Anti-ROR antibody constructs
Inventors
Bailey, Lucas • Li, Qufei • NOCULA-LUGOWSKA, MALGORZATA AGNIESZKA • Glaser, Bryan
Assignees
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Publication Number
US-12084496-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Anti-ROR antibody constructs, pharmaceutical compositions comprising the constructs, and methods of use thereof are presented.
Core Innovation
A tyrosine-protein kinase transmembrane receptor (ROR) antigen binding molecule is provided, comprising a first antigen binding site that includes an antibody heavy chain variable (VH) region and an antibody light chain variable (VL) region. The first antigen binding site is specific for ROR1 and ROR2, and the VH region contains VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NO: 140, while the VL region contains VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NO: 136.
The disclosed antibody construct platforms and architectures include multispecific ROR binding molecules targeting ROR1 and/or ROR2 and optionally CD3 for T-cell redirected killing. Multispecific formats include mono-/bis-/tris-/tetravalent ROR binding molecules, and the disclosure provides structural definitions for polypeptide chains and domains using antibody variable regions and constant-region segments including CH3/CH2/CH1/CL.
The described designs include additional antigen binding sites beyond the first antigen binding site and explicit pairing and orthogonalization strategies that engineer CH3/CH2/CH1/CL interactions, including engineered disulfide bridges, knob-in-hole, charge-pair mutations, and isoallotype mutations. Example constructs and reduced-Fc variants are described, including CH1-based purification to enrich fully assembled complexes, and pharmaceutical compositions and cancer treatment indications for multiple ROR-expressing tumor types are also disclosed.
Claims Coverage
The document includes one independent claim directed to a ROR antigen binding molecule with a specified first antigen binding site comprising defined VH and VL CDRs and specificity for ROR1 and ROR2. Dependent claims further refine the antibody format, add additional antigen binding sites, and include treatment-related aspects and cancer types.
Ror1 and ror2 specific first antigen binding site defined by vh and vl cdr sequences
A ROR antigen binding molecule comprising a first antigen binding site specific for ROR1 and ROR2, wherein the first antigen binding site comprises an antibody heavy chain variable (VH) region with VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NO: 140, and an antibody light chain variable (VL) region with VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NO: 136.
Antibody format selection for the ror antigen binding molecule
The ROR antigen binding molecule includes an antibody format chosen from a specified group of antibody fragment or engineered antibody types.
Additional antigen binding site beyond the first antigen binding site
The ROR antigen binding molecule includes a second antigen binding site beyond the first antigen binding site.
Third antigen binding site specific for ror1 and/or ror2
The ROR antigen binding molecule includes a third antigen binding site that is specific for ROR1 and/or ROR2.
Defined cdr sequences for a first antigen binding site
The first antigen binding site comprises heavy- and light-chain CDRs with corresponding SEQ ID NOs.
Overall claim coverage centers on a ROR antigen binding molecule whose first antigen binding site is specified by defined VH and VL CDR sequence sets that confer specificity for ROR1 and ROR2, with dependent coverage extending the molecule to selected antibody formats and adding further antigen binding sites, including a third binding site constrained to ROR1 and/or ROR2, as well as treatment-related aspects and cancer types.
Stated Advantages
Loss of FcγRIa and C1q binding and reduced ADCC/complement for Fc effector-function reduction.
Reported tumor growth reduction in PBMC-humanized NSG mouse xenograft models.
High purity as reported by one-step CaptureSelect™ CH1 affinity purification yielding >98% monomeric/unaggregated protein.
Documented Applications
In vitro ROR1-expressing cell cytotoxicity correlation in MDA-MB-231 and RPMI-8226, with PBMC activation measured by CD25/CD69 on CD8+ and CD4+ T cells and tumor-cell internalization measurements supporting antibody-drug conjugate strategies.
In vivo xenograft efficacy in PBMC-humanized NSG mice, including analyses of tumor growth reduction and T-cell humanization/infiltration.
Additional in vivo efficacy testing for selected ROR antigen binding variants, including constructs incorporating D54E and Y55Q.
Trivalent efficacy testing in the context of expanded ROR1/ROR2 targeting.
T-cell redirected killing.
Pharmaceutical compositions.
Cancer treatment indications for multiple ROR-expressing tumor types.
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