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Anti-CD47 antibodies, activatable anti-CD47 antibodies, and methods of use thereof

A technology of antibodies and antigens, applied in the fields of anti-CD47 antibodies, activatable anti-CD47 antibodies and their use, can solve problems such as limiting the effectiveness of therapy

Pending Publication Date: 2022-06-21
CYTOMX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007]Antibody-based therapies have proven to be effective treatments for several diseases, but in some cases, toxicity due to broad target expression limits the therapeutic effectiveness of these therapies sex
In addition, antibody-based therapeutics exhibit other limitations, such as rapid clearance from circulation after administration

Method used

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  • Anti-CD47 antibodies, activatable anti-CD47 antibodies, and methods of use thereof
  • Anti-CD47 antibodies, activatable anti-CD47 antibodies, and methods of use thereof
  • Anti-CD47 antibodies, activatable anti-CD47 antibodies, and methods of use thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0617] The studies presented herein were designed to evaluate the binding of anti-human CD47 antibodies of the present disclosure.

[0618] The anti-human CD47 monoclonal antibodies of the present disclosure were obtained using mouse hybridoma technology according to techniques known in the art. Mice were immunized with human CD47 and hybridomas were screened for binding to human CD47 by ELISA, followed by cytotoxicity in a piggyback assay and cell surface binding by FACS. The mouse anti-human CD47H4L2 monoclonal antibody of the present disclosure includes the heavy chain variable region (VH) of SEQ ID NO:1 and the light chain variable region (VL) of SEQ ID NO:2. In some embodiments of the present disclosure, an exemplary antibody of the present disclosure includes a heavy chain having the H4L2 heavy chain variable region of SEQ ID NO:1 and a light chain having the H4L2 light chain variable region of SEQ ID NO:2.

[0619]Mouse anti-human CD47 monoclonal antibody H4L2 was huma...

Embodiment 2

[0661] The studies presented herein were aimed at identifying and characterizing masking moieties for use in the activatable anti-human CD47 antibodies of the present disclosure.

[0662] Using methods similar to those described in PCT International Publication No. WO 2010 / 081173 published on July 15, 2010, the humanized anti-human CD47 hu H4L2 monoclonal antibody (VH and The VL of SEQ ID NO:2) was used to screen for a total diversity of 4x16 0 Random X of 15 A library of peptides, wherein X is any amino acid. Screening included Magnetic Activated Cell Sorting (MACS) and Fluorescence Activated Cell Sorting (FACS). The amino acid sequence of an exemplary single clone of the isolated and sequenced masking peptide (MM) is shown in Table 4.

[0663] Table 4. Anti-human CD47 masking peptide (MM)

[0664]

[0665]

[0666] These masking peptides were used to generate the anti-human CD47 activatable antibodies of the present disclosure. The sequences of some of these ant...

Embodiment 3

[0730] The studies presented herein were designed to determine that activatable anti-human CD47 antibodies of the present disclosure induce antibody-dependent cellular phagocytosis (ADCP) by affecting the FcyRIIa receptor pathway. As these exemplary results demonstrate, intact activatable antibodies containing masked peptides of the present disclosure exhibit lower ADCP activation through the FcyRIIa receptor pathway compared to unmasked parental anti-CD47 antibodies.

[0731] In this assay (FcyRIIa-H ADCP Reporter Bioassay, Promega), target cells expressing the target antigen are co-cultured with an engineered effector cell line with the FcyRIIa-H receptor. In the presence of an antibody that binds the target antigen through the antigen-binding domain while binding to FcγRIIa on the effector cell through the Fc effector domain, antibody binding results in aggregation of FcγRIIa receptors from the effector cell line, intracellular signaling and NFAT-RE mediation. induced lucif...

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Abstract

The present invention relates generally to activatable antibodies that bind to CD47 and methods of making and using these activatable antibodies in a variety of therapeutic, prophylactic and diagnostic environments. In some embodiments, the CD47 activatable antibody binds to human and cynomolgus CD47.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 904,534, filed September 23, 2019, the contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates generally to antibodies that specifically bind to CD47, activatable antibodies that specifically bind to CD47, and methods for making and using these antibodies and activatable antibodies in various therapeutic, prophylactic and diagnostic settings method. [0004] References to Sequence Listings [0005] Pursuant to Title 37 of the Code of Federal Regulations (C.F.R.) Section 1.821, the "Sequence Listing" submitted electronically in computer readable form (CFR) via EFS-Web as file name "CYTX-066-PCT_ST25" is referenced by way incorporated into this article. The electronic copy of the sequence listing was created on September 23, 2020 and has a disk capacity of 197 kilobytes. ...

Claims

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Application Information

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IPC IPC(8): A61K47/68C07K16/28
CPCC07K16/2803C07K2317/24C07K2317/33C07K2317/72C07K2317/73C07K2317/76C07K2317/92C07K2319/50A61K2039/505C07K2317/94A61K47/6849A61K47/6891
Inventor L·梅J·G·弗兰德斯D·丹尼尔K·A·蒂普顿D·R·霍斯特特
Owner CYTOMX THERAPEUTICS
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