Methods of treating ocular cancer using Anti-met antibodies and bispecific antigen binding molecules that bind met

An antigen-binding molecule and bispecific technology, applied in anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, chemical instruments and methods, antibodies, etc., can solve problems such as unmet medical needs

Pending Publication Date: 2021-11-30
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There remains a significant unmet medical need for improved anticancer drugs that effectively block ligand-dependent and ligand-independent MET for the treatment of ocular cancers, including uveal melanoma signaling

Method used

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  • Methods of treating ocular cancer using Anti-met antibodies and bispecific antigen binding molecules that bind met
  • Methods of treating ocular cancer using Anti-met antibodies and bispecific antigen binding molecules that bind met
  • Methods of treating ocular cancer using Anti-met antibodies and bispecific antigen binding molecules that bind met

Examples

Experimental program
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preparation example Construction

[0407] Production of Human Antibodies

[0408] Anti-MET antibodies and MET x MET bispecific antibodies useful according to the methods provided herein can be fully human antibodies. Methods for producing monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Human antibodies that specifically bind human MET can be prepared using any such known method in the context of the present disclosure.

[0409] For example, high affinity chimeric antibodies having human variable regions and the MET of mouse constant regions are initially isolated using VELOCIMMUNET™ technology or any other similar known method for producing fully human monoclonal antibodies. Antibodies are characterized and selected for desirable characteristics, including affinity, ligand blocking activity, selectivity, epitope, etc., as in the experimental section below. If necessary, mouse constant regions are replaced with desired human constant regions, such as wild-type or modif...

Embodiment 1

[0447] Example 1. Production of Anti-MET Antibodies

[0448] Cells comprising DNA encoding human immunoglobulin heavy chain and kappa light chain variable regions were immunized with an immunogen comprising a recombinant human MET extracellular domain fused to a human Fc (R&D Systems, catalog number 358-MT, Minneapolis, MN). Genetically engineered mice to obtain anti-MET antibodies. The mice used for immunization express the "universal light chain". That is, antibodies produced in this mouse have different heavy chain variable regions, but substantially identical light chain variable domains.

[0449] Antibody immune responses were monitored by MET-specific immunoassays. When the desired immune response is achieved, splenocytes are harvested and fused with mouse myeloma cells to maintain their viability and form hybridoma cell lines. Hybridoma cell lines were screened and selected to identify cell lines producing MET-specific antibodies. Using this technique, several anti-...

Embodiment 2

[0451] Example 2. Heavy and light chain variable region amino acid and nucleic acid sequences

[0452] Table 1 lists the amino acid sequence identifiers for the heavy and light chain variable regions and CDRs of selected anti-MET antibodies described herein. (As noted above, all antibodies generated in Example 1 had identical light chain variable regions, and thus also identical light chain CDR sequences). The corresponding nucleic acid sequence identifiers are listed in Table 2.

[0453] Table 1: Amino Acid Sequence Identifiers

[0454]

[0455]

[0456] Table 2: Nucleic acid sequence identifiers

[0457]

[0458]

[0459] Antibodies are generally referred to herein according to the following nomenclature: an Fc prefix (e.g., "H4H"), followed by a numerical identifier (e.g., "13290," "13291," "13295," etc.), followed by a "P2" suffix, such as Tables 1 and 2 are shown. Accordingly, according to this nomenclature, antibodies may be referred to herein, eg, "H4H13...

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Abstract

Provided herein are methods of treating ocular cancer such as uveal melanoma, orbital lymphoma, retinoblastoma, and medulloepithelioma using antibodies and bispecific antigen-binding molecules that bind MET or antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different epitopes of the extracellular domain of human MET. The ADCs comprise the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety. The antibodies and bispecific antigen-binding molecules are capable of blocking the interaction between human MET and its ligand HGF. A subject having ocular cancer, for example, an uveal melanoma expressing c-Met, can be treated by administering to the subject an antibody, a bispecific antigen-binding molecule, or an ADC thereof.

Description

technical field [0001] The present invention relates to antibodies that specifically bind to hepatocyte growth factor receptor (c-Met or MET) and modulate MET signal transduction, bispecific antibodies, and antigen-binding fragments thereof, and antibody-drug conjugates of such antibodies Use of a drug for the treatment of eye cancer, including uveal melanoma. [0002] sequence listing [0003] An official copy of the Sequence Listing is submitted electronically via EFS-Web in parallel with the specification as a Sequence Listing in ASCII format, with file name 10548WO01_SEQ_LIST_ST25.TXT, date of creation February 20, 2020, and size of approximately 140 kilobytes. The Sequence Listing contained in this document in ASCII format is part of the specification and is hereby incorporated by reference in its entirety. Background technique [0004] Uveal melanoma is the most common primary intraocular malignancy in adults, accounting for 79-81% of ocular melanomas. The incidenc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00A61K31/537A61K47/68C07K16/28C07K16/30A61P27/02
CPCA61K47/6803A61K47/6849A61K47/6879A61P35/00C07K16/2863C07K16/3023C07K16/3046C07K2317/31C07K2317/73C07K2317/76C07K2317/92A61P27/02A61K47/6851A61K47/6817A61K47/6889A61K31/5365A61K45/06A61K2039/505C07K2317/33
Inventor G·施瓦兹O·苏里加
Owner REGENERON PHARM INC
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