Abstract 742: Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies

Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. These antibody-based therapeutics are designed to selectively deliver cytotoxic payloads to tumor targets to improve efficacy and minimize toxicity. Cluster of differentiation 74 (CD74), a membrane-bound glycoprotein, is an antigen amenable ADC targeting because of its low expression in normal tissues and over expression in B-cell malignancies (multiple myeloma and non-Hodgkin9s Lymphoma). STRO-001, a well-defined, homogenous, and site-specific ADC, is comprised of maytansinoid cytotoxic drugs conjugated to an anti-CD74 aglycosylated antibody (SP7219) through a noncleavable linker at two engineered non-natural amino acids. In an in vitro immunological activation assay, STRO-001 did not elicit cytokine production when incubated with human PBMCs for 48 hours, suggesting a low risk for immunological response in cancer patients. In a tissue cross-reactivity study with human tissues, STRO-001-specific membranous staining was detected primarily in lymphoid organs and lymphocytic infiltrates in multiple non-lymphoid tissues. In an exploratory nonclinical safety study in cynomolgus monkeys, a pharmacologically relevant model for toxicity testing, STRO-001 was tolerated at 1, 3, and 10 mg/kg, but not at 30 mg/kg, when intravenously administered on days 1 and 15 followed by a 4-week observation period. Dose-dependent and transient decreases in B-cells and monocytes were observed at tolerated doses (on-target pharmacology), with no effects on NK/T-cells. At tolerated doses, the main findings included reversible toxicities to hematopoietic and lymphoid tissues that correlated with cytopenias. Hematopoietic toxicity is considered antigen-independent, clinically manageable, and consistent with that of other ADCs with similar payloads. Toxicokinetic analysis confirmed drug exposures (total antibody, ADC, and a prominent linker-maytansine catabolite) with evidence of non-linearity suggesting target-dependent clearance. In summary, STRO-001 ADC has a favorable nonclinical safety profile and Phase I study of STRO-001 in patients with B-cell malignancies is planned. Citation Format: Willy Solis, Venita De Almeida, Abigail Yu, Maureen Bruhns, James Zawada, Adam Galan, Shannon Matheny, Arturo Molina, Trevor Hallam, Mark Lupher. Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 742.