Preclinical development of ozuriftamab vedotin (BA3021), a novel ROR2-specific conditionally active biologic antibody-drug conjugate

Receptor tyrosine kinase-like Orphan Receptor (ROR2) has been identified as a highly relevant tumor-associated antigen in a variety of Cancer indications of high unmet medical need, including melanoma, renal cell carcinoma, osteosarcoma, gastrointestinal stromal tumor, colorectal Cancer, pancreatic ductal adenocarcinoma, and non-small cell lung Cancer. Overexpression of ROR2 often correlates with advanced disease or poor prognosis, making it an attractive target for Cancer therapy. We developed a novel, conditionally active biologic (CAB) antibody-drug conjugate (ADC), ozuriftamab vedotin (BA3021), which binds to ROR2 only in the acidic tumor microenvironment. In healthy tissue, binding to ROR2 is greatly reduced by a novel selection mechanism using physiological chemicals as protein-associated chemical switches (PaCS). The CAB anti-ROR2 ADC displays the anticipated binding properties and mediates potent lysis of ROR2-positive Cancer cell lines. In vivo, BA3021 has potent and durable antitumor activity in human Cancer xenograft mouse models, including patient-derived xenograft models. In non-human primates, BA3021 was well tolerated at doses of up to 10 mg/kg and showed excellent stability in vivo. These preclinical results indicate that CAB anti-ROR2 ADC is efficacious and well tolerated and may be a promising treatment for Cancer patients with ROR2-expressing tumors.

ADC; ROR2; conditionally active; tumor targeting.