Next generation ConjuAll BCMA antibody-drug conjugates (ADCs) LCB14-2524 and LCB14-2516 show increased efficacy in preclinical models of multiple myeloma

LCB14-2524 and LCB14-2516 are Antibody-Drug Conjugates (ADCs) targeting B cell maturation antigen (BCMA). This target has emerged as one of the most important for targeted therapies in relapsed/refractory multiple myeloma (RRMM) as demonstrated by the recent approval of the ADC belantamab mafodotin in combination with bortezomib and dexamethasone. While belantamab mafodotin has delivered meaningful benefit to patients, the high rate of keratopathy leaves room for improvement. We present data for next generation anti-BCMA ADCs designed for robust efficacy with the potential for reduced ocular toxicity. LCB14-2524 is an ADCC enhanced IgG1 anti-BCMA ADC utilizing the second generation beta-glucuronide (LBG) ConjuAll platform linker delivering a homogenous drug-antibody-ratio (DAR) of 2 monomethyl auristatin F (MMAF) microtubule inhibitor payloads. LCB14-2516 is an Fc silenced IgG1 anti-BCMA ADC that also utilizes the ConjuAll platform to deliver the highly potent pyrrolobenzodiazepine (PBD) DNA cross linking payload. These molecules were selected for progression through comparison of payload, conjugation method (ConjuAll vs maleimide), and antibody Fc properties (ADCC enhanced or silenced) to a belantamab mafodotin biosimilar in vitro and in vivo. In a panel of in vitro cytotoxicity assays the LBG-proPBD based ADCs were more potent than the belantamab mafodotin biosimilar or LBG-MMAF ADCs which demonstrated similar potency across cell lines. ADCC reporter assay showed potent activation by the Fc enhanced ADCs and antibodies, with no signal from the silenced ADCs or antibodies. The parental antibodies and the ADCs displayed similar activity in the ADCC reporter assay, suggesting no impact on function following conjugation. In vivo, both LCB14-2516 (LBG-proPBD) and LCB14-2524 (LBG-MMAF) were more active than the belantamab mafodotin biosimilar across OPM2, MM.1S and NCI-H929 CDX models. Both LCB14-2516 (LBG-proPBD) and LCB14-2524 (LBG-MMAF) ADCs utilize clinically validated LCB technology with promise to increase the therapeutic index of BCMA targeted ADCs and are progressing through IND enabling studies for clinical development.