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Antibodies to tigit and uses thereof

An antibody and antigen technology, applied in the direction of antibodies, antibody medical components, and resistance to vector-borne diseases, etc., can solve problems affecting drug pharmacology, immune cell damage, etc. Effects of T cell activity

Active Publication Date: 2022-03-01
AKESO BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

IgG4 molecules bind weakly to FcγRs other than FcγRI, and IgG4 molecules are less likely to cause CDC and NK cell-mediated ADCC; however, IgG4 subtype antibodies can mediate ADCP effects by binding to FcγRI, targeting immune The ADCP effect of antibody drugs in cells may cause immune cell damage and have negative effects on drug pharmacology

Method used

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  • Antibodies to tigit and uses thereof
  • Antibodies to tigit and uses thereof
  • Antibodies to tigit and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] Example 1: Preparation of anti-TIGIT antibody 26B12

[0163] 1. Preparation of hybridoma cell line LT019

[0164] The antigen used to prepare the anti-TIGIT antibody is human TIGIT-mFc (TIGIT is GenbankID: NP_776160.2). Splenocytes from immunized mice were fused with mouse myeloma cells to produce hybridoma cells. Using human TIGIT-mFc as an antigen, hybridoma cells were screened by indirect ELISA method to obtain hybridoma cells that can secrete antibodies that specifically bind to TIGIT. For the hybridoma cells obtained by screening, a stable hybridoma cell line was obtained by the limiting dilution method. The above hybridoma cell lines were named hybridoma cell line LT019, and the monoclonal antibodies secreted by them were named 26B12.

[0165] The hybridoma cell line LT019 was deposited in the China Center for Type Culture Collection (CCTCC) on October 23, 2020, with the deposit number CCTCC NO: C2020208, and the deposit address is Wuhan University, Wuhan, Ch...

Embodiment 2

[0168] Example 2: Sequence Analysis of Anti-TIGIT Antibody 26B12

[0169] The mRNA was extracted from the LT019 cell line cultured in Example 1 according to the method of the Bacteria Total RNA Extraction Kit (Tiangen, Cat. No. DP430).

[0170] cDNA was synthesized according to the Invitrogen SuperScript® III First-Strand Synthesis System for RT-PCR kit instructions, and PCR amplification was performed.

[0171] The PCR amplification product was directly cloned by TA. For specific operation, refer to the pEASY-T1 Cloning Kit (TransgenCT101) kit manual.

[0172] The products of TA clones were directly sequenced, and the sequencing results were as follows:

[0173] The nucleic acid sequence of the heavy chain variable region is shown in SEQ ID NO: 2, and the fragment is 363 bp in length.

[0174] The encoded amino acid sequence is shown in SEQ ID NO: 1, with a length of 121 amino acids.

[0175] The sequence of heavy chain HCDR1 is shown in SEQ ID NO: 3, the sequence of HCD...

Embodiment 3

[0179] Example 3: Light chain and heavy chain design and preparation of humanized antibodies against human TIGIT

[0180] 1. Light and heavy chain design of humanized antibodies 26B12H5L4, 26B12H5L1, 26B12H4L4, 26B12H1L4 and 26B12H4L1 against human TIGIT

[0181] According to the three-dimensional crystal structure of human TIGIT protein and the sequence of antibody 26B12 obtained in Example 2, the antibody model was simulated by computer, and then mutations were designed according to the model to obtain the variable region sequences of antibodies 26B12H5L4, 26B12H5L1, 26B12H4L4, 26B12H1L4 and 26B12H4L1 (antibody constant Region sequence, from the NCBI database, the heavy chain constant region is Ig gamma-1 chain C region, ACCESSION: P01857; the light chain constant region is Ig kappa chain C region, ACCESSION: P01834).

[0182] The designed variable region sequences are shown in Table A below.

[0183] Table A: Variable region sequences

[0184]

[0185] For the above...

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Abstract

The invention belongs to the field of biological medicine, and relates to an anti-TIGIT antibody and application thereof. Specifically, the invention relates to an anti-TIGIT antibody or an antigen binding fragment thereof, the antibody comprises a heavy chain variable region and a light chain variable region, the amino acid sequences of HCDR1 to HCDR3 of the heavy chain variable region are respectively shown as SEQ ID NOs: 3-5, and the amino acid sequences of LCDR1 to LCDR3 of the light chain variable region are respectively shown as SEQ ID NOs: 8-10; and according to an EU numbering system, the heavy chain constant region comprises mutation such as L234A and L235A. The antibody disclosed by the invention can be effectively combined with TIGIT, has small toxic and side effects and has the potential of being applied to tumor prevention and treatment.

Description

Technical field [0001] The invention belongs to the field of biomedicine and relates to anti-TIGIT antibodies and their uses. Specifically, the present invention relates to an anti-TIGIT monoclonal antibody, pharmaceutical compositions and uses. Background technique [0002] TIGIT (T cell Ig and ITIM domain, also known as WUCAM, Vstm3, VSIG9) is a member of the poliovirus receptor (PVR) / Nectin family. TIGIT consists of an extracellular immunoglobulin variable (IgV) domain, a type I transmembrane domain and has the classic immunoreceptor tyrosine inhibitory motif (ITIM) and immunoglobulin tyrosine tail (ITT) motifs of intracellular domains. TIGIT is highly expressed in lymphocytes, especially in effector and regulatory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, and natural killer (NK) cells (Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic ce...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/46A61K39/395A61P35/00
CPCC07K16/28A61K39/3955A61P35/00C07K2317/565C07K2317/56C07K2317/52C07K2317/31A61K2039/505A61K2039/507Y02A50/30
Inventor 王忠民张鹏李百勇夏瑜
Owner AKESO BIOPHARMA
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