Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001

// Cristina L. Abrahams 1 , Xiaofan Li 1 , Millicent Embry 1 , Abigail Yu 1 , Stellanie Krimm 1 , Sarah Krueger 2 , Nancy Y. Greenland 3 , Kwun Wah Wen 3 , Chris Jones 3 , Venita DeAlmeida 1 , Willy A. Solis 1 , Shannon Matheny 1 , Toni Kline 1 , Alice Y. Yam 1 , Ryan Stafford 1 , Arun P. Wiita 3 , Trevor Hallam 1 , Mark Lupher 1 and Arturo Molina 1 1 Sutro Biopharma, Inc., South San Francisco, California, USA 2 MI Bioresearch, Ann Arbor, MI, USA 3 Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA Correspondence to: Arturo Molina, email: amolina@sutrobio.com Keywords: CD74; antibody-drug conjugate; multiple myeloma; xenograft models; STRO-001 Received: November 22, 2018      Accepted: December 04, 2018      Published: December 28, 2018 ABSTRACT STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.