A novel fully human anti-ROR1 antibody PBA-0405 optimized for ADCC, induces potent anti-tumor activity against both solid and hematological malignancies.

[INTRODUCTION] B-cell malignancies, including chronic lymphocytic leukemia (CLL), pose a significant clinical challenge due to high relapse rates and dose-limiting toxicities seen with current therapies, particularly in elderly patients. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an attractive therapeutic target due to its high expression on malignant B-cells and minimal presence in normal adult tissues, allowing the development of more potent and safer drugs for cancer treatment. PBA-0405 (called 2.0405.aF in this manuscript) is a novel, fully human afucosylated anti-ROR1 monoclonal antibody, specifically engineered for optimal induction of antibody-dependent cellular cytotoxicity (ADCC) to improve treatment of cancer.

[METHODS] We evaluated 22.0405.aF for ADCC activity and tumor-cell killing in comparison with clinically tested anti-ROR1 antibodies, including zilovertamab and R12. Functional assessment included cytotoxicity assays, killing of patient-derived malignant B cells, and in vivo testing in humanized mice and murine xenograft models of hematologic and solid tumors. Safety was assessed through monitoring of healthy B-cell viability and toxicity .

[RESULTS AND DISCUSSION] Our findings demonstrate that 22.0405.aF exhibits far superior ADCC activity compared to anti-ROR1 antibodies, e.g. zilovertamab and R12, tested in clinical trials thus far. 22.0405.aF displayed potent tumor cell killing, both and , and induced more potent killing of patient-derived malignant B-cells compared to rituximab, without affecting healthy B-cells. Furthermore, in humanized mice, in murine xenograft models of both hematological and solid tumors, 22.0405.aF treatment induced robust inhibition of tumor growth without detectable toxicity.

[CONCLUSION] These results underscore the therapeutic potential of 22.0405.aF as a promising immunotherapy for treatment of ROR1-positive B-cell malignancies. Notably, 22.0405.aF has recently completed Phase 0 clinical trials in patients with head and neck carcinomas and soft tissue sarcomas, paving the way for further clinical development.