Abstract 644: Novel anti-B cell maturation antigen-monomethyl auristatin F antibody-drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity via enhanced effector function and direct tumor cell killing
Authors: Yu-Tzu Tai, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Patrick A. Mayes, Jenny Craigen, Louise Gliddon, James Smothers, Amanda L. Christie, Andrew L. Kung, Paul Richardson, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Cancer Research (2014)

Abstract B cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). We here investigated the anti-MM activity of J6M0-mcMMAF (GSK2857916), a humanized and afucosylated anti-BCMA antibody-drug conjugate (ADC) via uncleavable linker. This novel antagonist anti-BCMA antibody shows binding against all CD138-expressing MM cell lines and patient MM cells, confirming universal BCMA expression on the surface of myeloma cells. Real-time qRT-PCR also showed significantly upregulated BCMA mRNA in CD138+ cells purified from MM patients vs. normal donors (p &amp;lt; 0.03). In contrast, BCMA is undetectable in CD138-negative cells from MM patients. J6M0-mcMMAF inhibits cell growth and induces caspase 3-dependent apoptosis in both drug-sensitive and -resistant MM cell lines and patient CD138+ MM cells, alone and in co-culture with BMSCs. It strongly blocks colony formation of MM cell lines (ED50 ∼6-70 ng/ml) via induction of G2/M arrest, followed by apoptosis. This ADC does not affect viability of BCMA-negative NK, PBMC, and BMSCs, cultured alone or together, confirming its specific targeting of BCMA-positive MM cells. J6M0-mcMMAF, which has enhanced Fc-receptor binding due to afucosylation, significantly improved autologous antibody-dependent cellular cytotoxicity (ADCC) potency and maximum MM cell lysis against MM patient cells (n=5), when compared to J6M0 with normal Fc. The in vivo efficacy of J6M0-mcMMAF was evaluated in murine subcutaneous xenograft models using NCI-H929 and OPM2 cells, as well as in NK-deficient SCID-beige mice with diffuse human MM bone lesions using MM1Sluc cells. Administration of J6M0-mcMMAF at 4 mg/kg (q3d x 4, ip) completely eliminated NCI-H929 and OPM2 xenograft tumors in all mice which remained tumor-free until the termination of studies at 60 and 100 days, respectively. In the MM1Sluc bone marrow dissemination model, J6M0-mcMMAF eradicates detectable tumors after 2 doses at 0.4 mg/kg (q3d x 9, ip), which resulted in extended survival (p&amp;lt;0.0001) and no weight loss of mice following 120 days. J6M0 treatment, although less effective than J6M0-mcMMAF, also had significantly prolonged survival (p&amp;lt;0.03) and diminished tumor burden when compared with control vehicle and isotype-treated groups, indicating a potential role of macrophage-mediated phagocytosis. Indeed, J6M0-mcMMAF recruits macrophage and mediates phagocytosis of target MM cells. Taken together, our studies show that J6M0-mcMMAF potently and selectively induce direct and indirect killing of MM tumor cells both in vitro and in vivo, providing a very promising next-generation immunotherapeutic in this cancer. Note: This abstract was not presented at the meeting. Citation Format: Yu-Tzu Tai, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Patrick A. Mayes, Jenny Craigen, Louise Gliddon, James Smothers, Amanda L. Christie, Andrew L. Kung, Paul Richardson, Nikhil C. Munshi, Kenneth C. Anderson. Novel anti-B cell maturation antigen-monomethyl auristatin F antibody-drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity via enhanced effector function and direct tumor cell killing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 644. doi:10.1158/1538-7445.AM2014-644