Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases
AuthorYap, ML; McFadyen, JD; Wang, X; Ziegler, M; Chen, Y-C; Willcox, A; Nowell, CJ; Scott, AM; Sloan, EK; Hogarth, PM; ...
PublisherIVYSPRING INT PUBL
University of Melbourne Author/sHogarth, Phillip; Scott, Andrew; Yap, May Lin; Wang, Xiaowei; Chen, Yung-Chih; Peter, Karlheinz
AffiliationMedicine and Radiology
Document TypeJournal Article
CitationsYap, M. L., McFadyen, J. D., Wang, X., Ziegler, M., Chen, Y. -C., Willcox, A., Nowell, C. J., Scott, A. M., Sloan, E. K., Hogarth, P. M., Pietersz, G. A. & Peter, K. (2019). Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases. THERANOSTICS, 9 (4), pp.1154-1169. https://doi.org/10.7150/thno.29146.
Access StatusOpen Access
Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results: In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.
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