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Title: Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases.
Austin Authors: Yap, May Lin;McFadyen, James D;Wang, Xiaowei;Ziegler, Melanie;Chen, Yung-Chih;Willcox, Abbey ;Nowell, Cameron J;Scott, Andrew M ;Sloan, Erica K;Hogarth, P Mark;Pietersz, Geoffrey A;Peter, Karlheinz
Affiliation: Department of Hematology, The Alfred Hospital, Melbourne, 3004, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
University of Melbourne, Melbourne, Victoria, Australia
Baker Heart and Diabetes Institute, Melbourne, 3004, Australia
Department of Medicine, Monash University, Melbourne, 3800, Australia
Department of Immunology, Monash University, Melbourne, 3800, Australia
Department of Clinical Pathology, The University of Melbourne, Melbourne, 3010, Australia
Burnet Institute, Melbourne, 3004, Australia
College of Health and Biomedicine, Victoria University, Melbourne, 3021, Australia
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 7-Feb-2019 2019-02-07
Publication information: Theranostics 2019; 9(4): 1154-1169
Abstract: 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.
DOI: 10.7150/thno.29146
ORCID: 0000-0002-6656-295X
PubMed URL: 30867822
Type: Journal Article
Subjects: Activated platelets
Antibody-drug conjugate
Appears in Collections:Journal articles

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