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-11629188-B2
Publication Date
2023-04-18
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 chimeric and humanized anti-human CTLA4 antibody compositions and antigen binding fragments for cancer immunotherapy. The antibodies are defined by specific light chain and heavy chain variable regions comprising CDR1, CDR2, and CDR3 amino acid sequences identified using SEQ ID NOs. The compositions include CDR-defined variants and Fc-engineered versions.
The disclosed material includes ELISA epitope-mapping and specificity data for humanized anti-CTLA4 antibody PP4637 and related antibodies against CTLA4Fc wild-type and mutant proteins M1–M11. The data indicate that only mutant M11 selectively ablates binding and that introduced mutations abrogate epitope recognition adjacent to the B7-1 binding domain.
The document further describes combination concepts with checkpoint agents, including anti-PD-1 and/or anti-4-1BB, and optional bispecific antibody formats. It includes a biomarker concept using B7.1/B7.2 upregulation to monitor in vivo CTLA4 blockade, and it provides supporting characterization including binding assays and analytical characterization of humanized antibody candidates.
The disclosure also states in vivo anti-tumor immunotherapy results showing that combining anti-CTLA4 with anti-4-1BB synergizes to reject established tumors in the MC38 model. The results include reduced liver metastasis and long-lasting immunity, and the anti-tumor activity is CD8 T cell-dependent.
Claims Coverage
The relevant independent claim is directed to a method of treating lung cancer using an anti-CTLA4 antibody or antigen binding fragment that binds human CTLA4 and is defined by specific light- and heavy-chain CDR sequence sets. Across the dependent claims, the coverage expands to co-administration of additional immune checkpoint agents and specific functional outcome limitations.
Lung cancer treatment with human CTLA4 binding anti-CTLA4 antibody or antigen binding fragment defined by CDR sequences
A method of treating lung cancer in a subject in need thereof by administering an anti-CTLA4 antibody or antigen binding fragment capable of binding human CTLA4, wherein the light chain and heavy chain variable regions comprise CDR1, CDR2, and CDR3 amino acid sequences set forth by specific SEQ ID NOs.
Combination immunotherapy with anti-PD-1 or anti-4-1BB
The method further includes administering an additional agent that is an anti-PD-1 antibody or an anti-4-1BB antibody together with the anti-CTLA4 antibody or antigen binding fragment.
Bispecific antibody format combining anti-CTLA4 with anti-PD-1 and/or anti-4-1BB
The method provides that the anti-PD-1 antibody, anti-4-1BB antibody, and anti-CTLA4 antibody are combined into a single bispecific antibody molecule.
Defined CDR2 sequence options using specified SEQ ID pairings
The method defines antibody variants using light chain CDR2 and heavy chain CDR2 amino acid sequences selected from specified SEQ ID NOs.
Reduced binding to soluble CTLA4
The method includes using an anti-CTLA4 antibody or antigen binding fragment that has reduced binding to soluble CTLA4.
Local Treg deletion with local T cell activation and minimal systemic activation
The method includes a composition that causes strong deletion of Treg and local T cell activation in the tumor microenvironment while causing minimal systemic T cell activation.
Across the relevant independent claim and its dependencies, the inventive coverage centers on lung cancer treatment with an anti-CTLA4 antibody or fragment defined by specific CDR sequence sets, with further refinement by enumerated CDR2 options, reduced binding to soluble CTLA4, optional co-therapy with anti-PD-1 and/or anti-4-1BB, and an explicit biological effect profile emphasizing strong local Treg deletion and local T cell activation with minimal systemic activation.
Stated Advantages
Reduced autoimmune-related toxicity.
Improved CTLA4 blockade and/or effector function.
Reduced binding to soluble CTLA4.
Minimal systemic T cell activation while achieving strong local Treg deletion and local T cell activation.
Synergizes with anti-4-1BB to reject established tumors.
Reduces liver metastasis.
Demonstrates CD8 T cell dependence of the anti-tumor activity.
Reduces host anti-antibody responses to co-administered anti-CTLA4 antibodies.
Enhances anti-human CTLA4 knock-in mouse tumor rejection with long-lasting immunity.
Documented Applications
Treating lung cancer in a subject in need thereof using an anti-CTLA4 antibody or antigen binding fragment binding human CTLA4 defined by CDR sequences.
Cancer immunotherapy contexts involving combination checkpoint concepts with anti-PD-1 and/or anti-4-1BB, including optional bispecific antibody formats.
Monitoring in vivo CTLA4 blockade using a B7.1/B7.2 upregulation biomarker concept.
Preclinical tumor rejection evaluation in CTLA4 knock-in mouse models using tumor models referenced as MC38 colon cancer model and B16-F1 melanoma model.
Anti-tumor immunotherapy in the MC38 model, including rejection of established tumors and reduction of liver metastasis.
Use involving human CTLA4 knock-in mouse tumor rejection with long-lasting immunity.
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