Single domain antibodies that bind to CD137
Inventors
BRUCKLACHER-WALDERT, Verena • Edwards, Carolyn • Legg, James • MAJITHIYA, Jayesh • MCGUINNESS, Brian • Rossant, Christine • TENG, Yumin
Assignees
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Publication Number
US-12077595-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The disclosure relates to CD137 binding agents and the use of such binding agents in the treatment, prevention and detection of disease.
Core Innovation
The invention provides an isolated single variable heavy chain domain antibody that binds to human CD137 but does not elicit CD137 signalling when bound as a monospecific entity. The antibody is defined by specific CDR1, CDR2, and CDR3 sequences shown in SEQ ID NOs and in Table 1, and the disclosed single-domain antibody maintains CD137 binding while avoiding CD137 signalling.
The disclosure further provides nucleotide sequence listings for CD137 single-variable heavy-chain antibodies, including SEQ ID NOs 635-785 and associated V_H nucleic acids 2.1-2.51. The nucleotide sequence disclosure is supported by homology and sequence identity options, including specified ranges such as 50% to 99% and 70% to 99%, to define related sequences tied to the CDR-defined binding entities for CD137.
The sequences are described for use in constructs and recombinant host cells, and in binding molecules targeting CD137 and selected tumor antigens. The disclosure includes bispecific and fusion formats, together with conjugation to one or more moieties and half-life extension options.
Claims Coverage
The claim coverage centers on isolated monospecific single variable heavy-chain domain antibodies that bind human CD137 without eliciting CD137 signalling, specified by multiple CDR1/CDR2/CDR3 sequence sets. The coverage also includes linker-mediated bispecific binding, selectable tumor antigen targets, conjugatable moieties, half-life extension options, and VH sequence selection by listed SEQ ID NOs or homology thresholds. Across the provided claim content, there are at least 5 main inventive feature groups.
Isolated cd137-binding single variable heavy chain without cd137 signalling
An isolated single variable heavy chain domain antibody that binds to human CD137 but does not elicit CD137 signalling when bound to CD137 as a monospecific entity.
Cdr-defined antibody specificity
The single variable heavy chain domain antibody comprises specified CDR1, CDR2, and CDR3 sequences shown in SEQ ID NOs, with multiple alternative CDR1/CDR2/CDR3 sets shown in Table 1.
Linker-mediated bispecific binding to CD137 and a second antigen
A binding molecule wherein a single variable heavy chain domain antibody binding to CD137 is linked via a peptide linker to a single variable heavy chain domain antibody binding to a second antigen.
Selectable tumor antigen and conjugatable moieties
The second antigen is a tumor specific antigen from an enumerated set, and the CD137-binding antibody is conjugated to one or more moieties selected from toxin, enzyme, radioisotope, half-life extending moiety, label, therapeutic molecule, or other chemical moiety.
Vh sequence selection by SEQ ID NOs or homology threshold
The single variable heavy chain domain antibody comprises a VH sequence selected from listed SEQ ID NOs or a sequence with at least 90% homology thereto.
Overall, the claim coverage is directed to CD137-binding monospecific single-domain antibodies defined by specific CDR sequence sets and the functional requirement that binding does not elicit CD137 signalling. The provided claim content further extends to bispecific constructs, tumor antigen targeting, conjugation and half-life extension, and VH sequence constraints.
Stated Advantages
Avoidance of CD137 signalling when bound to CD137 as a monospecific entity.
Reduced CD137 toxicity associated with existing agonist CD137 therapies.
Enables agonism when dual-engaged with a second tumour-specific antigen in a bispecific format.
Blocking CD137L.
Minimal internalisation.
No NF-κB/IL-2 agonism as monomers while NF-κB signalling is observed for bispecific constructs.
In vivo tumour growth effect is described.
Documented Applications
Use of CD137-binding single variable heavy-chain domain antibodies as monospecific binders to avoid CD137 signalling and internalisation, and as bispecific constructs dual-engaged with a second tumour-specific antigen to enable CD137 agonism.
Bispecific constructs targeting tumour-specific antigens selected from PSMA, Her2, CD123, CD19, CD20, CD22, CD23, CD74, BCMA, CD30, CD33, CD52, EGFR, CECAM6, CAXII, CD24, CEA, Mesothelin, cMet, TAG72, MUC1, MUC16, STEAP, EphvIII, FAP, GD2, IL-13Ra2, L1-CAM, PSCA, GPC3, Her3, gpA33, 5T4, and ROR1.
In vivo evaluation in an NCG mouse model with huPBMC engrafted and DU145 PSMA is described at the level of in vivo tumour growth effect.
Therapeutic use for CD137-mediated diseases, including cancer and disorder categories as described in the provided summary text.
Diagnostic applications and diagnostic kit use.
Therapy combination uses with other therapies.
Use in constructs and recombinant host cells.
Binding molecules in bispecific or fusion formats targeting CD137 and selected tumor antigens.
Immune modulation and anti-CD137 therapeutic application contexts.
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