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Anti-LAP monoclonal antibody as well as antigen binding fragment and application thereof

A monoclonal antibody and binding fragment technology, applied in the field of biomedicine, can solve serious and limited clinical benefits and other problems, and achieve the effect of improving tumor immune response

Active Publication Date: 2021-09-17
BEIJING DONGFANG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Small-molecule inhibitors of ALK5 targeting TGFβ type I receptor kinase or antibodies that simultaneously block the three isoforms of TGFβ1, TGFβ2, and TGFβ3 exhibited severe heart valve virulence in mice, rats, and dogs, implying that Broad-spectrum inhibition of signaling pathways driven by one or more isoforms limits the clinical benefit of this class of drugs
LAP is the protein cage of TGFβ1, which locks mature TGFβ1 in the latent complex. Drugs acting on the target of LAP can regulate the release or inhibition of TGFβ1 by regulating the structure of the LAP-TGFβ1 complex, thereby regulating the active pathway mediated by TGFβ1. At present, there is no drug of the same variety on the market at home and abroad. In order to meet the market demand, it is urgent to develop an anti-LAP monoclonal antibody that can regulate the release of TGFβ1 and improve the tumor microenvironment, its antigen-binding fragment and its application

Method used

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  • Anti-LAP monoclonal antibody as well as antigen binding fragment and application thereof
  • Anti-LAP monoclonal antibody as well as antigen binding fragment and application thereof
  • Anti-LAP monoclonal antibody as well as antigen binding fragment and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 of the present invention provides an anti-LAP monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, and the amino acid sequence of HCDR1 in the heavy chain variable region is selected from SEQ ID NO : 1, SEQ ID NO: 7, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO: 24 or SEQ ID NO: 30; the amino acid sequence of the HCDR2 of the heavy chain variable region is selected from SEQ ID NO: 2. SEQ ID NO: 8, SEQ ID NO: 14, SEQ ID NO: 20, SEQ ID NO: 25 or SEQ ID NO: 31; the amino acid sequence of HCDR3 of the heavy chain variable region is selected from SEQ ID NO: 3 , SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 21, SEQ ID NO: 26 or SEQ ID NO: 32; the amino acid sequence of the LCDR1 of the light chain variable region is selected from SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 16, SEQ ID NO: 22, SEQ ID NO: 27 or SEQ ID NO: 33; the amino acid sequence of the LCDR2 of the light chain variable region is se...

Embodiment 2

[0054] In Example 2 of the present invention, an anti-LAP monoclonal antibody was obtained by immunizing mice with LAP antigen, optimizing the immunization method, and creating a phage display library. The anti-LAP monoclonal antibody or its antigen-binding fragment obtained by screening was selected from any of the following kind:

[0055]

Embodiment 3

[0057] Example 3 of the present invention specifically provides a screening method for anti-LAP single-chain antibody on the basis of Example 2 as follows: Step 1: LAP antigen immunization of mice

[0058] 1. Experimental animals:

[0059] Species and strains: BALB / c, female, mouse; body weight: 18-20g;

[0060] Experimental animal provider: Beijing Huafukang Biotechnology Co., Ltd.

[0061] 2. Immunization: the mice were immunized, and the immune antigen was human LAP (a gene synthesized by Nanjing KingScript Biotechnology Co., Ltd., the company constructed a vector and expressed and purified it).

[0062] Step 2: Construction of phage antibody library

[0063]Take mouse splenocytes with higher titer, use Trizol reagent (purchased from Ambion, article number: 15596026), extract total RNA in mouse splenocytes, obtain cDNA by RT-PCR, use cDNA as a template, and use degenerate primers ( The degenerate primer reference used: Journal of Immunological Methods 233 (2000) 167-177)...

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Abstract

The invention relates to the field of biological medicine, and provides an anti-LAP monoclonal antibody or an antigen binding fragment thereof, and the anti-LAP monoclonal antibody comprises heavy chain variable regions HCDR1, HCDR2 and HCDR3 and light chain variable regions LCDR1, LCDR2 and LCDR3. The anti-LAP monoclonal antibody provided by the invention inhibits release of TGF beta1 from the source, deletes inhibitory T cells and improves tumor immune response, can be combined with various immunotherapy drugs for application, can be expanded to more types of cancers, autoimmune diseases and fibrosis diseases, and has huge clinical requirements and huge market potential; the cancers are selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, liver cancer, ovarian cancer, breast cancer, melanoma or glioma; the fibrosis diseases comprise pulmonary fibrosis or hepatic fibrosis; and the autoimmune diseases are selected from systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis or xerosis.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to an anti-LAP monoclonal antibody, an antigen-binding fragment thereof and applications thereof. Background technique [0002] Cancer immunotherapy is to use the body's immune mechanism to enhance the patient's immune function through active or passive methods to achieve the purpose of killing tumor cells. Currently, cancer immune checkpoint inhibitor therapy has made breakthroughs and durable cancer immunotherapy response and is gradually becoming the first-line standard of care for an increasing number of cancers. But there are still a large number of cancer patients who do not respond to this treatment, suggesting that there are other mechanisms that prevent the immune system from targeting tumor cells for elimination. [0003] In the current retrospective analysis of clinical data of cancer patients, the activation of TGFβ signaling pathway was found to be a key factor in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18C12N15/13C12N15/85C12N5/10A61K39/395A61P35/00A61P11/00A61P1/16A61P37/02
CPCC07K16/18C12N15/85A61K39/39558A61K39/39533A61K39/39566A61P35/00A61P11/00A61P1/16A61P37/02C07K2317/56C07K2317/565A61K2039/505A61K2300/00
Inventor 白义
Owner BEIJING DONGFANG BIOTECH
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