Chimeric and humanized anti-human CTLA4 monoclonal antibodies and uses thereof
Inventors
Liu, Yang • Zheng, Pan • DEVENPORT, Martin
Assignees
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Publication Number
US-10618960-B2
Publication Date
2020-04-14
Expiration Date
Abstract
This invention relates to compositions of chimeric and humanized antibodies that bind to the human CTLA4 molecule and their use in cancer immunotherapy and for reduction of autoimmune side effects compared to other immunotherapeutic agents.
Core Innovation
The invention relates to an anti-CTLA4 antibody defined by specific light chain variable region and heavy chain variable region complementarity determining regions, with amino acid sequences set forth in SEQ ID NOs. The antibody is characterized as capable of blocking CTLA4-mediated interactions, including B7.1/B7.2 interaction blockade, and the binding site lies adjacent to the B7-1 binding region based on epitope mapping and structure-based rationale.
The invention describes reduced binding to soluble CTLA4 (sCTLA4), which is linked to reduced autoimmune-related adverse effects relative to another anti-CTLA4 antibody. It further reports engineered Fc mutations intended to enhance effector function and humanized candidates including PP4631, PP4637, and PP4638 with improved safety.
The document provides in vivo evidence in human CTLA4 knock-in mouse models and MC38 colon cancer models showing strong tumor rejection, selective intra-tumoral Treg depletion, and minimal systemic T cell activation. It also reports anti-4-1BB and anti-PD-1 combination rationale, including synergistic CD8 T cell-dependent tumor rejection, reduced tumor growth, reduced liver metastasis, reduced host anti-anti-CTLA-4 antibody responses, and preserved long-lasting immunity after tumor rechallenge.
Claims Coverage
The independent claim coverage centers on a sequence-defined anti-CTLA4 antibody with specified light chain and heavy chain CDR1, CDR2, and CDR3 regions. Across the provided claims material, inventive features further include reduced binding to soluble CTLA4, pharmaceutical composition context, combination with anti-PD-1 and/or anti-4-1BB, bispecific antibody formats, and local tumor microenvironment effects with minimal systemic T cell activation.
Sequence-defined anti-CTLA4 antibody with defined CDRs
An anti-CTLA4 antibody comprising a light chain variable region and a heavy chain variable region with CDR1, CDR2, and CDR3 amino acid sequences set forth in specified SEQ ID NOs.
Reduced binding to soluble CTLA4
An anti-CTLA4 antibody characterized by reduced binding to soluble CTLA4 (sCTLA4).
Pharmaceutical composition with therapeutically effective amount
A pharmaceutical composition comprising a therapeutically effective amount of the anti-CTLA4 antibody, or an antigen-binding fragment, together with a physiologically acceptable carrier or excipient.
Combination with anti-PD-1 and/or anti-4-1BB
A method that administers an additional agent selected from anti-PD-1 and anti-4-1BB antibodies together with the anti-CTLA4 antibody.
Bispecific format combining anti-PD-1 or anti-4-1BB with anti-CTLA4
A method that combines anti-PD-1 or anti-4-1BB antibodies with an anti-CTLA4 antibody into a single bispecific antibody molecule.
Local tumor microenvironment effect with minimal systemic T cell activation
A method that induces strong deletion of Treg and local T cell activation in the tumor microenvironment while producing minimal systemic T cell activation.
The claims cover a sequence-defined anti-CTLA4 antibody with specified light and heavy chain CDR regions, with dependent features directed to reduced soluble CTLA4 binding, pharmaceutical compositions, combination therapy with anti-PD-1 and/or anti-4-1BB, bispecific formats, and local tumor microenvironment activity with minimal systemic T cell activation.
Stated Advantages
Reduced autoimmune-related adverse effects versus another anti-CTLA4 antibody (10D1).
Improved safety profile after humanization, including PP4631, PP4637, and PP4638.
Milder irAEs with anti-PD-1 for L3D10-based antibodies compared with 10D1.
Strong tumor rejection with selective intra-tumoral Treg depletion while producing minimal systemic T cell activation.
Enhanced effector function via engineered Fc mutations.
Increased antitumor effect from the combination of anti-CTLA-4 with anti-4-1BB.
Reduced autoimmune side effects.
Improved anti-antibody response, including reduced host anti-anti-CTLA-4 antibody responses and preserved long-lasting immunity after tumor rechallenge.
Documented Applications
Cancer immunotherapy using anti-CTLA4 antibodies, including chimeric and humanized L3D10-derived antibodies, with in vivo tumor rejection in human CTLA4 knock-in mouse models.
Combination therapy using anti-CTLA4 antibodies together with anti-PD-1 and/or anti-4-1BB antibodies.
Bispecific antibody formats combining anti-PD-1 or anti-4-1BB with an anti-CTLA4 antibody.
Immunotherapy for cancer using combination treatment with anti-CTLA-4 and anti-4-1BB, demonstrated in MC38 colon cancer models including reduced tumor growth, eradication in a majority of mice, reduced liver metastasis, and CD8 T cell-dependent tumor rejection.
Use in contexts involving tumor rechallenge to support long-lasting immunity.
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