AUTHOR=Liu Wei , Yu Juntao , Sun Kaiwen , Song Qin , Li Yuling , He Yanyun , Wang Yanrong , Xu Gang , Wang Changyu , Chen Bo 

TITLE=Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1410457

DOI=10.3389/fimmu.2024.1410457

ISSN=1664-3224

ABSTRACT=CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. There exist unique sequences at complementaritydetermining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38 + cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38.However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or offtarget risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. Thus, our finding identifies CM313 as a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.