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Antagonistic cd40 monoclonal antibodies and uses thereof

An antibody, CDR2 technology, applied in the direction of antibodies, antibody medical components, anti-tumor drugs, etc., can solve the problems of limited stimulation potential and weak availability of anti-CD40 antibodies

Active Publication Date: 2021-07-23
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the availability of the anti-CD40 antibody Chi220 is limited by its weak stimulatory potential

Method used

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  • Antagonistic cd40 monoclonal antibodies and uses thereof
  • Antagonistic cd40 monoclonal antibodies and uses thereof
  • Antagonistic cd40 monoclonal antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0205] Example 1: Binding of mouse anti-human CD40 antibody to human CD40

[0206] Mouse anti-human CD40 antibodies were raised and tested for binding to human CD40 by surface plasmon resonance (SPR). Table 8 shows the Vh and Vk sequences of each antibody.

[0207] Table 8

[0208] Mouse anti-human CD40 variable heavy and light chain sequences

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] CD40 kinetics and avidity data for the binding of human CD40 monomers to mouse anti-human CD40 antibody captured on the protein A sensor chip surface were assessed by SPR. Data are shown in Table 9. Data shown are for a single concentration of CD40 analyte (1 μΜ) and are therefore reported as apparent (app) values.

[0217] Table 9

[0218] SPR kinetics / affinity data

[0219]

[0220] Based on SPR data and sequence data, three antibodies ADX_Y1258.ZZ0-1, ADX_Y1262.ZZ0-1 and ADX_Y1268.ZZ0-1 were selected for humanization.

Embodiment 2

[0221] Example 2: Humanization of Y12XX and selection of humanized variants

[0222] The humanization background / procedure was as discussed in the section "II. Engineered and Modified Antibodies" in WO2017004006, which is incorporated herein by reference in its entirety. Based on this analysis, nine (9) humanized Vh sequences (Vh-hz1, Vh-hz2, Vh-hz3, Vh-hz4, Vh-hz5, Vh-hz6, Vh-hz9, Vh-hz10 and Vh-hz11 were selected. ) and three (3) humanized VK sequences (Vk-hz1, Vk-hz2 and Vk-hz3) were tested. In addition, five (5) humanized Vh sequences (Vh-hz7, Vh-hz8, Vh-hz12, Vh-hz13 and Vh-hz14) were designed to contain mutations aimed at reducing the designed chemical liability risk. Mutations include D100Q (Y1262_IGHV1.6908-D100Q) and P101A (Y1262_IGHV1.6908-P101A) mutations to mitigate potential hydrolysis risk in Y1262_IGHV1.6908. Mutations also include N55Q (Y1268_IGHV1.6908-N55Q), G56A (Y1268_IGHV1.6908-G56A) and S54T-N55T double mutation (Y1268_IGHV1.6908-S54T-N55T) to alleviate...

Embodiment 3

[0271] Example 3: In vitro Fc receptor analysis

[0272] Antibodies can exert effector functions, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), by binding the Fc region to Fcγ receptors (FcγR) or complement factors on the surface of immune cells. Antibody-dependent phagocytosis is another potential Fc effector function. To further characterize the properties of the humanized Y12XX antibody, the complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) of the antibody were analyzed. Table 15 lists the antibodies analyzed in this example.

[0273] Table 15

[0274]

[0275] CDC analysis was performed as follows. "CDC assay medium" refers to Roswell Park Memorial Institute medium (RPMI) 1640 (HyClone) with L-glutamine, without phenol red (HyClone), supplemented with 0.1% BSA (Sigma) and 1% penicillin-streptomycin (Life Technologies). Fi...

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Abstract

The disclosure provides for antibodies that bind CD40, including a humanized antibody. The antibodies bind CD40 and do not exhibit CD40 agonist activity. The antibodies may comprise a modified IgG1 Fc domain, and exhibit minimal activation of immature dendritic cells. Compositions comprising antibodies, methods of use for treatment of diseases involving CD40 activity, and use in the preparation of a medicament for treatment of a disease involving CD40 activity are provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 769,514, filed November 19, 2018, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been electronically filed in ASCII format and is hereby incorporated by reference in its entirety. Created on November 13, 2019, this ASCII copy is named 200896-0015-00-WO-592417_SL.txt and is 170,111 bytes in size. technical field [0005] The application provides antibodies that bind CD40. The antibody polypeptides bind CD40 and do not exhibit CD40 agonist activity. These antibodies may comprise a modified IgGl Fc domain and show minimal activation of immature dendritic cells. Compositions comprising antibodies, methods for treating diseases involving CD40 activity, and uses in the preparation of medicaments for treating diseases involving CD40 activity are provid...

Claims

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Application Information

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IPC IPC(8): A61P35/02C07K16/28A61K39/00
CPCC07K16/2878C07K2317/21C07K2317/24C07K2317/34C07K2317/72C07K2317/73C07K2317/75A61K2039/505A61P35/02A61K39/3955A61K45/06A61K47/68A61K47/6803A61K47/6849C07K14/70578C07K16/468C07K2317/52C07K2317/565C07K2317/622C07K2317/76C07K2317/92A61P37/00C07K2317/71C12N15/63
Inventor A·亚姆尼克M·斯特拉瑟斯小斯坦利·R·克里斯泰克A·纳伊姆G·莱克斯特罗
Owner BRISTOL MYERS SQUIBB CO
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