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
  • 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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