ADAM17 binding molecules and uses thereof
Inventors
Nikolov, Dimitar • Saha, Nayanendu • Zhu, Zhongyu • Dimitrov, Dimiter Stanchev • ROBEV, DOROTHEA • WHITE, THOMAS EDGEWORTH
Assignees
Memorial Sloan Kettering Cancer Center • Tri Institutional Therapeutics Discovery Institute Inc • US Department of Health and Human Services
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Publication Number
US-12378321-B2
Publication Date
2025-08-05
Expiration Date
Abstract
The present invention provides various ADAM17 binding molecules (including antibodies and fragments thereof), compositions comprising such ADAM17 binding molecules, and methods of using such ADAM17 binding molecules and compositions, for example in inhibiting binding of ADAM17 to ADAM17 substrates (such as ErbB ligands), in inhibiting the proliferation of cancer cells, and in treating cancer.
Core Innovation
Isolated ADAM17 binding molecules are disclosed, including antibody heavy and light chain variable regions that comprise specific CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 domains defined by SEQ ID NOs in alternative combinations. The disclosed ADAM17 binding molecules are further presented as affinity-matured derivatives of lead clones D5 and D8, including variants such as D5.P1.A4, D5.P2.A11, D5.P2.B3, D8.P1.C1, and D8.P2.C6.
The disclosed ADAM17 binding molecules target an ADAM17 substrate-recognition domain rather than the catalytic site, and are supported by binding/specificity assessment including cross-reactivity against ADAM10 and ADAM19. The molecules are presented in antibody formats including IgG1 and antibody fragments, and sequence/epitope-related support is provided by tables listing full antibody sequences and CDR sequences with SEQ ID assignments.
Biological effects are disclosed for these ADAM17 binding molecules, including inhibition of ADAM17-dependent cleavage/signaling of ErbB ligands (EGFR/ErbB/Her pathways), inhibition of tumor cell proliferation and killing in vitro and in vivo, and tumor xenograft anti-tumor effect. Additional assay and imaging formats are described as including a FRET cleavage assay using a TNF-alpha-derived peptide substrate and PK/biodistribution imaging using 89Zr PET, with candidate selection based on ADAM17 binding and/or functional inhibition in tumor samples.
Claims Coverage
The independent claims define isolated ADAM17 binding molecules with defined CDR sequence identifiers and cover four main inventive application areas: the molecular binding constructs themselves, methods inhibiting tumor cell proliferation or killing, methods inhibiting ADAM17-related biological activity in cells or tissue, and treatment and candidate determination in subjects with tumors. Across the independent claims, the core construct definition is anchored to specific heavy- and light-chain CDR domain combinations defined by SEQ ID NOs.
Isolated ADAM17 binding molecule with defined CDR sets
An isolated ADAM17 binding molecule comprising one of the specified heavy chain variable region CDR H1, CDR H2, CDR H3 domains and the specified light chain variable region CDR L1, CDR L2, CDR L3 domains, where the CDR domains are defined by SEQ ID NOs in alternative configurations.
Method for inhibiting tumor cell proliferation or killing using defined ADAM17 binder CDR set
A method of inhibiting the proliferation of, or killing, tumor cells by delivering an effective amount of an ADAM17 binding molecule comprising specified heavy- and light-chain variable-region CDR domains defined by SEQ ID NOs.
Method of inhibiting ADAM17-related biological activity in cells or tissue
A method of inhibiting a biological activity in cells or in a tissue, where the biological activity is selected from binding of ADAM17 to an ADAM17 substrate, proteolytic cleavage of an ADAM17 substrate by ADAM17, activation of an ADAM17 substrate, or signaling by an ADAM17 substrate, by delivering an effective amount of an ADAM17 binding molecule comprising specified heavy- and light-chain variable-region CDR domains defined by SEQ ID NOs to cells or tissue that expresses or contains ADAM17.
Treatment method and candidate determination based on ADAM17 binder binding
A method of treating cancer in a subject by administering an effective amount of an ADAM17 binding molecule comprising specified heavy- and light-chain variable-region CDR domains defined by SEQ ID NOs, and a method of determining whether a subject with a tumor is a candidate for treatment by contacting a tumor sample or cells therefrom with the ADAM17 binding molecule and performing an assay to determine whether the binding molecule binds to ADAM17 in the sample, wherein binding indicates candidate status for treatment.
The independent claims collectively cover isolated ADAM17 binding molecules defined by specific heavy- and light-chain CDR sequence identifiers and methods that use these defined ADAM17 binders to inhibit tumor cell proliferation or killing, inhibit ADAM17-related biological activity in cells or tissue, treat cancer in a subject, and determine candidate status by assaying binding to ADAM17 in a tumor sample.
Stated Advantages
Increased potency of affinity-matured clones versus parental antibodies.
Inhibition of ADAM17-dependent cleavage/signaling of ErbB ligands (EGFR/ErbB/Her pathways).
Inhibition of tumor cell proliferation/killing in vitro and in vivo.
Tumor xenograft anti-tumor effect in vivo.
Determination of whether a subject with a tumor is a candidate for treatment based on whether the ADAM17 binding molecule binds to ADAM17 in the sample.
Diagnostic/detection and imaging support, including PK/biodistribution imaging using 89Zr PET.
Documented Applications
Inhibition of ADAM17-dependent cleavage/signaling of ErbB ligands (EGFR/ErbB/Her pathways).
Inhibiting tumor cell proliferation/killing in vitro and in vivo.
Anti-tumor effect in tumor xenograft assays.
FRET cleavage assay using a TNF-alpha-derived peptide substrate.
PK/biodistribution imaging using 89Zr PET.
Detecting or assessing ADAM17 binding in a tumor sample for determining whether a subject is a candidate for treatment with an ADAM17 binding molecule.
Treatment of cancer in a subject, including triple-negative breast cancer.
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