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Humanized anti-human TIGIT antibody and application thereof

A technology of antibodies and amino acids, applied in the field of biomedicine, can solve problems such as drug resistance, unclear reasons, and poor tumor effects

Active Publication Date: 2021-04-20
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At the same time, the in-depth exploration of clinical practice has gradually revealed the outstanding problems faced by the first generation of immune checkpoint antibodies: limited benefit patients, poor efficacy of most tumors, drug resistance, etc.
As mentioned above (1) (2), the regulatory functions of TIGIT on immune effector cells and Treg cells are completely opposite (inhibition and promotion), and the reason is not clear

Method used

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  • Humanized anti-human TIGIT antibody and application thereof
  • Humanized anti-human TIGIT antibody and application thereof
  • Humanized anti-human TIGIT antibody and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Embodiment 1, the generation of human source anti-human TIGIT antibody

[0122] 1. Materials

[0123] 1. Materials: The large-capacity fully synthetic phage single-chain antibody library was constructed by the Institute of Bioengineering of the former Academy of Military Medical Sciences (now the Academy of Military Medical Sciences) of the Chinese People's Liberation Army (ZL200910091261.8), with a library capacity of 1.35×10 10 . The host strain for phage infection was XL1-Blue (Stratagene, USA), the plasmid amplification strain was Top10 (Beijing Quanshijin Biotechnology Co., Ltd.), the helper phage was M13KO7 (Invitrogene, USA), horseradish catalase (HRP )-labeled anti-M13KO7 antibody (11973-MM05T-H) is a product of Beijing Sino Biological Technology Co., Ltd. CHO cells and TransIntro EL Transfection Reagent (L20313) were purchased from Beijing Quanshijin Biotechnology Co., Ltd. Opti-MEM serum-free medium for transfection and 1640 medium for cell culture, 0.25% try...

Embodiment 2

[0149] Example 2, the binding activity of AET2010

[0150] 1. Materials and methods

[0151] 1. Materials: Anti-TIGIT monoclonal antibody MK7684 can be obtained from Merck & Co., USA, and its light and heavy chain genes can also be synthesized and cloned into pABK ( figure 1 ) and pABG vectors were prepared according to the preparation method of AET2010 in Example 1 (patent number: US20160355589A1), the light chain and heavy chain amino acid sequences of MK7684 are shown in SEQ ID NO.11 and SEQ ID NO.12 respectively, and the light chain of MK7684 The gene sequences of the heavy chain and heavy chain are respectively shown in SEQ ID NO.13 and SEQ ID NO.14, and MK7684 is used as a control antibody.

[0152] Wherein, the light chain expression vector of MK7684 is a recombinant vector obtained by replacing the recognition sequence between Xba I and Nar I of the pABK expression vector with the light chain variable region gene shown in positions 1-327 of SEQ ID NO.13, The recombin...

Embodiment 3

[0178] Example 3, the blocking activity of AET2010

[0179] 1. Materials and methods

[0180] 1. Materials: The human CD155 (HG29682-UT) cDNA cloning vector is a product of Beijing Sino Biological Technology Co., Ltd. HiTrap for protein purification TM The Q-Sepharose FF anion adsorption column was produced by GE, the FITC-labeled mouse anti-human IgG / Fc flow antibody was produced by Biolegend, and the HRP-labeled goat anti-human IgG / Fc antibody was produced by Beijing Baixinyi Biotechnology Co., Ltd. The isotype control antibody (C103S) is a product of Beijing Sino Biological Technology Co., Ltd. Other related material source is the same as embodiment 1,2.

[0181] 2. Method:

[0182] 2.1 Preparation of AET2010-Fab, MK7684-Fab and CD155-Fc recombinant protein

[0183] The antibody Fab segment heavy chain expression vector is a pABG vector without CH2 and CH3 gene sequences, and its name is pABG-Fab ( figure 1 , whose sequence is SEQ ID NO.22 in the sequence listing), t...

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Abstract

The invention discloses a humanized anti-human TIGIT antibody and application thereof. The anti-human TIGIT antibody disclosed by the invention contains the heavy chain variable region VH(subscript) and the light chain variable region VL(subscript), and the VH(subscript) and the VL(subscript) are composed of the complementarity determining region and the framework region, respectively; the complementarity determining regions of the VH(subscript) and the VL(subscript) are composed of CDR1, CDR2 and CDR3, respectively; the amino acid sequences of CDR1, CDR2 and CDR3 of the VH(subscript) are shown as the amino acids at the 30-35th site, at the 50-66th site and at the 99-107th site of SEQ ID No. 10; and the amino acid sequences of CDR1, CDR2 and CDR3 of the VL(subscript) are shown as the amino acids at the 23-33rd site, at the 49-55th site and at the 88-96th site of SEQ ID No. 9. The antibody disclosed by the invention can bind to TIGIT with high affinity, can effectively block the binding of CD155 and TIGIT, and has anti-tumor activity.

Description

technical field [0001] The invention relates to the human anti-human TIGIT antibody and its application in the field of biomedicine. Background technique [0002] Cancer immunotherapy (Cancer Immunotherapy) is a frontier hot field in the basic and clinical research of tumor treatment in recent years. In 2011, the CTLA-4 inhibitor Ipilimumab (Ipilimumab, also known as "Y drug") was approved for marketing. The antibody exerts an anti-tumor effect by activating the immune response mediated by T cells; A whole new era of immunotherapy. Since 2014, PD-1 / PD-L1 antibodies such as Nivolumab (also known as "O drug") and Pembrolizumab (also known as "K drug") have been released one after another. It has achieved remarkable curative effect and profoundly changed the paradigm of cancer treatment. James Allison, an American scientist who promotes the development of CTLA-4 drugs, and Tasuku Honjo, a Japanese scientist who discovered PD-1 / PD-L1 molecules, also won the 2018 Nobel Prize f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/13A61K39/395A61K35/17A61P35/00
Inventor 杜鹏杨志新韩冬徐银凤岳俊杰余云舟陆建昇
Owner ACADEMY OF MILITARY MEDICAL SCI
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