Method of treating cancer using anti-AV8 antibodies
Inventors
Niessen, Kyle Steven • Samuel, Dharmaraj • Holst, Charles Ray • Drever, Matthew Ross • Sheppard, Dean • Akurst, Rosemary J. • Atakilit, Amha • Meyer, Dominique • Rondon, Isaac J. • Dal Porto, Joseph
Assignees
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Publication Number
US-12371499-B2
Publication Date
2025-07-29
Expiration Date
Abstract
The invention provides antibodies, and antigen-binding fragments thereof, that specifically bind to αvβ8 integrin. The invention includes uses, and associated methods of using the antibodies.
Core Innovation
The document describes anti-αvβ228 integrin antibodies and antigen-binding fragments that specifically bind αvβ228 integrin. It targets inhibition of αvβ228-mediated activation of latent TGFβ through Latency Associated Peptide (LAP), and states that the antibodies reduce TGFβ1 and TGFβ3 signaling and promote anti-tumor immune responses.
The document characterizes multiple light chain and heavy chain amino-acid sequences, including variant substitutions, and defines antibodies by particular combinations of CDR-L1, CDR-L2, CDR-L3, and CDR-H1, CDR-H2, CDR-H3 amino-acid sequences. It further specifies variable light and variable heavy regions by deposited plasmid insert sequences with ATCC accession numbers and provides additional sequence-defined variants using explicit SEQ ID NO ranges, including constant-region options such as effectorless or IgG constant-region options.
The document also reports functional characterization of anti-αvβ228 antibodies, including selective blocking of αvβ228-LAP interaction, inhibition of TGF-β signaling, and tumor responses in animal models. It discusses combinatorial cancer therapy concepts involving checkpoint inhibitors and radiotherapy in the context of tumor regression, immune infiltration markers, and diagnostic detection of αvβ228 using immunohistochemistry (IHC).
Claims Coverage
The independent claims cover three therapeutic and inhibitory methods using an αvβ228 integrin-specific antibody or antigen-binding fragment selected from defined sequence-identified variants. Across the independent claims, the inventive content centers on antibody or fragment identity via specific CDR amino-acid sequences and/or specific VL/VH sequences tied to SEQ ID NOs and deposited plasmid accession numbers, applied to treatment, survival and cancer-outcome improvement, or inhibition of αvβ228 binding.
Treating a cancer by administering an αvβ228-specific antibody or antigen-binding fragment
Administering to a subject a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds αvβ228 integrin, where the antibody or antigen-binding fragment is selected from variants defined by specific CDR-L1/CDR-L2/CDR-L3 and CDR-H1/CDR-H2/CDR-H3 amino-acid sequences, or by specific VL/VH regions encoded by plasmids deposited with ATCC, or by specified VL/VH sequence combinations.
Improving cancer-related survival and lesion/tissue/symptom outcomes with an αvβ228-specific antibody or antigen-binding fragment
Administering to a subject a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds αvβ228 integrin, where the antibody or antigen-binding fragment is selected from variants defined by specific CDR amino-acid sequences or by specific VL/VH regions and sequence combinations. The intended outcome includes improving survival rate and decreasing appearance of cancer lesions, extent of tissue damage, duration of the cancer, and/or symptoms related to the cancer.
Inhibiting αvβ228 integrin binding with an αvβ228-specific antibody or antigen-binding fragment
Administering to a subject a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds αvβ228 integrin, where the antibody or antigen-binding fragment is selected from variants defined by specific CDR amino-acid sequences, specific VL/VH regions, and defined LC/HC or VL/VH sequence combinations, to inhibit αvβ228 integrin binding.
The independent claims provide coverage for administering defined αvβ228 integrin-specific antibody or antigen-binding fragment variants, specified by CDR sequence sets and/or VL/VH or LC/HC sequence sets, and in some instances tied to ATCC plasmid accession numbers. The claimed methods apply to treating cancer, improving survival and cancer outcome measures, and inhibiting αvβ228 integrin binding.
Stated Advantages
Improving survival rate of a subject having a cancer.
Decreasing the appearance of cancer lesions.
Decreasing the extent of tissue damage from the cancer.
Decreasing the duration of the cancer.
Reducing the number, extent, or duration of symptoms related to the cancer.
Inhibiting αvβ228 integrin binding.
Inhibiting αvβ228-LAP interaction.
Inhibiting TGF-β signaling.
Selectivity against αvβ228 homologs.
Tumor regression in animal models.
Improved overall survival as indicated by Kaplan-Meier overall survival.
Diagnostic detection of αvβ228 using immunohistochemistry (IHC).
Improved properties including high-affinity and specificity versus murine ADWA11.
Reduced Fc effector activity, including lower ADCC and CDC.
Reduction of TGFβ1 and TGFβ3 signaling via inhibition of αvβ228-mediated activation of latent TGFβ through LAP.
Promotion of anti-tumor immune responses.
Documented Applications
Treating a cancer in a subject by administering a therapeutically effective αvβ228 integrin-binding antibody or antigen-binding fragment.
Improving survival rate and other cancer-related outcomes in a subject having a cancer.
Inhibiting αvβ228 integrin binding in a subject by administering an αvβ228 integrin-binding antibody or antigen-binding fragment.
Combination regimens involving immune checkpoint inhibitor agents such as PD-1/PD-L1 and CTLA-4.
Diagnostic detection of αvβ228 using immunohistochemistry (IHC).
Reported experimental use cases include tumor immunity effects and treatment synergy with anti-PD1, anti-CTLA-4, 4-1BB agonist, radiation therapy, and durable protection upon tumor re-challenge in multiple syngeneic models; additionally, reported human relevance includes αvβ228 protein detection on specific human myeloid populations and ITGB8 expression in many tumors.
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