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Compositions and methods for tcr reprogramming using target specific fusion proteins

A fusion protein and composition technology, applied in the direction of introducing foreign genetic material, fusion polypeptide, drug combination, etc.

Pending Publication Date: 2021-06-25
TCR2 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

High and manageable clinical efficacy of CAR T cells is currently limited to patients with BCMA-positive and CD-19-positive B-cell malignancies and HLA-A2-expressing NY-ESO-1-peptide-expressing synovial sarcoma

Method used

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  • Compositions and methods for tcr reprogramming using target specific fusion proteins
  • Compositions and methods for tcr reprogramming using target specific fusion proteins
  • Compositions and methods for tcr reprogramming using target specific fusion proteins

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0384] Example 1: TFP constructs

[0385] Anti-TAA V HH The domain (or SD domain) DNA fragment was cloned into the p510 vector ((System Biosciences (SBI)) to engineer the anti-TAA TFP construct by encoding a short linker (SL): AAAGGGGSGGGGSGGGGSLE (SEQ ID NO: 2 ) or long linker (LL): the DNA sequence of AAAIEVMYPPPYLGGGGSGGGGSGGGGSLE (SEQ ID NO: 3) is ligated to CD3 or TCR DNA. Other vectors, such as pLRPO vectors, can also be used.

[0386] Examples of anti-TAA TFP constructs generated include p510_anti-TAA_LL_TCRα (anti-TAA V HH - long linker - human full-length T cell receptor alpha chain), p510_TAA_LL_TCRαC (anti-TAA V HH -long linker-human T cell receptor α constant domain chain), p510_anti-TAA_LL_TCRβ (anti-TAA V HH -long linker-human full-length T cell receptor beta chain), p510_anti-TAA_LL_TCRβC (anti-TAA V HH -long linker-human T cell receptor beta constant domain chain), p510_anti-TAA_LL_CD3γ (anti-TAA V HH -long linker-human CD3γ chain), p510_anti-TAA_LL_CD3δ...

Embodiment 2

[0390] Example 2: Antibody Sequence

[0391] Generation of Antibody Sequences

[0392] Production of scFv

[0393] Human or humanized anti-TAA IgG can be used to generate scFv sequences for TFP constructs. Coding human or humanized V is available L and V H The DNA sequence of the domain and optionally the codons of the construct can be optimized for expression in cells from Homo sapiens. V L Domain and V H The order in which the domains appear in the scFv is different (i.e., V L -V H or V H -V L orientation), three copies of "G4S" or "G 4 S” subunit (G 4 S) 3 The variable domains are linked to generate scFv domains. Anti-TAA scFv plasmid constructs can have optional Flag, His or other affinity tags and can be electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays included binding analysis by FACS, kinetic analysis using Proteon, and staining of MUC16-expressing cells, IL13Rα2-expressing cells, or MSLN-expressing...

Embodiment 3

[0430] Embodiment 3: the preparation of anti-IL13Rα2 nanobody

[0431] library construction

[0432] Immunization

[0433] Vicuna were subcutaneously injected on day 0, day 7, day 14, day 21, day 28, and day 35, each with about 150 μg of recombinant human IL13Rα2 (hIL13Rα2-Fc) fused to the Fc domain of human IgG1. ) (R&D Systems). The adjuvant used was GERBU Adjuvant P (GERBU Biotechnik GmbH). On day 40, approximately 100 ml of anticoagulated blood was collected from vicuna for lymphocyte preparation.

[0434] Construction of VHH library

[0435] Construction of V from llama lymphocytes HH Libraries to screen for the presence of antigen-specific Nanobodies. To this end, total RNA from peripheral blood lymphocytes was used as template for first-strand cDNA synthesis using oligo(dT) primers. Using this cDNA, V was amplified by PCR HH The coding sequence was digested with PstI and NotI and cloned into the PstI and NotI sites of the phagemid vector pMECS. The resulting ...

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Abstract

Provided herein are T cell receptor (TCR) fusion proteins (TFPs), T cells engineered to express one or more MUC16 or IL13R[alpha]2 or MSLN TFPs, and methods of use thereof for the treatment of diseases, including cancer.

Description

[0001] cross reference [0002] This application claims U.S. Provisional Patent Application No. 62 / 703,824, filed July 26, 2018, U.S. Provisional Patent Application No. 62 / 725,066, filed August 30, 2018, U.S. Provisional Patent Application No. 62 / 725,066, filed July 26, 2018 Application No. 62 / 703,834, U.S. Provisional Patent Application No. 62 / 727,469, filed September 5, 2018, and U.S. Provisional Patent Application No. 62 / 727,459, filed September 5, 2018, the U.S. Provisional Patent Application Each of the applications is hereby incorporated by reference in its entirety. [0003] Background of the invention [0004] Most patients with advanced solid tumors are incurable with standard therapies. Additionally, conventional treatment options often have serious side effects. Many attempts have been made to harness a patient's immune system to reject cancer cells, an approach collectively known as cancer immunotherapy. However, several obstacles make it difficult to achieve cli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/435C07K14/705C07K14/715C07K14/725C07K16/28C07K16/30G01N33/574C12N15/12C12N15/63
CPCA61P35/00C07K14/7051C07K14/4748C07K14/7155C07K2319/02C07K2319/03C07K2319/21C07K2319/30C07K2319/33C07K2319/00C12N2510/00C12N5/0636C07K2317/622C07K16/3092C07K16/2866C07K2317/569C07K16/30C07K2317/24A61K39/4611A61K2239/31A61K2239/38A61K39/46447A61K39/4632A61K2239/59A61K39/464468A61K39/4631A61K38/177A61K39/39558C12N15/62C07K14/70578C12N15/85C12N15/86A61K2039/585A61K35/17A61K39/00117A61K2039/5156A61K2039/5158A61K38/00A61K2039/505C07K2317/92
Inventor 帕特里克·亚历山大·博伊尔勒罗伯特·霍夫梅斯特丹尼尔·盖茨瓦尼亚·阿什米诺瓦丁健
Owner TCR2 THERAPEUTICS INC
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