Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma

Yifei 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 MuddRaushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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 development of effective therapeutics in 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 on 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.

Original languageEnglish (US)
Pages (from-to)903-913
Number of pages11
JournalMolecular cancer therapeutics
Volume21
Issue number6
DOIs
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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