thereof.4. The method according to wherein said monoclonal antibody is based on an H8 5T4-specific antibody or a 2E4 5T4-specific antibody.5. The method according to any one of to claim 3 , wherein said antibody is in the form of an antibody-drug conjugate.6. The method according to wherein said 5T4-targeting agent is an immune cell.7. The method according to wherein said immune cell is a T cell claim 6 , NK cell or NKT cell.8. The method according to wherein said immune cell is a T cell.9. The method according to any of to wherein said cell comprises a 5T4-specific chimeric antigen receptor (CAR) or T cell receptor (TCR).10. The method of wherein said 5T4-targeting agent is a 5T4 vaccine.11. The method according to any of the above claims wherein said 5T4-targeting agent is administered via intravenous administration.12. The method according to any of the above claims wherein said subject is a mammalian subject.13. The method according to any of the above claims wherein said subject is a human subject.14. The method according to any of the above claims wherein said ...

Immune cell compositions and methods of use

Disclosed herein are immunostimulatory cells recombinantly engineered for adoptive cellular therapy. Additionally provided are pharmaceutical compositions comprising such immunostimulatory cells and methods of using such immunostimulatory cells to treat cancer or pathogen infections in a subject in need thereof.

SERINE PROTEASE MOLECULES AND THERAPIES

Cell-targeted serine protease constructs are provided. Such constructs can be used in methods for targeted cell killing such as for treatment cell of proliferative diseases (e.g., cancer). In some aspects, recombinant serine proteases, such as Granzyme B polypeptides, are provided that exhibit improved stability and cell toxicity. Methods and compositions for treating lapatinib or trastuzumab-resistant cancers are also provided. 1102.-. (canceled)103. A cell-targeting construct comprising:(a) cytotoxic moiety;(b) an antibody heavy chain constant (Fc) domain; and(c) a cell-targeting hormone domain.104. The cell-targeting construct of claim 103 , wherein the polypeptide comprises from N- to C-terminus (a) the cytotoxic moiety; (b) the Fc domain; and (c) the cell-targeting hormone domain.105. The cell-targeting construct of claim 104 , wherein the cell-targeting hormone domain is human chorionic gonadotropin claim 104 , gonadotropin releasing hormone claim 104 , an androgen claim 104 , an estrogen claim 104 , thyroid-stimulating hormone claim 104 , follicle-stimulating hormone claim 104 , luteinizing hormone claim 104 , prolactin claim 104 , growth hormone claim 104 , adrenocorticotropic hormone claim 104 , antidiuretic hormone claim 104 , oxytocin claim 104 , thyrotropin-releasing hormone claim 104 , growth hormone releasing hormone claim 104 , corticotropin-releasing hormone claim 104 , somatostatin claim 104 , dopamine claim 104 , melatonin claim 104 , thyroxine claim 104 , calcitonin claim 104 , parathyroid hormone claim 104 , glucocorticoids claim 104 , mineralocorticoids claim 104 , adrenaline claim 104 , noradrenaline claim 104 , progesterone claim 104 , insulin claim 104 , glucagon claim 104 , amylin claim 104 , erythropoitin claim 104 , calcitriol claim 104 , calciferol claim 104 , atrial-natriuretic peptide claim 104 , gastrin claim 104 , secretin claim 104 , cholecystokinin claim 104 , neuropeptide Y claim 104 , ghrelin claim 104 , PYY3-36 claim 104 , ...

Compositions and methods for treating cancer

Disclosed are compositions and methods for targeted treatment of cancer. The present disclosure provides chimeric antigen receptors and cells expressing such chimeric antigen receptors. In certain embodiments, engineered cells expressing the chimeric antigen receptors are specific for a low density cancer antigen or peptide in groove antigen.

CHIMERIC ANTIGEN RECEPTORS COMPRISING BCMA-SPECIFIC FIBRONECTIN TYPE III DOMAINS AND USES THEREOF

BCMA-specific fibronectin type III (FN3) domains, BCMA-targeting chimeric antigen receptors (CARs) comprising the FN3 domains, and engineered BCMA-targeting immune cells expressing the CARs are described. Also described are nucleic acids and expression vectors encoding the FN3 domains and the CARs, recombinant cells containing the vectors, and compositions comprising the engineered immune cells. Methods of making the FN3 domains, CARs, and engineered immune cells, and methods of using the engineered immune cells to treat diseases including cancer are also described. 113-. (canceled)14. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) comprising:an extracellular domain having an FN3 domain that binds to BCMA;a transmembrane domain; andan intracellular signaling domain.15. The isolated polynucleotide of claim 14 , wherein the FN3 domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 1; and wherein the FN3 domain binds to a human BCMA with a KD less than 1×10M as determined by using surface plasmon resonance.16. The isolated polynucleotide of claim 14 , wherein the FN3 domain comprises the amino acid sequence of SEQ ID NO: 7.17. The isolated polynucleotide of claim 14 , wherein the FN3 domain comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 8-44 and 58-145.18. The isolated polynucleotide of claim 14 , wherein the FN3 domain comprises the amino acid sequence of any one of SEQ ID NOs: 8-44 and 58-145.19. The isolated polynucleotide of claim 14 , wherein the CAR further comprises a signal peptide at the amino terminus.20. The isolated polynucleotide of claim 19 , wherein the CAR further comprises a hinge region connecting the extracellular domain and the transmembrane domain.21. The isolated polynucleotide of claim 20 , wherein the hinge region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3.22. The isolated polynucleotide of claim 21 , wherein the ...

Complex Comprising A Cell Penetrating Peptide, A Cargo And A TLR Peptide Agonist For Treatment Of Colorectal Cancer

The present invention provides a novel complex for use in the prevention and/or treatment of colorectal cancer, the complex comprising a) a cell penetrating peptide, b) at least one antigen or antigenic epitope, and c) at least one TLR peptide agonist, wherein the components a)-c) are covalently linked. In particular, compositions for use in the prevention and/or treatment of colorectal cancer, such as a pharmaceutical compositions and vaccines are provided. 1. A method for treating colorectal cancer or initiating , enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a complex comprising:a) a cell penetrating peptide;b) at least one antigen or antigenic epitope; andc) at least one toll-like receptor (TLR) peptide agonist, wherein the at least one TLR peptide agonist is a TLR2 and/or TLR4 peptide agonist; andwherein the components a)-c) are covalently linked.2. The method according to claim 1 , wherein the complex is a recombinant polypeptide or a recombinant protein.3. The method according to claim 1 , wherein the cell penetrating peptide(i) has a length of the amino acid sequence of said peptide of 5 to 50 amino acids in total; and/or(ii) has an amino acid sequence comprising a fragment of the minimal domain of ZEBRA, said minimal domain extending from residue 170 to residue 220 of the ZEBRA amino acid sequence according to SEQ ID NO: 3, wherein, optionally, 1, 2, 3, 4, or 5 amino acids have been substituted, deleted, and/or added without abrogating said peptide's cell penetrating ability.4. The method according to claim 1 , wherein the cell penetrating peptide has an amino acid sequence comprising or consisting of an amino acid sequence according to SEQ ID NO: 6 (CPP3/Z13) claim 1 , SEQ ID NO: 7 (CPP4/Z14) claim 1 , SEQ ID NO: 8 (CPPS/Z15) claim 1 , or SEQ ID NO: 11 (CPPB/Z18) claim 1 , or a sequence variant thereof sharing at least 90% sequence identity to SEQ ID NOs 6 claim 1 , 7 claim 1 , 8 or 11 ...

Chimeric antigen receptor (car) signalling system

The present invention relates to a chimeric antigen receptor (CAR) signalling system comprising; (i) a receptor component comprising an extracellular antigen-binding domain, a transmembrane domain and a intracellular first chemical inducer of dimerization binding domain 1 (CBD1); and (ii) an intracellular signalling component comprising a signalling domain and a second chemical inducer of dimerization binding domain 2 (CBD2); wherein CBD1 and CBD2 are capable of simultaneously binding to a chemical inducer of dimerization (CID); wherein, in the absence of the CID, binding of the antigen-binding component to antigen does not result in signalling through the signalling component; whilst, in the presence of the CID, the receptor component and the signalling component heterodimerize and binding of the antigen-binding domain to antigen results in signalling through the signalling domain.

HIGH AFFINITY CELL RECEPTOR FOR RECOGNIZING AFP ANTIGEN

Provided in the present invention is a T cell receptor (TCR) having the property of binding to a FMNKFIYEI-HLA A0201 complex; and the binding affinity of the TCR to the FMNKFIYEI-HLA A0201 complex is at least 2 times the binding affinity of the wild-type TCR to the FMNKFIYEI-HLA A0201 complex. Also provided in the present invention is a fusion molecule of such TCRs with therapeutic agents. Such TCRs can be used alone or in combination with therapeutic agents, so as to target tumor cells presenting the FMNKFIYEI-HLA A0201 complex. 2. The TCR of claim 1 , wherein there are 3-8 mutations in the 3 CDR regions of the TCR α chain variable domain and/or 4-8 mutations in the 3 CDR regions of the TCR β chain variable domain; orthe affinity of the TCR for FMNKFIYEI-HLA A0201 complex is at least 2 times of that of the wild type TCR; or;the mutated position in the α chain variable domain of the TCR includes position 7 and/or position 8 of CDR3α.35-. (canceled)7. The TCR of claim 1 , wherein the TCR comprises a TCR α chain variable domain and a TCR β chain variable domain claim 1 , and said TCR α chain variable domain comprises CDR1α claim 1 , CDR2α and CDR3α claim 1 , wherein the amino acid sequence of CDR1α is selected from the group consisting of: TSINN claim 1 , TPISS claim 1 , TDIYK claim 1 , TAVDS claim 1 , TEISS and TDVSS; and/or the amino acid sequence of CDR2α is IRSNERE; and/or the CDR3α comprises a sequence selected from the group consisting of: ATDPSMSPNSKLT claim 1 , ATDPSLSPNSKLT and ATDPSLQSNSKLT.814-. (canceled)15. The TCR of claim 1 , wherein the TCR comprises a TCR α chain variable domain and a TCR β chain variable domain claim 1 , and said TCR β chain variable domain comprises CDR1I claim 1 , CDR20 and CDR30 claim 1 , wherein the CDR2β comprises a sequence selected from the group consisting of: FQGDME claim 1 , FQGDLE and FHGDLE; and/or the amino acid sequence of CDR3p is ASEGLAYEQY.16. (canceled)18. The TCR of claim 1 , wherein the TCR is soluble.19. The TCR ...

Chimeric T Cell Receptors, Nucleic Acids, And Methods Of Making And Using The Same

Compositions and methods for eradicating tumor cells using novel compositions are contemplated. In one aspect, a pharmaceutical composition comprising a CAR scaffold and an antigen binding domain in a single chimeric species is provided. In some aspects, the CAR scaffold may comprise a CD28 costimulatory signaling region and a CD3ζ activation domain or a complete CD3ζ activation domain. In some aspects, the CAR scaffold may be codon-optimized for improved expression in mammalian cell lines and/or for improved function upon transfection into natural killer (NK) or other immune cells. In further aspects, the antigen binding domain may comprise a VL and VH domain linked by a spacer and may be codon optimized. A CD64 leader sequence may be attached to the antigen binding domain, e.g., at the N-terminus of the antigen binding domain. 1. An isolated nucleic acid sequence , optimized for expression in a mammalian cell , encoding a chimeric antigen receptor (CAR) polypeptide , wherein the CAR polypeptide comprises:an antigen binding domain coupled to a CAR scaffold, wherein the CAR scaffold is selected from the group consisting of:a CD28 domain coupled to a CD3ζ domain comprising two immunoreceptor tyrosine-based activation motifs (ITAMs); ora complete CD3ζ domain.2. The isolated nucleic acid sequence of claim 1 , wherein the CAR scaffold comprises the CD28 domain coupled to the CD3ζ domain claim 1 , and the nucleic acid sequence comprises one or more of:the nucleic acid sequence of SEQ ID NO: 27 or a nucleic acid sequence with 85% identity thereof that encodes an ectodomain;the nucleic acid sequence of SEQ ID NO: 28 or a nucleic acid sequence with 85% identity thereof that encodes a transmembrane domain; andthe nucleic acid sequence of SEQ ID NO: 29 or a nucleic acid sequence with 85% identity thereof that encodes a cytoplasmic domain.3. The isolated nucleic acid sequence of claim 1 , wherein the CAR scaffold comprises the complete CD3ζ domain claim 1 , and the nucleic ...

Inhibitory chimeric antigen receptors

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.

METHODS AND COMPOSITONS FOR MODULATIONS OF IMMUNE RESPONSE

Disclosed herein are isolated follicular helper T cell (TFH) and engineered follicular helper T cell (TFH) and methods of isolating or engineering such cells. Further disclosed herein are methods of using such cells for treating diseases, such as cancer. 1. An engineered T-follicular helper (Tfh)-like tumor-infiltrating cell engineered to modulate expression of the surface markers CD4 , CXCL13 and CXCR5 or one or more proteins selected from MAF , SH2D1A (SAP) , PDCD1 , BTLA , CD200 , and BCL6.2. The cell of claim 1 , wherein the cell is engineered to express the surface markers CD4 and CXCL13 and lack the surface marker CXCR5.3. The cell of wherein the cell is further engineered to express GZMB.4. The cell of claim 1 , wherein the cell is a Tfh-like tumor-infiltrating cell that activates a CD8 CTL response.5. The cell of claim 4 , wherein the CD8 CTL response is activated in a tumor or tumor microenvironment.6. The cell of claim 1 , wherein the cell is a Tfh-like tumor-infiltrating cell that activates a CD8 TRM response.7. The cell of claim 6 , wherein the CD8 TRM response is activated in a tumor or tumor microenvironment.89.-. (canceled)10. An isolated T-follicular helper (Tfh)-like tumor-infiltrating cell expressing the surface markers CD4 and CXCL13 and lacking the surface marker CXCR5.11. The cell of claim 10 , wherein the cell is a cytotoxic Tfh-like tumor-infiltrating cell expressing GZMB.12. The cell of claim 1 , wherein the cell is engineered to increase expression and/or function of one or more of: TNFRSF18 claim 1 , TNFRSF4 claim 1 , IFNG claim 1 , Granzyme B and/or IL21 in the cell.13. The cell of claim 1 , wherein the cell is engineered to expresses an antigen binding domain that binds at least one tumor antigen.14. The cell of claim 13 , wherein the tumor antigen comprises any one of: a CD19 claim 13 , a disialoganglioside-GD2 claim 13 , a c-mesenchymal-epithelial transition (c-Met) claim 13 , a mesothelin claim 13 , a ROR1 claim 13 , an EGFRvIII claim ...

COMPOSITIONS AND METHODS FOR INCREASING PROTEIN HALF-LIFE IN A SERUM

Novel antibodies, such as single domain antibodies (sdAbs), or antigen-binding fragments thereof that specifically bind a transferrin are described. Compositions, methods and systems for increasing the half-life of a target protein in a serum using an antibody or fragment thereof against a transferrin are also described. 1. A polypeptide comprising at least one immunoglobulin single domain antibody (sdAb) that specifically bind human and cynomolgus monkey serum transferrin protein and protein A resin , wherein the sdAb can be purified by a protein A column and used for half-life extension fragments for short half-life proteins or fragments.2. The isolated sdAb according to claim 1 , the antibody or antigen-binding fragment thereof comprising: a. SEQ ID NO: 46-SEQ ID NO: 90; and', 'b. amino acid sequences that have 4, 3, 2, or 1 amino acid(s) difference with the amino acid sequences of SEQ ID NOs: 46-SEQ ID NO: 90;, '(a) a complementarity determining region (CDR)1 having an amino acid sequence selected from the group consisting of'}and/or a. SEQ ID NO: 136-SEQ ID NO: 180; and', 'b. amino acid sequences that have 4, 3, 2, or 1 amino acid(s) difference with the amino acid sequences of SEQ ID NOs: 136-SEQ ID NO: 180; and/or, '(b) a CDR2 having an amino acid sequence selected from the group consisting of'} a. SEQ ID NO: 226-SEQ ID NO: 270; and', 'b. amino acid sequences that have 4, 3, 2, or 1 amino acid(s) difference with the amino acid sequences of SEQ ID NOs: 226-SEQ ID NO: 270., '(c) a CDR3 having an amino acid sequence selected from the group consisting of'}3. The isolated antibody or antigen-binding fragment thereof of claim 1 , being a single-domain antibody (sdAb).4. The isolated antibody or antigen-binding fragment thereof of claim 3 , comprising an amino acid sequence at least 95% identical to a sequence selected from the group consisting of SEQ ID NO: 316-SEQ ID NO: 360.6. The isolated antibody or antigen-binding fragment thereof of claim 1 , having a ...

CHIMERIC ANTIGEN RECEPTOR

The present invention provides a chimeric antigen receptor (CAR) which binds a low density target antigen, which comprises a Fab antigen binding domain. The invention also relates to cells expressing such a CAR and their use in the treatment of disease. 1. A chimeric antigen receptor (CAR) which binds B cell maturation antigen (BCMA) , wherein the CAR comprises a Fab antigen binding domain.24-. (canceled)6. A CAR according to claim 5 , wherein the Fab antigen-binding domain comprises a VH domain having the sequence shown as SEQ ID No. 29; and a VL domain having the sequence shown as SEQ ID No. 30.7. A CAR according to wherein the Fab antigen-binding domain comprises a first binding domain which binds a first target antigen and a second binding domain which binds a second target antigen.8. (canceled)9. A CAR according to claim 7 , which comprises a cleavable linker between the first and second binding domains.10. A CAR according to claim 9 , wherein the linker is cleavable with a matrix metalloproteinase (MMP).11. A nucleic acid sequence which encodes a CAR according to .12. A nucleic acid construct which encodes a CAR according to and has one of the following general structures:VH-CH-spacer-TM-endo-coexpr-VL-CL;VL-CL-coexpr-VH-CH-spacer-TM-endo;VL-CL-spacer-TM-endo-coexpr-VH-CH; orVH-CH-coexpr-VL-CL-spacer-TM-endo;in which:VH is a nucleic acid sequence encoding a heavy chain variable region;CH is a nucleic acid sequence encoding a heavy chain constant region spacer is a nucleic acid encoding a spacer;TM is a nucleic acid sequence encoding a transmembrane domain;endo is a nucleic acid sequence encoding an endodomain;coexpr is a nucleic acid sequence enabling co-expression of the first and second polypeptides;VL is a nucleic acid sequence encoding a light chain variable region; andCL is a nucleic acid sequence encoding a light chain constant region.13. A nucleic acid construct which encodes a CAR according to and has one of the following general structures:VH1-L1-VH2- ...

INTRABODIES FOR REDUCING FUT8 ACTIVITY

The present document describes an alpha-(1,6)-fucosyltransferase (FUT8) antibody, antigen binding domain thereof, or a fusion protein thereof, operable to inhibit FUT8 activity in a cell, and methods of producing recombinant proteins, in particular antibodies, having reduced fucosylation. The present document also describes methods of inhibiting expression and/or activity of a protein in a cell by expressing an antibody and/or a fusion protein operable to inhibit expression and/or activity of the protein. The antibody, antigen binding domain thereof, or fusion protein thereof may comprise a transmembrane domain of a protein resident in an endoplasmic reticulum (ER), a cis Golgi apparatus, a trans Golgi apparatus, or a combination thereof. 1. An alpha-(1 ,6)-fucosyltransferase (FUT8) antibody , an antigen binding domain thereof , or a fusion protein thereof , comprising a variable region of a heavy (V) and a light (V) chain thereof , the antibody or antigen binding domain thereof , or fusion protein thereof being operable to inhibit FUT8 activity in a cell.2. The FUT8 antibody claim 1 , antigen binding domain thereof claim 1 , or fusion protein thereof of claim 1 , wherein said fusion protein comprises a transmembrane domain of a protein resident in an endoplasmic reticulum (ER) claim 1 , a cis Golgi apparatus claim 1 , a trans Golgi apparatus claim 1 , or a combination thereof.3. A cell expressing the FUT8 antibody claim 1 , antigen binding domain thereof or fusion protein thereof of .4. A method for producing a recombinant protein or antibody having reduced fucosylation comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a) culturing a host cell expressing a FUT8 antibody, antigen binding domain thereof or fusion protein thereof of ,'}wherein said host cell expresses said recombinant protein or antibody under conditions which permit the production of said recombinant protein or antibody; andb) isolating said recombinant protein or antibody.57.-. (canceled ...

ANHYDROUS HYDROGEL COMPOSITION AND DELIVERY SYSTEM

The present disclosure relates to anhydrous hydrogels useful as mucoadhesive (oral compositions) or as topical agents and may be used to deliver an active agent such as active pharmaceutical agents (API's), coagulants, fragrances, flavors, and other actives and excipients. 1. An anhydrous hydrogel , comprising 1-50% by weight of a biocompatible polymer , 1-20% by weight of a polyalcohol , and an effective amount of an active agent.2. An anhydrous hydrogel according to claim 1 , wherein said biocompatible polymer is sodium carboxymethyl cellulose.3. An anhydrous hydrogel according to claim 2 , wherein said polyalcohol is anhydrous glycerin.4. An anhydrous hydrogel according to wherein said active agent is a pharmaceutical agent selected from analgesics claim 3 , decongestants claim 3 , bronchodilators claim 3 , antiasthmatic agents claim 3 , cardiovascular agents claim 3 , diabetic agents claim 3 , antihistamines claim 3 , anesthetics claim 3 , antifungals claim 3 , anti-nauseants claim 3 , antiemetics claim 3 , antibacterial agents claim 3 , antifungal agents claim 3 , corticosteroids claim 3 , neurological agents claim 3 , anti-inflammatories claim 3 , vaccines claim 3 , biological agents claim 3 , wound healing agents claim 3 , anticonvulsants and vitamins.5. An anhydrous hydrogel according to wherein said active agent is wound healing agent selected from becaplermin claim 3 , antimicrobial agents claim 3 , silver claim 3 , povidone-iodine claim 3 , polyhexamethylene biguanide claim 3 , dialkylcarbamoylchloride claim 3 , lactoferrin claim 3 , and growth factors.6. An anhydrous hydrogel according to wherein said active agent is a cosmetic agent.7. An anhydrous hydrogel according to wherein said active agent is the cosmetic agent ubiquinone.8. An anhydrous hydrogel according to wherein said anhydrous hydrogel comprises from 5-30% NaCMC claim 3 , 95-70% anhydrous glycerin and 0.1-30% active agent.9. An anhydrous hydrogel according to wherein said anhydrous hydrogel ...

Engineered Exosomes for the Delivery of Bioactive Cargo Using Transmembrane Tetraspanins

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 ...

Engager cells for immunotherapy

Embodiments concern methods and/or compositions related to immunotherapy for cancer. In particular embodiments, engager immune cells harbor a vector that encodes a secretable engager molecule. In particular cases, the engager molecule has an activation domain and an antigen recognition domain. In some embodiments, the engager molecules further comprise a cytokine or co-stimulatory domain, for example.

Fusion Protein Comprising Diphtheria Toxin Non-Toxic Mutant CRM197 or Fragment Thereof

Provided in the present invention are a diphtheria toxin non-toxic mutant CRM197 or a fragment thereof as an adjuvant in a fusion protein and the use thereof to enhance the immunogenicity of a target protein fused therewith, for example, an HEV capsid protein, or an influenza virus M2 protein or an immunogenic fragment thereof. Also provided is a method for enhancing the immunogenicity of a target protein, comprising the fusion expression of the CRM197 or the fragment thereof with the target protein to form a fusion protein. Further provided is a fusion protein comprising the CRM197 or the fragment thereof and a target protein, the CRM197 or the fragment thereof enhancing the immunogenicity of the target protein. The present invention also provides an isolated nucleic acid encoding the fusion protein, a construct and a vector comprising said nucleic acid, and a host cell comprising the nucleic acid.

Claudin-6-specific immunoreceptors and t cell epitopes

The present invention provides Claudin-6-specific immunoreceptors (T cell receptors and artificial T cell receptors (chimeric antigen receptors; CARs)) and T cell epitopes which are useful for immunotherapy.

DEFINED COMPOSITION GENE MODIFIED T-CELL PRODUCTS

Aspects of the invention described herein, concern approaches to make genetically modified T-cells comprising a chimeric antigen receptor for human therapy. In some alternatives, the methods utilize a selection and/or isolation of CD4+ and/or CD8+ T-cells from a mixed T-cell population, such as, peripheral blood or apheresis derived mononuclear cells. Once selected/isolated, the CD4+ and/or CD8+ T-cells are then activated, genetically modified, and propagated, preferably, in separate or isolated cultures in the presence of one or more cytokines, which support survival, engraftment and/or proliferation of the cells, as well as, preferably promoting or inducing the retention of cell surface receptors, such as CD62L, CD28, and/or CD27. Included herein are also methods of treatment, inhibition, amelioration, or elimination of a cancer by administering to a subject in need thereof, one or more types of the genetically engineered T-cells or compositions that comprise the genetically engineered T-cell prepared as described herein. 1. A method of making genetically modified T-cells , which have a chimeric antigen receptor , comprising:separating or enriching a CD8+ expressing population of T-cells and/or a CD4+ expressing population of T-cells, such as T-cells that are derived from thymocytes or T-cells that are derived from engineered precursors, desirably iPS cells, from a mixed population of T-cells so as to generate a separated or enriched population of T-cells;stimulating the separated or enriched population of T-cells so as to generate a stimulated population of CD8+ T-cells and/or CD4+ T-cells;transducing the stimulated population of CD8+ T-cells and/or CD4+ T-cells with a vector, wherein the vector encodes a chimeric antigen receptor and a marker sequence, wherein said marker sequence encodes a cell surface selectable marker, so as to generate a transduced population of CD8+ T-cells and/or CD4+ T-cells;contacting the transduced population of CD8+ T-cells and/or CD4+ ...

ADHERENT CANCER CELL LINE EXPRESSING A HEMATOLOGICAL TUMOR ANTIGEN

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 ...

ANTI-TAU CONSTRUCTS

The present invention provides anti-tau constructs. Anti-tau constructs of the invention are polynucleotide sequences encoding a polypeptide comprising at least one tau binding moiety and optionally comprising a signal peptide and/or a purification moiety. The present invention also provides isolated polypeptides encoded by anti-tau constructs, vectors comprising anti-tau constructs, and isolated cells comprising said vectors. 1. A polynucleotide sequence encoding a polypeptide , the polypeptide comprising at least one tau binding moiety attached to a targeting moiety via a linker and optionally comprising a signal peptide and/or a purification moiety , wherein:(a) each tau binding moiety is independently selected from the group consisting of a VH fragment, a VL fragment, a Fv fragment, a single-chain variable fragment (scFv), a minibody, a diabody, a triabody, and a tetrabody; (i) a polypeptide that binds to the low-density lipoprotein receptor (LDLR),', '(ii) a polypeptide that binds to the low-density lipoprotein receptor-related protein (LRP1),', '(iii) a polypeptide comprising the transmembrane and intracellular domain of LRP1 or LDLR;', '(iv) a polypeptide comprising a HSC-binding motif, and', '(v) ubiquitin or ubiquitin mutant;, '(b) the targeting moiety is selected from the group consisting of{'sub': n', 'n, '(c) the linker has the polypeptide sequence (GGGS/T)or S/T(GGGS/T), wherein n is an integer from 1 to 6, inclusive.'}2. The polynucleotide sequence of claim 1 , wherein the ubiquitin mutant comprises a K48R point mutation or a K63R point mutation.3. The polynucleotide sequence of claim 1 , wherein the targeting moiety is selected from the group consisting of:(i) a polypeptide that binds to the low-density lipoprotein receptor (LDLR),(ii) a polypeptide that binds to the low-density lipoprotein receptor-related protein (LRP1), and(iii) a polypeptide comprising the transmembrane and intracellular domain of LRP1 or LDLR.4. The polynucleotide sequence of any ...

SIGNALLING SYSTEM

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- ...

Car immune cells to treat cancers

A chimeric antigen receptor (CAR) that binds to CEACAM6, an epitope or fragment thereof, or a variant thereof.