CD80 and CD86 binding protein compositions and uses thereof
Inventors
Liu, Yang • Zheng, Pan • DEVENPORT, Martin • Wu, Wei • DU, Xuexiang • Liu, Mingyue • Tang, Fei
Assignees
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Publication Number
US-12227557-B2
Publication Date
2025-02-18
Expiration Date
Abstract
This invention relates to CTLA-4 protein compositions and their use in the mitigation of autoimmune adverse events associated with cancer immunotherapy.
Core Innovation
The invention relates to CTLA-4 protein compositions intended to mitigate immune-related adverse events (irAEs) associated with anti-CTLA-4 cancer immunotherapy while preserving anti-tumor efficacy. It uses CTLA-4 protein extracellular domains that retain binding to B7-1 (CD80) and B7-2 (CD86) but are altered so that binding by anti-CTLA-4 antibodies is reduced or abolished.
A core concept is engineered soluble CTLA-4 fusion proteins, including CTLA-4Fc (CTLA-4Ig)-type formats, and CTLA-4 or variant sequences that retain B7 binding. The disclosure links reduced anti-sCTLA-4 binding to improved safety in the context of cancer immunotherapy, including rationale connecting CTLA-4 biology to autoimmunity and irAEs.
The disclosure further includes identification of an antibody binding region adjacent to the B7-1 MYPPPY motif, with mutations described as selectively abolishing antibody binding while preserving B7 binding. Additional examples evaluate mutant CTLA-4Fc proteins for protection against irAE in vivo and report modulation of T-cell phenotypes, NKT cells, and Tregs in humanized mouse models.
Claims Coverage
The partial claims include two independent claims focused on CTLA-4 proteins defined by specific sequence identity to SEQ ID NO: 47 and SEQ ID NO: 43. Across these independent claims, the main inventive features are sequence-defined CTLA-4 proteins, with dependent claim coverage extending into Fc fusion formatting, binding to B7-1/B7-2, pharmaceutical composition formulation, and treatment of irAEs associated with cancer immunotherapy including anti-CTLA-4 and optionally anti-PD-1 combinations.
Sequence-defined CTLA-4 protein with SEQ ID NO: 47 extracellular domain
A CTLA-4 protein comprising an extracellular domain of CTLA-4 comprising the sequence set forth in SEQ ID NO: 47.
Sequence-defined CTLA-4 protein with SEQ ID NO: 43
A CTLA-4 protein, wherein the amino acid sequence of the CTLA-4 protein consists of the sequence set forth in SEQ ID NO: 43.
Overall claim coverage centers on CTLA-4 proteins defined by specific SEQ ID sequences (SEQ ID NO: 47 and SEQ ID NO: 43), with dependent claims further specifying CTLA-4 extracellular domain binding to B7-1/B7-2 and CTLA-4 extracellular domain C-terminal fusion to a human Ig Fc region (IgG1, IgG4, or IgM), as well as therapeutic use for treating adverse events associated with cancer immunotherapy, including anti-CTLA-4 and optionally anti-PD-1 combinations.
Stated Advantages
Mitigates immune-related adverse events (irAEs) from anti-CTLA-4 cancer immunotherapy while preserving anti-tumor efficacy.
Engineered CTLA-4 proteins retain anti-tumor activity while showing reduced toxicity, including in combination with anti-PD-1.
Mutants selectively ablate anti-CTLA-4 antibody binding while preserving B7 binding, supporting improved safety.
Supports uncoupling of checkpoint blockade from irAE mitigation, including findings that saturating blockade of B7-1/B7-2 does not prevent ipilimumab tumor rejection.
Provides in vivo protection against irAE with mutant CTLA-4Fc proteins, including modulation of immune-cell phenotypes (T cells, NKT cells, and Tregs).
Documented Applications
Treating adverse events associated with cancer immunotherapy in a subject by administering the CTLA-4 protein.
Treatment context includes cancer immunotherapy comprising an anti-CTLA-4 antibody, including Ipilimumab.
Treatment context optionally includes cancer immunotherapy comprising an anti-PD-1 antibody in combination.
Broadly described applications include pharmaceutical compositions and methods for treating autoimmune/inflammatory disease and cancer immunotherapy-associated irAEs.
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