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dc.contributor.authorYap, ML
dc.contributor.authorMcFadyen, JD
dc.contributor.authorWang, X
dc.contributor.authorZiegler, M
dc.contributor.authorChen, Y-C
dc.contributor.authorWillcox, A
dc.contributor.authorNowell, CJ
dc.contributor.authorScott, AM
dc.contributor.authorSloan, EK
dc.contributor.authorHogarth, PM
dc.contributor.authorPietersz, GA
dc.contributor.authorPeter, K
dc.date.accessioned2020-12-10T01:42:51Z
dc.date.available2020-12-10T01:42:51Z
dc.date.issued2019-01-01
dc.identifierpii: thnov09p1154
dc.identifier.citationYap, 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.
dc.identifier.issn1838-7640
dc.identifier.urihttp://hdl.handle.net/11343/253772
dc.description.abstractRationale: 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.
dc.languageEnglish
dc.publisherIVYSPRING INT PUBL
dc.titleActivated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases
dc.typeJournal Article
dc.identifier.doi10.7150/thno.29146
melbourne.affiliation.departmentMedicine and Radiology
melbourne.affiliation.departmentClinical Pathology
melbourne.source.titleTheranostics
melbourne.source.volume9
melbourne.source.issue4
melbourne.source.pages1154-1169
dc.rights.licenseCC BY-NC
melbourne.elementsid1372088
melbourne.contributor.authorHogarth, Phillip
melbourne.contributor.authorScott, Andrew
melbourne.contributor.authorYap, May Lin
melbourne.contributor.authorWang, Xiaowei
melbourne.contributor.authorChen, Yung-Chih
melbourne.contributor.authorPeter, Karlheinz
dc.identifier.eissn1838-7640
melbourne.accessrightsOpen Access


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