Variants of humanized immunomodulatory monoclonal antibodies
Inventors
Rotem-Yehudar, Rinat • Schickler, Michael
Assignees
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Publication Number
US-9416175-B2
Publication Date
2016-08-16
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 describes humanized immunomodulatory monoclonal antibody variants derived from hBAT-1 (murine BAT-1/CT-011). The variants specify light-chain variable-region sequence options and heavy-chain variable-region sequence options, together with site-specific amino-acid substitutions and modifications in the variable regions and related constant-region modifications.
In particular, the humanized antibody variants include a light chain variable region as set forth in SEQ ID NO: 1 with a substitution of Phe 97, and a heavy chain variable region as set forth in SEQ ID NO: 5 with a substitution of Trp 107. Additional enumerated substitutions/modifications are described, including Light Phe93 and further modifications in the variable and constant regions.
The described embodiments include treating cancer and immunodeficiency disorders using a pharmaceutical composition containing the humanized antibody or an antigen binding fragment thereof. The document further asserts stability-related improvements and antitumor activity versus hBAT-1, with example sequences and evidence including CD4+ T-cell viability comparisons.
Claims Coverage
The document contains one independent claim directed to treating cancer or an immunodeficiency disorder, with multiple dependent claims narrowing the treated subject population and the antibody/antigen-binding fragment format. The independent claim centers on the combination of specific light- and heavy-chain variable-region sequences with defined amino-acid substitutions.
Treating cancer or immunodeficiency with a defined humanized antibody variant
A method for treating cancer or an immunodeficiency disorder in a subject in need thereof by administering an effective amount of a pharmaceutical composition comprising an antibody or antigen binding fragment and a pharmaceutically acceptable carrier, diluent or stabilizer, where the antibody or fragment contains a light chain variable region as set forth in SEQ ID NO: 1 and a heavy chain variable region as set forth in SEQ ID NO: 5 with defined amino-acid substitutions.
Treatment restricted to non-solid tumors or hematologic malignancies
The method where the subject has a non-solid tumor or a hematologic malignancy.
Treatment for cancer selected from an enumerated group of cancer types
The method where the cancer is selected from a specified group including colorectal carcinoma, non-small lung cancer (NSCLC), small cell lung cancer (SCLC), breast carcinoma, melanoma, ovarian carcinoma, cervical carcinoma, pancreatic cancer, head and neck carcinoma, gastrointestinal carcinoma, esophageal tumor, hepatocellular carcinoma, multiple myeloma, renal cell carcinoma, prostate tumor, non-Hodgkin’s lymphoma, Hodgkin’s disease, mantle cell lymphoma, Kaposi’s sarcoma, squamous cell carcinoma, basal cell carcinoma, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
Antigen-binding fragment format selected from specified fragment classes
The method where the antibody or antigen binding fragment is selected from Fv, F(ab′), F(ab′)2, or a single-chain antibody.
Overall, the claims cover administration of a humanized immunomodulatory monoclonal antibody or antigen binding fragment defined by specific light- and heavy-chain variable-region sequences for treating cancer or immunodeficiency. Dependent claims narrow eligible cancers to non-solid tumors or hematologic malignancies, provide an enumerated list of cancer types, and restrict antibody format to Fv, F(ab′), F(ab′)2, or a single-chain antibody.
Stated Advantages
Stability-related improvements are asserted versus hBAT-1, including reduction of aggregation/deamidation/glycosylation risk.
Antitumor activity is asserted versus hBAT-1.
An example figure indicates improved CD4+ T-cell viability for CT-011 compared with an example double mutant.
Documented Applications
Treating cancer in a subject in need thereof.
Treating an immunodeficiency disorder in a subject in need thereof.
Treatment evidence/application includes CD4+ T-cell viability comparisons using CT-011 and an example double mutant.
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