Antibody molecules that bind CD137 and OX40
Inventors
Tuna, Mihriban • Gaspar, Miguel • Morrow, Michelle • Poon, Edmund
Assignees
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Publication Number
US-12252537-B2
Publication Date
2025-03-18
Expiration Date
Abstract
The present application relates to antibody molecules that bind and am able to agonise both CD137 and OX40. The antibody molecules comprise a CDR-based binding site for CD137, and an OX40 antigen-binding site that is located in a constant domain of the antibody molecule. The antibody molecules of the invention find application, for example, in the treatment of diseases, such as cancer and infectious diseases.
Core Innovation
The invention relates to an antibody molecule that binds to CD137 and OX40 and comprises a CDR-based antigen-binding site for CD137 and an OX40 antigen-binding site. The CD137 binding site is defined by VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 according to the ImMunoGeneTics (IMGT) numbering scheme and/or the Kabat numbering scheme, using specific SEQ ID-defined CDR components.
The OX40 antigen-binding site is located in a CH3 domain and comprises sequences in the AB loop, CD loop, and EF loop according to the IMGT numbering scheme. The antibody combines the defined CD137 antigen-binding site with the CH3-domain OX40 antigen-binding site to produce an antibody that binds both targets and engages immune co-receptors OX40 and CD137 through engineered binding features.
The document describes autonomous dual agonism and simultaneous receptor binding in T-cell assays, including contexts involving SEA and pan-T/CD4+/CD8+ T-cell activation, without requiring artificial crosslinking. It further describes Fcb3R-independent action and reduced Fcb3R binding/ADCC by using an IgG1 LALA Fc format, together with in vivo anti-tumor activity in CT26 syngeneic tumor models and combination rationales including PD-1/PD-L1 blockade and other immunotherapies.
Claims Coverage
The included claim content covers an engineered antibody that binds CD137 and OX40, with defined CD137 CDR components and an OX40 antigen-binding site in a CH3 domain. The partial claim set also includes dependent refinements for immune-cell clustering, reduced or eliminated CH2 binding to Fcb3 receptors, nucleic acid encoding, and therapeutic use for cancer or infectious disease.
Dual CD137 and OX40 binding antibody with defined CD137 CDRs and CH3-domain OX40 loop sequences
An antibody that binds to CD137 and OX40, comprising a CDR-based antigen-binding site for CD137 defined according to the ImMunoGeneTics (IMGT) numbering scheme and/or the Kabat numbering scheme, wherein the CDR-based antigen-binding site for CD137 comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 defined according to specific SEQ ID NO combinations; and an OX40 antigen-binding site located in a CH3 domain, wherein the OX40 antigen-binding site comprises a first sequence comprising SEQ ID NO: 51 in the AB loop, a second sequence comprising SEQ ID NO: 52 in the CD loop, and a third sequence comprising SEQ ID NO: 53 in the EF loop of the CH3 domain according to the IMGT numbering scheme.
OX40 and/or CD137 clustering on immune cells
An antibody that binds to OX40 and CD137 on immune cells such that this binding causes clustering of OX40 and/or clustering of CD137 on the immune cell.
Reduced or eliminated CH2-domain binding to Fcb3 receptors
An antibody that has been modified to reduce or eliminate binding of its CH2 domain to one or more Fcb3 receptors.
Nucleic acid encoding the antibody
A nucleic acid that encodes the antibody described in claim 1.
Therapeutic administration for cancer or an infectious disease
A method for treating cancer or an infectious disease by administering to an individual a therapeutically effective amount of the antibody described in claim 1.
Overall claim coverage centers on a dual CD137/OX40 antibody architecture with IMGT- and Kabat-defined CD137 CDR components and a CH3-domain OX40 antigen-binding site defined by AB, CD, and EF loop sequences, with dependent claims further specifying immune-cell clustering, CH2/Fcb3 receptor binding reduction, nucleic acid encoding, and therapeutic use for cancer or infectious disease.
Stated Advantages
Reduced need for artificial crosslinking (crosslinking-independent dual activation).
Fcb3R-independent activation.
Reduction of ADCC-mediated depletion/toxicity.
Improved safety/localization to co-expressing sites, including the tumor microenvironment.
Reduced or eliminated binding of the antibodys CH2 domain to one or more Fcb3 receptors.
Reduced risk of CD137 Fcb3R-mediated toxicity.
Autonomous dual agonism with simultaneous receptor binding without requiring artificial crosslinking.
Improved survival in the in vivo CT26 anti-tumor efficacy context for the OX40/CD137 mAb2.
Reduced tumor growth in the in vivo CT26 anti-tumor efficacy context for the OX40/CD137 mAb2.
Documented Applications
In vivo CT26 anti-tumor efficacy in a syngeneic tumor model, including measurements of tumor growth rate and survival, and analysis of Ki67 and CD69 and Foxp3/Tregs in the disclosed context.
T cell functional assays using isolated human CD4+ and CD8+ T cells, reporting dual agonism activation outcomes for dual OX40/CD137 antibody formats versus single-agent anti-CD137 and anti-OX40 controls.
A mouse surrogate OX40/CD137 mAb2 pan-T activation data context with IL-2 EC50/max responses.
Competition experiments indicating that dual receptor engagement is required for activity in the disclosed T cell assay context.
Additional analytical and stability characterization for OX40/CD137 mAb2 variants, including monomer purity and stability characterization.
Treating cancer by administering a therapeutically effective amount of the antibody.
Treating an infectious disease by administering a therapeutically effective amount of the antibody.
Combination with PD-1/PD-L1 blockade for cancer therapy.
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