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"Cell Surface Capture" Workflow for Label-Free Quantification of the Cell Surface Proteome
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Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma
Yifei Wang1, Xiangjun Tian2, Wendong Zhang1
1Department of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
Researchers identified novel cell-surface targets for osteosarcoma (bone cancer) therapies. An MT1-MMP-targeted toxin conjugate showed promising antitumor activity in preclinical models, validating this approach for developing new cancer treatments.
Area of Science:
- Oncology
- Proteomics
- Transcriptomics
Background:
- Immunoconjugates targeting cell-surface antigens are effective in various cancers.
- Osteosarcoma lacks specific cell-surface targets for targeted therapies.
Purpose of the Study:
- To identify and validate osteosarcoma-specific cell-surface antigens for therapeutic development.
- To evaluate the therapeutic potential of targeting identified antigens.
Main Methods:
- Integrated proteomic and transcriptomic surfaceome profiling to identify highly expressed osteosarcoma antigens.
- Validation of target overexpression in osteosarcoma tissues.
- Preclinical testing of an MT1-MMP-targeted toxin conjugate (BT1769) in patient-derived xenograft models.
Main Results:
- Identified several cell-surface proteins highly expressed in osteosarcoma.
- Validated overexpression of MT1-MMP, CD276, and MRC2 in osteosarcoma.
- BT1769 demonstrated significant antitumor activity, high target affinity, and favorable pharmacokinetics in preclinical models.
Conclusions:
- The surfaceome profiling approach successfully identifies novel, therapeutically relevant targets in osteosarcoma.
- MT1-MMP is a promising target for developing novel osteosarcoma therapeutics.
- Targeted toxin conjugates represent a viable therapeutic strategy for osteosarcoma.
