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Anti-pd-1/lag3 bispecific antibodies

A bispecific antibody, PD-1 technology, applied in anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, anti-animal/human immunoglobulin, specific peptide, etc., can solve tumor immune response Impaired, weakened T cell activation immune surveillance and other issues

Pending Publication Date: 2020-10-27
MERCK SHARP & DOHME BV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, PD-L1-expressing tumor cells have been proposed to interact with PD-1-expressing T cells to attenuate T-cell activation and evade immune surveillance, resulting in impaired immune responses against tumors

Method used

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  • Anti-pd-1/lag3 bispecific antibodies
  • Anti-pd-1/lag3 bispecific antibodies
  • Anti-pd-1/lag3 bispecific antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0375] 6.1 Example 1: Affinity Maturation and Binding Affinity Studies of Humanized 08A Antibody

[0376] 6.1.1 Affinity maturation of 08A by single CDR codon-based mutagenesis library

[0377] CDRH3, CDRL1 and CDRL3 of humanized 08A (with S61N glycosylation site correction, numbered according to SEQ ID sequence) Fab001 (SEQ ID NOs: 1 and 2) were targeted for codon-based mutagenesis. The H3, L1 and L3 libraries were randomized at positions H95-H100B, L27B-L32 and L90-L97, respectively. Sequencing of a representative single colony from each library confirmed randomization in the expected CDRs of the targeted residues. Each library yields more than 10 8 a single colony, indicating that the size of the library is sufficient to account for every possible combination of amino acids within the target region.

[0378] Libraries were subjected to four rounds of affinity-based solution-phase phage display selection, each round with decreasing antigen concentration. The first round ...

Embodiment 2

[0405] 6.2 Example 2: Affinity of mouse and humanized anti-PD-1 mAbs to human PD1

[0406] 6.2.1 Surface kinetics determined by BIAcore

[0407] Surface plasmon resonance (SPR)-based assays using capture mode were used to determine the binding kinetics and affinity of anti-PD-1 antibodies to polyhistidine-tagged human PD-1 (hPD1-His, 98AFK). The S-series sensor chip CM5 (GE Healthcare, BR100530) was activated using an amine coupling kit (GE Healthcare, BR100050) according to the manufacturer's instructions. Human capture kit (anti-human Fc, 25 μg / mL, GE Healthcare, BR100839) or mouse capture kit (anti-mouse Fc, 30 μg / mL, GE Healthcare) diluted in provided pH 5.0, 10 mM sodium acetate buffer , BR100838) antibody was immobilized on the activated surface for 7 min. After fixation, the surface was inactivated with 1M ethanolamine / HCl (pH 8.5) for 7 minutes. In each of the four flow cells, final immobilization levels reached -8,000 resonance units (RU) for mouse capture and -12,...

Embodiment 3

[0422] 6.3 Example 3: Generation of anti-PD-1 / LAG3 bispecific antibodies

[0423] Anti-PD-1 / LAG-3 bispecific antibody (BsAb) 18ASS has an anti-PD-1 heavy chain with the heavy chain variable region of affinity matured Fab100 (with CDRH2 S61N and G56A corrections) and an IgG1 constant region (with CH1 mutations L145E, K147T, Q175E and S183L, CH2 mutations L234A, L235A and D265S, CH3 mutations T350V, L351Y, F405A, Y407V) (SEQ ID NO: 102); anti-PD-1 light chain with affinity matured Fab100 Light chain variable region and kappa constant region with Cκ mutations Q124R, T178R (SEQ ID NO: 103); anti-LAG3 heavy chain with heavy chain variable region and IgG1 constant region of humanized 22D2 antibody Ab6 of WO 2016028672 ( With CH1 mutation S181K, CH2 mutation L234A, L235A and D265S, CH3 mutation T350V, T366L, K392L and T394W) (SEQ ID NO: 96); anti-LAG3 light chain, light chain variable region and kappa constant of antibody Ab6 of WO2016028672 Region (with CK mutations Q124E, S131T, T...

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Abstract

Provided herein are anti-PD-1 / LAG3 bispecific antibodies and antigen-binding fragments. Also provided here are methods and uses of these antibodies and antigen-binding fragments in the treatment of cancer or infectious disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] The application claims the benefit of priority to International Serial Number PCT / CN2018 / 074918, filed February 1, 2018, the disclosure of which is incorporated herein by reference in its entirety. [0003] sequence listing [0004] This specification is submitted with a copy of the Sequence Listing in computer readable form (CRF). This CRF, titled 14463-001-228_SEQ_LISTING.TXT, created on January 2, 2019 and having a size of 208,390 bytes, is also used as a paper copy of the Sequence Listing and is incorporated herein by reference in its entirety. [0005] 1. Technical field [0006] Provided herein are treatments for conditions that are ameliorated by combating tumor-mediated immunosuppression. More specifically, provided herein are anti-PD-1 / LAG3 bispecific antibodies, and the use of these antibodies in the treatment of diseases such as cancer and infectious diseases. [0007] 2. Background technology [0008] PD-1 ...

Claims

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Application Information

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IPC IPC(8): C07K16/28
CPCC07K2317/565C07K2317/76C07K2317/92C07K16/2818C07K16/2803C07K2317/31C07K16/468C07K2317/55C07K2317/24C07K2317/41
Inventor L·法雅达特-迪尔曼V·阮S·卡恩黄劭鹏应华E·E·卡雷拉G·德斯贾丁斯
Owner MERCK SHARP & DOHME BV
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