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.
Highlights
Treatment of patients with multiple myeloma (MM) with proteasome inhibitors, such as bortezomib, and immunomodulatory agents, such as lenalidomide, in frontline and maintenance settings has greatly improved survival [1, 2]
CD74 is overexpressed on MM and non-Hodgkin lymphoma (NHL) cell lines and various tumors, including the majority of MM patient biopsies tested, but its expression in normal tissues is limited to B cells, monocytes, macrophages, dendritic cells, Langerhans cells, activated T-cell subsets, and thymic epithelium [7,8,9,10,11,12]
STRO-001 was designed to overcome several known problems previously encountered by antibody-drug conjugate (ADC)
Summary
Treatment of patients with multiple myeloma (MM) with proteasome inhibitors, such as bortezomib, and immunomodulatory agents, such as lenalidomide, in frontline and maintenance settings has greatly improved survival [1, 2]. Second generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory agents (e.g., pomalidomide), histone deacetylase inhibitors (e.g., panobinostat), and monoclonal antibodies (e.g., elotuzumab and daratumumab) have proven to be highly effective in relapsed and refractory MM, when used in combination therapy [1, 3, 4]. Many patients with MM, relapse and die of progressive disease. In 2017 alone, it was estimated that over 30,000 people would be diagnosed with MM in the US and that 12,500 patients would die of the disease [4]. This underscores the need for new agents which are both effective and well tolerated [3, 5]. In a phase 1 study of 25 heavily pretreated patients, no objective responses were observed, moderate decreases of B-cell levels and a 26% disease stabilization rate were reported [14]
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