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-11261233-B2
Publication Date
2022-03-01
Expiration Date
Abstract
This invention relates to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) protein compositions and their use in the mitigation of autoimmune adverse events associated with cancer immunotherapy. Specifically, the disclosure provides a CTLA-4 protein comprising a mutant extracellular domain of CTLA-4, wherein the CTLA-4 protein exhibits reduced binding to an anti-CTLA-4 antibody as compared to a wild-type extracellular domain of CTLA-4, wherein the anti-CTLA-4 antibody has anti-cancer immunotherapeutic activity.
Core Innovation
The invention relates to CTLA-4 compositions intended for use with anti-CTLA-4 cancer immunotherapy, where immune-related adverse events (irAEs) occur without loss of anti-tumor effects. The background states that immune checkpoint blockade via B7/CTLA-4 is not required for anti-tumor activity, and that irAEs correlate with reduced binding to soluble CTLA-4 (sCTLA-4), including sCTLA-4 compared with B7 blockade contexts.
The core concept is provided by CTLA-4 proteins and CTLA-4Fc fusion proteins that retain binding to B7-1 (CD80) and B7-2 (CD86) while selectively reducing or ablating binding to anti-CTLA-4 antibodies such as Ipilimumab and Tremelimumab. Engineered CTLA-4 proteins are described as having extracellular-domain mutations that selectively reduce or ablate binding to anti-CTLA-4 antibodies while maintaining B7-1/B7-2 binding.
The document further describes functional support for differential toxicity using chimeric CTLA-4 variants, including L3D10 versus 10D1, where comparable tumor rejection can be associated with different toxicity in an anti-PD-1 combination context. Epitope mapping using CTLA-4Fc mutants identifies antigenic sites adjacent to the B7-1 MYPPPY motif, including mutations that selectively abolish anti-CTLA-4 antibody binding while retaining B7 binding, and selected CTLA-4Fc mutants are described as mitigating irAEs without interfering with anti-CTLA-4 anti-tumor activity.
Claims Coverage
The claim coverage centers on one independent claim, with dependent refinements that specify a CTLA-4 protein extracellular domain, B7-1/B7-2 binding, non-blocking of anti-cancer anti-CTLA-4 antibody effects, an Ipilimumab embodiment, an Fc-fusion embodiment, and administration for minimizing autoimmune adverse events associated with anti-CTLA-4 cancer immunotherapy.
Extracellular-domain CTLA-4 sequence selection
A CTLA-4 protein comprising an extracellular domain of CTLA-4 comprising the sequence set forth in any one of SEQ ID NOs: 34, 36, 39, 40, and 46-48.
B7-1/B7-2 binding capability
The CTLA-4 protein has the ability to bind at least one of B7-1 and B7-2.
Non-blocking of anti-CTLA-4 antibody anti-cancer effects
The CTLA-4 protein does not block the anti-cancer immunotherapeutic effects of an anti-CTLA-4 antibody.
Ipilimumab as the anti-CTLA-4 antibody
The anti-CTLA-4 antibody is Ipilimumab.
Fc fusion of CTLA-4 extracellular domain
The extracellular domain of CTLA-4 is fused to a Fc region of a human immunoglobulin protein.
Minimizing autoimmune adverse events during anti-CTLA-4 cancer immunotherapy
Minimizing autoimmune adverse events associated with cancer immunotherapy by administering the CTLA-4 protein to a subject in need thereof.
Overall, the claims cover a sequence-defined CTLA-4 extracellular-domain protein that retains B7-1/B7-2 binding, does not block anti-cancer effects of an anti-CTLA-4 antibody including Ipilimumab, includes an optional Fc-fusion to a human immunoglobulin Fc region, and is directed to minimizing autoimmune or immune-related adverse events associated with anti-CTLA-4 cancer immunotherapy.
Stated Advantages
Reduces immune-related adverse events (irAEs) from anti-CTLA-4 cancer immunotherapy while preserving anti-tumor effects.
Selectively reduces or ablates binding to anti-CTLA-4 antibodies while retaining B7-1/B7-2 binding.
Mitigates irAEs without interfering with anti-CTLA-4 anti-tumor activity.
Saturating blockade of B7-1/B7-2 does not impair Ipilimumab tumor rejection.
Documented Applications
Reducing immune-related adverse events (irAEs) associated with anti-CTLA-4 cancer immunotherapy (e.g., Ipilimumab/Tremelimumab) while preserving anti-tumor effects.
Minimizing autoimmune adverse events associated with cancer immunotherapy by administering the CTLA-4 protein to a subject in need thereof.
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