Molecular Cancer Therapeutics: Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma (Houghton, Kurmasheva)

m_molcanther_21_6_coverYifei Wang; Xiangjun Tian; Wendong Zhang; Zhongting Zhang; Rossana Lazcano; Pooja Hingorani; Michael E. Roth; Jonathan D. Gill; Douglas J. Harrison; Zhaohui Xu; Sylvester Jusu; Sankaranarayanan Kannan; Jing Wang; Alexander J. Lazar; Eric J. Earley; Stephen W. Erickson; Tara Gelb; Philip Huxley; Johanna Lahdenranta; Gemma Mudd; Raushan T. Kurmasheva; Peter J. Houghton; Malcolm A. Smith; Edward A. Kolb; Richard Gorlick

Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable the development of effective therapeutics for this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed in normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP–targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.
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