Variants of humanized immunomodulatory monoclonal antibodies
Inventors
Rotem-Yehudar, Rinat • Schickler, Michael
Assignees
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Publication Number
US-8686119-B2
Publication Date
2014-04-01
Expiration Date
Abstract
The present invention relates to humanized monoclonal antibodies, pharmaceutical compositions that include the same, and use thereof for the treatment of a variety of indications, particularly cancer and immunodeficiency disorders. In particular, the present invention provides modified antibodies or fragments thereof having specific amino acid modifications compared to the humanized monoclonal immunomodulatory antibody termed hBAT-1.
Core Innovation
The invention relates to humanized immunomodulatory monoclonal antibodies derived from hBAT-1/mBAT-1. It focuses on site-specific amino-acid modifications in the light-chain and heavy-chain variable regions to produce an isolated anti-BAT antibody or antigen-binding fragment with defined variable-region sets.
The document provides antibody and antigen-binding fragments including Fv, F(ab′)2, and single-chain formats, together with associated polynucleotides, vectors, and host cells. The variable regions are specified by SEQ ID variable-region sets, and the substitutions and deletions are described as part of the allowed variant definition.
The stated rationale links the selected amino-acid substitutions to reduced immunogenicity and improved stability and solubility. Functional outcomes described include retaining immunomodulatory activity and antitumor activity similar to or greater than mBAT-1/hBAT-1.
Claims Coverage
The partial content contains one independent claim, with two dependent claims that narrow fragment format and add pharmaceutical composition elements. The independent claim is grounded in variable-region sets defined by SEQ ID NO: 1 (light chain) and SEQ ID NO: 5 (heavy chain), together with specified substitutions.
Anti-BAT antibody with defined light- and heavy-chain substitutions
An isolated anti-BAT antibody or antigen binding fragment comprising a light chain variable region set forth in SEQ ID NO: 1 wherein Phe 97 is substituted with Ala, and a heavy chain variable region set forth in SEQ ID NO: 5 wherein Trp 107 is substituted with Ala.
Antigen-binding fragment in selected antibody fragment formats
The antigen binding fragment is selected from the group consisting of Fv, F(ab′)2, and a single chain antibody.
Pharmaceutical composition with pharmaceutically acceptable carrier components
A pharmaceutical composition comprising as an active ingredient the isolated antibody of claim 1 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier, diluent or stabilizer.
Overall claim coverage focuses on an isolated anti-BAT antibody or antigen-binding fragment defined by specific SEQ ID variable-region sets and the Phe97Ala and Trp107Ala substitutions, with dependent claims further limiting the fragment format and requiring a pharmaceutical composition that includes pharmaceutically acceptable carrier, diluent or stabilizer.
Stated Advantages
Reduced immunogenicity.
Enhanced stability and solubility.
Retention of immunomodulatory activity.
Antitumor activity similar to or greater than mBAT-1/hBAT-1.
Reduced disulfide formation risk.
Reduced deamidation.
Reduced O-linked glycosylation risk.
Reduced degradation.
Documented Applications
Treating cancer.
Treating immunodeficiency disorders.
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