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Publication Number
US-11401342-B2
Publication Date
2022-08-02
Expiration Date
Abstract
The invention relates to improved binding molecules that bind specifically to prostate specific membrane antigen (PSMA), in particular, single human variable heavy chain domain antibodies and related methods for treatment of cancer.
Core Innovation
The invention relates to improved prostate specific membrane antigen (PSMA)-targeting therapeutic binding molecules in the form of single human variable heavy chain domain (V_H) antibody binding molecules. The binding molecules comprise a single V_H domain antibody selected from specified CDR1/CDR2/CDR3 sequence identifier sets defined by SEQ ID NOs, and the described molecules bind to human PSMA and cyno PSMA in the reported characterization.
The invention further provides PSMA-targeting binding formats that support functional performance such as internalization and cytotoxicity when configured as toxin-conjugated formats, including monovalent, bivalent, and biparatopic formats. It also includes immunoconjugate embodiments in which the V_H binding molecules are linked to auristatin payloads, including MMAE and MMAF, using linker systems described with examples such as vc-val-cit-PAB and mc-maleimidocaproyl.
The invention also encompasses compositions and biological constructs using the described V_H domain antibodies, including pharmaceutical compositions, nucleic acids encoding the V_H antibodies, recombinant expression vectors, and host cells. The documented characterization includes PSMA inhibition and PSMA detection/imaging, including in vivo SPECT/CT with Tc-99m and quantitative biodistribution comparisons of V_H constructs versus benchmark anti-PSMA monoclonal antibody formats.
A further aspect of the disclosed invention is the definition and use of selection and characterization approaches for the described PSMA-binding V_H domain antibodies. These include antibody library generation and selection approaches, epitope mapping/binning, and functional characterization such as binding assays and internalization-related readouts, supported by reported assay frameworks and quantitative performance measurements for the resulting binding molecules and toxin-conjugated formats.
Claims Coverage
The independent claim defines one core inventive concept: a binding molecule that binds human PSMA and is a single human V_H domain antibody specified by sets of CDR1/CDR2/CDR3 sequence identifiers (SEQ ID NOs). Dependent claims refine this core by specifying additional SEQ ID alternatives, defining epitope relationships for multi-antibody formats, adding linker length constraints for certain embodiments, and claiming immunoassay detection use in test samples.
Single V_H domain anti-human PSMA binding molecule defined by CDR sequence identifiers
A binding molecule capable of binding human PSMA comprising a single human variable heavy chain domain (V_H) antibody selected from the group consisting of single V_H domain antibodies defined by specified CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs.
Additional SEQ ID alternatives for the single V_H domain antibody CDRs
The binding molecule further comprises a single V_H domain antibody including a sequence chosen from an additional set of specified SEQ ID NOs.
Two V_H domains binding to the same PSMA epitope
A binding molecule including two single human heavy chain variable (V_H) domain antibodies that bind to the same epitope on human PSMA.
Two V_H domains binding to distinct non-identical PSMA epitopes
The binding molecule uses two single human heavy chain variable (V_H) domain antibody molecules that bind to two distinct, non-identical epitopes on PSMA.
Peptide linker length constraint (3 to 50 amino acids)
A binding molecule including a peptide linker that is 3 to 50 amino acids long.
Immunoassay method to determine whether PSMA is present in a test sample
A method to determine whether PSMA is present in a test sample by immunoassay using a binding molecule and at least one detectable label.
Overall, the claim set centers on PSMA-binding single human V_H domain antibodies defined by specified CDR sequence identifier combinations, with further claim coverage for alternative CDR sequence sets, epitope relationships for multi-antibody formats, a linker-length constraint for certain embodiments, and an immunoassay detection method for PSMA in a test sample.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Pharmaceutical compositions containing the described PSMA-targeting V_H domain binding molecules.
Immunoconjugates with auristatin (including MMAE and MMAF) linked to the described V_H domain antibodies using described linkers.
Nucleic acids/constructs/host cells encoding or expressing the described V_H domain antibodies.
In vivo PSMA detection/imaging, including SPECT/CT with Tc-99m.
PSMA inhibition and PSMA detection/imaging use contexts associated with the described binding molecules.
Immunoassay detection to determine whether PSMA is present in a test sample using the described binding molecules and a detectable label.
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