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Anti-hla-dq2.5 antibody

A polymer and antigen-binding molecule technology, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, recombinant DNA technology, anti-plant immunoglobulin, etc., can solve the problem of completely eliminating gluten exposure, etc. question

Pending Publication Date: 2022-01-18
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In practice, however, it is difficult to completely eliminate gluten exposure even with GFD

Method used

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Experimental program
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Embodiment approach

[0635] 1) Immunoconjugates

[0636] The invention also provides immunoconjugates comprising an anti-HLA-DQ2.5 antibody herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, Toxins (eg protein toxins, enzymatically active toxins of bacterial, fungal, vegetable or animal origin, or fragments thereof), or radioactive isotopes.

[0637] In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC), wherein the antibody is conjugated to one or more drugs, including but not limited to maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); auristatins such as monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588 and 7,498,298); dorax Dolastatin; calicheamicin or derivatives thereof (see U.S. Pat. (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin or doxorubicin (see Kratz et...

Embodiment 1

[0670] Expression and purification of recombinant proteins

[0671] 1.1. Recombinant HLA-DQ2.5 / 33-mer gliadin peptide complex, HLA-DQ8 / gliadin peptide complex, HLA-DQ5.1 / DBY peptide complex, HLA-DQ2.2 / CLIP Expression and purification of peptide complexes, HLA-DQ7.5 / CLIP peptide complexes, HLA-DQ2.5 / γ2 gliadin peptide complexes, and HLA-DQ2.5 / BC hordein peptide complexes

[0672] Expression and purification of recombinant HLA-DQ2.5 / 33-mer gliadin peptide complex:

[0673] The sequences used for expression and purification are: HLA-DQA1*0501 (Protein Database Accession No. 4OZG) and HLA-DQB1*0201 (Protein Database Accession No. 4OZG), both of which have the CAMPATH-1H signal sequence: MGWSCIILFLVATATGVHS (SEQ ID NO :37). HLA-DQA1*0501 has a C47S mutation, a GGGG linker (SEQ ID NO: 38) and a c-fos leucine zipper sequence (PNAS, September 29, 1998; 95(20): 11828-33) and in HLA-DQA1 *Flag-Tag at the C-terminus of 0501. HLA-DQB1*0201 has a 33-mer gliadin peptide sequence: LQLQPF...

Embodiment 2

[0687] 2.1 Establishment of J.RT3-T3.5 cell line expressing D2 TCR

[0688] The D2 TCRα chain cDNA (SEQ ID NO: 97) was inserted into the expression vector pCXND3 (WO2008 / 156083). The D2 TCR β chain cDNA (SEQ ID NO: 49) was inserted into the expression vector pCXZD1 (US2009 / 0324589). Linearized D2 TCRα chain-pCXND3 and D2 TCRβ chain-pCXZD1 (1500 ng each) were simultaneously introduced into the J,RT3-T3,5 cell line by electroporation (LONZA, 4D-Nucleofector X). The transfected cells were then cultured in a medium containing geneticin and bleomycin (Zeocin), and then sorted using AriaIII (Becton Dickinson) to obtain a high-expressing cell population. Single cell cloning is then performed to obtain cells that highly express the desired D2 TCR molecule.

[0689] 2.2 Expression of HLA-DQ2.5, HLA-DQ2.2, HLA-DQ7.5, HLA-DQ8, HLA-DQ5.1, HLA-DQ6.3, HLA-DQ7.3, HLA-DR and HLA-DP Establishment of Ba / F3 cell line

[0690] HLA-DQA1*0501cDNA (IMGT / HLA accession number HLA00613), HLA-DQA1*0...

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Abstract

The present invention provides anti-HLA-DQ2.5 antibodies. The anti-HLA-DQ2.5 antibodies of the invention have binding activity to complexes formed by HLA-DQ2.5 and a gluten peptide, but have substantially no binding activity to complexes formed by HLA-DQ2.5 and an irrelevant peptide. Furthermore, it was found that the antibodies of the invention have inhibitory effects on T cell activation.

Description

technical field [0001] The present invention relates to anti-HLA-DQ2.5 antibodies Background technique [0002] Celiac disease is an autoimmune disorder in which ingestion of gluten causes damage to the small intestine in genetically susceptible patients (NPL 1 to 5). About 1% of the Western population, or 8 million people in the United States and the European Union, is thought to have celiac disease; however, no significant therapeutic advances have been made since the disease was recognized in the 1940s. [0003] Human leukemia antigens (HLA) belonging to class II of the major histocompatibility complex (MHC) include HLA-DR, HLA-DP, and HLA-DQ molecules, such as the HLA-DQ2.5 isotype (hereinafter referred to as "HLA- DQ2.5"), which form heterodimers consisting of α and β chains on the cell surface. The majority (>90%) of celiac disease patients have the HLA-DQ2.5 haplotype allele (NPL 6). This isoform is thought to have a stronger affinity for gluten peptides. Like ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/16C12N1/15C12N1/19C12N1/21C12N5/10C12N15/13C12N15/63C12P21/08
CPCC07K16/16C07K16/2833C07K2317/32C07K2317/31C07K2317/92C07K2317/76C07K16/2803A61K2039/505A61P37/00C07K2317/565
Inventor 大仓有生高桥德行津岛崇祖尔卡尔奈恩·哈尔富丁
Owner CHUGAI PHARMA CO LTD
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