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Publication Number
US-11332532-B2
Publication Date
2022-05-17
Expiration Date
Abstract
The invention provides bispecific antibodies having one arm binding to a cancer associated antigen on a cancer cell, such as CD33, EGFR or PD-L1, and a second arm binding to a costimulatory molecule, such as OX40, CD40, GITR, ICOS or 4-1BB. Bridging by the bispecific antibody between cancer cells expressing the cancer associated antigen and immune cells expressing the costimulatory molecule results in clustering of the costimulatory molecules and selective activation of the immune cells at a location proximate to the cancer cells. Thus, the immune cells can exert an immunotherapeutic effect against the cancer cells with reduced toxicity to healthy tissue.
Core Innovation
The document describes bispecific antibodies having binding sites specifically binding to PD-L1 and GITR, respectively. The first binding site includes PD-L1 specificity, and the second binding site includes GITR specificity, as supported by sequence-defined variable-region content. The described antibody examples include mature heavy and light chain variable regions and specified CDR sets.
The disclosed antibodies produce functional immunological activity measured in human T cells or PBMC. IL-2 induction is reported upon stimulation involving PD-L1 and GITR-related targets, including OX40, GITR, ICOS, and CD40, and additional functional readouts include luciferase-based T-cell activation requiring bispecific bridging and increased cytokine outputs including IL-2 and IL-10 with specific examples such as BS859.
The document further describes structural variants using disulfide-linked scFv stabilization and scFv fusion formats. Disulfide-stabilized scFv formats are described for GITR, OX40, CD40, and ICOS with retention of binding and enhanced multimeric cross-linking effects, and example constructs are described in the context of expression and functional assays, including humanized antibody formats and CH3-HuPRO scFv fusion architecture.
Claims Coverage
The partial claim set includes two independent claims. Overall, the inventive features cover defined sequence-specific PD-L1-binding and GITR-binding regions in antibodies, including a bispecific antibody architecture and a PD-L1-specific monoclonal antibody with defined CDR-containing variable regions.
PD-L1/GITR bispecific antibody with defined CDR sets
A bispecific antibody comprising a first binding site specifically binding to PD-L1 and a second binding site specifically binding to GITR, wherein the first binding site comprises a mature heavy chain variable region comprising CDRs H1, H2 and H3 of SEQ ID NOS:62-64 respectively and a mature light chain variable region comprising CDRs L1, L2 and L3 of SEQ ID NOS:66-68 respectively, and the second binding site comprises a mature heavy chain variable region comprising CDRs H1, H2 and H3 of SEQ ID NOS:33-35 respectively and a mature light chain variable region comprising CDRs L1, L2 and L3 of SEQ ID NOS:37-39 respectively.
PD-L1 monoclonal antibody with defined CDR sets
A monoclonal antibody specifically binding to PD-L1 comprising a mature heavy chain variable region comprising CDRs H1, H2 and H3 of SEQ ID NOS:62-64 respectively and a mature light chain variable region comprising CDRs L1, L2 and L3 of SEQ ID NOS:66-68 respectively.
The claim coverage is grounded in sequence-defined variable regions for PD-L1 binding and, for the bispecific claim, GITR binding. The partial claim set also indicates dependent narrowing to structural architectures and specific constant-region mutation constraints, and a cancer treatment use involving PD-L1 antagonism and GITR agonism.
Stated Advantages
Selective immune activation near tumor cells via local clustering and cross-linking of costimulatory receptors.
Reduced toxicity.
Increased functional signaling, including increased luciferase or IL-2/IL-10 expression, only when both binding arms engage their respective cells.
Documented Applications
Treating a cancer subject by administering a bispecific antibody that antagonizes PD-L1 and agonizes GITR.
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