2. Academic Validation
  3. Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma

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

  • Mol Cancer Ther. 2022 Jun 1;21(6):903-913. doi: 10.1158/1535-7163.MCT-21-0836.
Yifei Wang 1,  Xiangjun Tian 2,  Wendong Zhang 1,  Zhongting Zhang 1,  Rossana Lazcano 3,  Pooja Hingorani 1,  Michael E Roth 1,  Jonathan D Gill 1,  Douglas J Harrison 1,  Zhaohui Xu 1,  Sylvester Jusu 1,  Sankaranarayanan Kannan 1,  Jing Wang 2,  Alexander J Lazar 3,  Eric J Earley 4,  Stephen W Erickson 4,  Tara Gelb 5,  Philip Huxley 6,  Johanna Lahdenranta 5,  Gemma Mudd 6,  Raushan T Kurmasheva 7,  Peter J Houghton 7,  Malcolm A Smith 8,  Edward A Kolb 9,  Richard Gorlick 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3 Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4 RTI International, Research Triangle Park, North Carolina.
  • 5 Bicycle Therapeutics, Lexington, Massachusetts.
  • 6 Bicycle Therapeutics, Babraham Research Campus, Cambridge, United Kingdom.
  • 7 Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
  • 8 Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
  • 9 Division of Pediatric Hematology/Oncology, A.I. duPont Hospital for Children, Wilmington, Delaware.
PMID: 35312779 DOI: 10.1158/1535-7163.MCT-21-0836
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.

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