Abstract 67: Characterization and preclinical development of STRO-001, a novel CD74-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies
Authors: Cristina Abrahams, Xiaofan Li, Venita DeAlmeida, Millicent Embry, Abigail Yu, Stellanie Krim, Heidi Hoffmann, James Zawada, Maureen Bruhns, Shannon Matheny, Stuart Bussell, Toni Kline, Alice Yam, Ryan Stafford, Trevor Hallam, Mark Lupher, Arturo Molina
Journal: Cancer Research (2017)

Abstract CD74 is a type II transmembrane glycoprotein involved in the formation and transport of MHC class II protein. CD74 is highly expressed in many B-cell malignancies with limited expression in normal tissues (Stein R. et al., CCR 2007). STRO-001 is a novel CD74-targeting ADC containing an anti-CD74 aglycosylated human IgG1 antibody (SP7219) conjugated to a non-cleavable dibenzocyclooctyne (DBCO)-maytansinoid linker-warhead. SP7219 was discovered from a Fab ribosome display library based on Sutro’s Xpress CFTM technology. Highly efficient site-specific conjugation enabled by our cell-free antibody production and click chemistry results in a well-defined homogeneous ADC drug product with a drug-antibody ratio (DAR) of 2. Conjugation sites were selected based on highest stability both in vitro and in vivo, thereby limiting loss of drug moiety from STRO-001 in circulation. Due to its limited cell permeability, the major catabolite released by STRO-001 has 1000X lower cell killing activity on CD74 positive and negative cells compared to the reference cytotoxic maytansine. In vitro cytotoxicity assays show potent activity of STRO-001 in a diverse panel of B-cell tumor lines including 4 multiple myeloma (MM), 9 germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL), 3 activated B-cell (ABC) DLBCL, and 3 mantle cell lymphoma (MCL) cell lines with IC50 ranging from 0.17-20 nM. CD74 cell surface expression is required for STRO-001 cytotoxic activity but expression level, as measured by antibody-binding capacity, does not correlate with in vitro potency (R2=0.4640). STRO-001 inhibits the formation of visceral tumors (p&amp;lt;0.004) and prevents growth of CD138+ plasma cells in bone marrow (BM) after 4 weekly doses of 3 mg/kg in the ARP-1 disseminated MM xenograft model. STRO-001 dosed at 3 mg/kg weekly x 3 also eradicates malignant BM plasma cells (p&amp;lt;0.0001) and prolongs survival in the MM.1S disseminated model (100% animals alive at &amp;gt;90 days). STRO-001 exhibits dose-dependent tumor growth inhibition in SU-DHL-6 xenografts starting at 2.5 mg/kg weekly x 3 doses. The combination of bendamustine/rituximab (BR) + STRO-001 further improves tumor suppression in SU-DHL-6 xenografts compared to vehicle (p = 0.002) or BR alone (p = 0.02). Preliminary studies with a MCL xenograft model, Jeko-1, demonstrate potent anti-tumor activity compared to vehicle (p&amp;lt;0.0001) starting at a single STRO-001 dose of 3 mg/kg, with ongoing tumor stasis up to 21 days after treatment. STRO-001 reduces normal B-cells in cynomologous monkeys, providing pharmacodynamic evidence of B-cell targeting. Based on these encouraging observations, STRO-001 is advancing to IND-enabling studies for the treatment of CD74-expressing B-cell malignancies. Citation Format: Cristina Abrahams, Xiaofan Li, Venita DeAlmeida, Millicent Embry, Abigail Yu, Stellanie Krim, Heidi Hoffmann, James Zawada, Maureen Bruhns, Shannon Matheny, Stuart Bussell, Toni Kline, Alice Yam, Ryan Stafford, Trevor Hallam, Mark Lupher, Arturo Molina. Characterization and preclinical development of STRO-001, a novel CD74-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2017-67