Anti-TIM-3 antibodies and methods of use thereof
Inventors
van Dijk, Marc • Breous-Nystrom, Ekaterina Vladimirovna • Wilson, Nicholas Stuart • Waight, Jeremy Dale • Underwood, Dennis John
Assignees
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Publication Number
US-12011481-B2
Publication Date
2024-06-18
Expiration Date
Abstract
The instant disclosure provides antibodies that specifically bind to TIM 3 and antagonize TIM-3 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.
Core Innovation
The invention relates to an isolated antibody that specifically binds human T-cell immunoglobulin and mucin-domain containing-3 (TIM-3). The antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), with complementarity determining regions CDRH1, CDRH2, and CDRH3 for VH and CDRL1, CDRL2, and CDRL3 for VL. The VH CDRs and VL CDRs are selected from specified amino acid sequences associated with SEQ ID NOs 24, 25, 26, 37, 39, 40, 41, 44, and 47.
The disclosure further describes allowed VH and VL sequence pair combinations and sequence-identity constraints relative to the specified SEQ ID NOs. It also supports engineered heavy-chain constant-region formats, including variants with altered Fc gamma receptor binding affinity and Fc modifications. This defines a TIM-3-binding antibody with a particular sequence architecture at both the variable-region and constant-region levels.
The disclosure characterizes TIM-3 binding in terms of epitope and functional effects, including HDX-defined regions, cross-competition, epitope overlap, and binding behavior for TIM-3 variants with weakened or absent binding. The disclosed antibody is associated with reduced survival of TIM-3-expressing cells relative to Fc controls and increased T cell activation. Therapeutic use concepts are described, including combination with other cancer immunotherapies and use of antibody conjugates with cytotoxic/cytostatic/toxin/radionuclide/detectable labels.
Claims Coverage
The provided claim set centers on one independent claim defining an isolated human TIM-3-binding antibody by selected VH and VL CDR sequences. Additional dependent claims refine this by sequence-identity thresholds, specific VH/VL SEQ ID pair combinations, engineered heavy-chain constant-region variants affecting Fc gamma receptor binding affinity, and pharmaceutical composition embodiments. One independent claim is explicitly identified.
Isolated TIM-3-binding antibody defined by selected CDR sequences
An isolated antibody that specifically binds human T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) comprising a VH with CDRH1, CDRH2, and CDRH3 selected from amino acid sequences corresponding to SEQ ID NOs 24, 25, and 26, and a VL with CDRL1, CDRL2, and CDRL3 selected from amino acid sequences corresponding to SEQ ID NOs 37, 39, 40, 41, 44, and 47.
Sequence-identity constraint for VH and VL
The isolated antibody where the VH comprises CDRH1, CDRH2, and CDRH3 with an amino acid sequence at least 95% identical to a sequence selected from SEQ ID NOs 24, 25, and 26, and the VL comprises CDRL1, CDRL2, and CDRL3 with an amino acid sequence at least 95% identical to a sequence selected from SEQ ID NOs 37, 39, 40, 41, 44, and 47.
Specified VH and VL sequence pair combinations
The isolated antibody where the VH and VL pair combinations include SEQ ID NOs 26 and 41, 24 and 41, 25 and 39, 24 and 47, 25 and 40, 26 and 47, 25 and 37, 25 and 44, 25 and 41, or 25 and 47.
Engineered heavy-chain constant region variants
The isolated antibody wherein the heavy chain constant region is selected from a variant of the wild type human IgG heavy chain constant region with lower Fc gamma receptor binding affinity, the variant comprises N297A, N297Q, or both, and the heavy chain constant region is selected from the group consisting of a non-fucosylated IgG1 and an IgG4 with a S228P mutation.
Pharmaceutical composition comprising the antibody
A pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier or excipient.
The claim coverage is anchored on a specifically TIM-3-binding isolated antibody whose VH and VL are defined by selected CDR sequence identities using specified SEQ ID NOs. Dependent claim refinements further constrain CDR sequence identity thresholds, allowable VH/VL pairings, engineered heavy-chain constant-region variants, and pharmaceutical composition embodiments.
Stated Advantages
Decreased TIM-3 signaling and decreased TIM-3 ligand binding (phosphatidylserine).
Decreased cytokine production including IFN-γ and TNF-α.
Internalization upon TIM-3 binding.
Decreased survival of TIM-3-expressing cells.
Cross-competition and overlapping epitope binding.
Functional activity with antagonist/functional effects described for TIM-3-binding.
Reduced survival of TIM-3-expressing cells relative to Fc controls.
Increased T cell activation.
Documented Applications
Use in cancer, including effects assessed in PBMCs and TILs.
Use in infectious disease.
Therapeutic use concepts for cancer immunotherapy, including combination with anti-PD-1 (pembrolizumab) and use in antibody conjugates with cytotoxic/cytostatic/toxin/radionuclide/detectable labels.
Pharmaceutical composition use of the antibody with a pharmaceutically acceptable carrier or excipient.
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