Novel Fully Human Anti-ROR1 Antibody, PBA-0405, Optimized for ADCC, Induces Potent Anti-Tumor activity against both Solid and Hematological Malignancies

Niina Veitonmäki^1*Anna Kostyn¹Sonia Kołt¹Aleksandra Ziemblicka¹Beata Romanowska¹Sabina Oleksy¹Ewelina Krzywińska¹Kamilla Sołtys¹Łukasz Świderski¹Piotr Naporowski¹Piotr Mamczur¹Monika Świtoń¹Marek Orłowski^1,2Ying Zhang³Jianming Xu³Anna Andrzejczak⁴Aleksandra Bielawskiej-Pohl⁴Lidia Karabon⁴Dariusz Wołowiec⁵Wondossen Sime⁶Ramin Massoumi⁶Sameer Deshmukh¹Jakub Kołodziejski¹Tomasz Klaus¹Pieter Spee^1*

• ¹Pure Biologics S.A., Wroclaw, Poland
• ²Politechnika Wroclawska, Wrocław, Poland
• ³Gempharmatech Co. Ltd, Nanjing, China
• ⁴Instytut Immunologii i Terapii Doswiadczalnej im Ludwika Hirszfelda Polskiej Akademii Nauk, Wrocław, Poland
• ⁵Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu Medycznego Klinika Hematologii Transplantologii i Chorob Wewnetrznych, Warsaw, Poland
• ⁶IVRS AB, Lund, Sweden

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 22.0405.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. Our findings demonstrate that 22.0405.aF exhibits 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 in vitro and in vivo, and induced more potent killing of patient-derived malignant B-cells ex vivo 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. 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 (PBA-0405) 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.