Oncotarget

Research Papers:

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

Cristina L. Abrahams, Xiaofan Li, Millicent Embry, Abigail Yu, Stellanie Krimm, Sarah Krueger, Nancy Y. Greenland, Kwun Wah Wen, Chris Jones, Venita DeAlmeida, Willy A. Solis, Shannon Matheny, Toni Kline, Alice Y. Yam, Ryan Stafford, Arun P. Wiita, Trevor Hallam, Mark Lupher and Arturo Molina _

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Oncotarget. 2018; 9:37700-37714. https://doi.org/10.18632/oncotarget.26491

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Abstract

Cristina L. Abrahams1, Xiaofan Li1, Millicent Embry1, Abigail Yu1, Stellanie Krimm1, Sarah Krueger2, Nancy Y. Greenland3, Kwun Wah Wen3, Chris Jones3, Venita DeAlmeida1, Willy A. Solis1, Shannon Matheny1, Toni Kline1, Alice Y. Yam1, Ryan Stafford1, Arun P. Wiita3, Trevor Hallam1, Mark Lupher1 and Arturo Molina1

1Sutro Biopharma, Inc., South San Francisco, California, USA

2MI Bioresearch, Ann Arbor, MI, USA

3Department 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.


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