Discovery And Preclinical Development Of Novel Cd74-Targeting Antibody-Drug Conjugates (Adcs) With Significant Activity In Multiple Myeloma (Mm) Cell Lines And Xenograft Models

CD74, also known as HLA-DR-associated invariant chain, is a type II transmembrane glycoprotein highly expressed in many B-cell malignancies. The limited expression of CD74 in normal tissues suggests it may be a suitable ADC target for these tumor types. Accordingly, we engineered an anti-CD74 human IgG1 antibody (SP7219) using novel Fab-based ribosome display methods. The selected Fabs were readily reformatted and directly screened as IgGs using Sutro9s unique high-throughput, cell-free protein synthesis platform, Xpress CF TM . We then developed novel, potent ADCs, SP7676 and SP7675 (STRO-001), comprised of our lead antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-warheads with an average drug-antibody ratios (DAR) of 2. We used site-specific conjugation technology which results in a high degree of homogeneity characterized by the drug linker covalently binding to a single defined site. The sites for conjugation were selected based on highest cell killing activity and stablity in vitro and in vivo . Both ADCs demonstrate potent cell killing activity across multiple B-cell tumor lines in vitro , and anti-tumor activity in preclinical multiple myeloma xenograft models. In vitro cytotoxicity assays show nanomolar potency of STRO-001 in four MM cell lines: Mc/CAR (IC 50 0.8 nM), MM.1S (IC 50 10-11 nM), U266B1 (IC 50 8.5 -9.3 nM), and ARP-1 (IC 50 4.3-22 nM). CD74 cell surface expression is required for ADC anti-proliferative effect but the expression level does not seem to correlate with in vitro potency. SP7676 elicited a robust anti-tumor response in the ANBL-6 multiple myeloma xenograft model. Durable regressions were observed in all mice at ≥ 3 mg/kg, with equivalent efficacy (regression) at 3 mg/kg (every 3 days x5) and 10 mg/kg (every 3 days x5 or weekly x3). SP7676 also elicited a clear survival benefit in a disseminated multiple myeloma CAG xenograft model starting at 1mg/kg every 3 days x 5 doses. Similarly, both SP7676 and STRO-001 inhibited the formation of internal visceral tumors in the ARP-1 xenograft model after 3 weekly doses of 3 mg/kg. Evaluation of our lead candidate, STRO-001 in additional MM cell lines and primary patient samples is planned. The tolerability of STRO-001 in non-human primates is under evaluation. STRO-001 was administered to cynomolgous monkeys in an exploratory dose-escalating study up to 30 mg/kg x 2 doses on Day 1 and 15. STRO-001 reduces normal B-cell populations at ≥1 mg/kg after a single dose, providing pharmacodynamic evidence of B-cell targeting while other hematopoietic lineages are mostly affected only at the highest dose studied. Anticipated hematologic toxicities were readily reversible at 1, 3 and 10 mg/kg and target organs of interest were identified. Based on these encouraging data, STRO-001 is advancing to IND-enabling studies for the treatment of CD74 expressing multiple myeloma and other B-cell malignancies. Disclosures Abrahams: Sutro Biopharma: Employment. Li: Sutro Biopharma: Employment. Yu: Sutro Biopharma: Employment. Krimm: Sutro Biopharma: Employment. Kahana: Celgene: Employment. Narla: Celgene: Employment. Schwartz: Celgene: Employment. Boylan: Celgene: Employment. Hoffmann: Sutro Biopharma: Employment. Steiner: Sutro Biopharma: Employment. Zawada: Sutro Biopharma: Employment. Stephenson: Sutro Biopharma: Employment. Bruhns: Sutro Biopharma: Employment. DeAlmeida: Sutro Biopharma: Employment. Matheny: Sutro Biopharma: Employment. Bussell: Sutro Biopharma: Employment. Galan: Sutro Biopharma: Employment. Kline: Sutro Biopharma: Employment. Vasquez: Sutro Biopharma: Employment. Yam: Sutro Biopharma: Employment. Stafford: Sutro Biopharma: Employment. Heinsohn: Sutro Biopharma: Employment. Sato: Sutro Biopharma: Employment. Molina: Sutro Biopharma: Employment. Hallam: Sutro Biopharma: Employment. Lupher: Sutro Biopharma: Employment.