Please use this identifier to cite or link to this item:
https://ahro.austin.org.au/austinjspui/handle/1/20535
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DC Field | Value | Language |
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dc.contributor.author | Yap, May Lin | - |
dc.contributor.author | McFadyen, James D | - |
dc.contributor.author | Wang, Xiaowei | - |
dc.contributor.author | Ziegler, Melanie | - |
dc.contributor.author | Chen, Yung-Chih | - |
dc.contributor.author | Willcox, Abbey | - |
dc.contributor.author | Nowell, Cameron J | - |
dc.contributor.author | Scott, Andrew M | - |
dc.contributor.author | Sloan, Erica K | - |
dc.contributor.author | Hogarth, P Mark | - |
dc.contributor.author | Pietersz, Geoffrey A | - |
dc.contributor.author | Peter, Karlheinz | - |
dc.date | 2019-02-07 | - |
dc.date.accessioned | 2019-04-02T01:08:22Z | - |
dc.date.available | 2019-04-02T01:08:22Z | - |
dc.date.issued | 2019-02-07 | - |
dc.identifier.citation | Theranostics 2019; 9(4): 1154-1169 | - |
dc.identifier.uri | https://ahro.austin.org.au/austinjspui/handle/1/20535 | - |
dc.description.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. | - |
dc.language.iso | eng | - |
dc.subject | Activated platelets | - |
dc.subject | Antibody-drug conjugate | - |
dc.subject | Cancer | - |
dc.subject | GPIIb/IIIa | - |
dc.title | Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases. | - |
dc.type | Journal Article | - |
dc.identifier.journaltitle | Theranostics | - |
dc.identifier.affiliation | Department of Hematology, The Alfred Hospital, Melbourne, 3004, Australia | en |
dc.identifier.affiliation | School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia | en |
dc.identifier.affiliation | University of Melbourne, Melbourne, Victoria, Australia | en |
dc.identifier.affiliation | Baker Heart and Diabetes Institute, Melbourne, 3004, Australia | en |
dc.identifier.affiliation | Department of Medicine, Monash University, Melbourne, 3800, Australia | en |
dc.identifier.affiliation | Department of Immunology, Monash University, Melbourne, 3800, Australia | en |
dc.identifier.affiliation | Department of Clinical Pathology, The University of Melbourne, Melbourne, 3010, Australia | en |
dc.identifier.affiliation | Burnet Institute, Melbourne, 3004, Australia | en |
dc.identifier.affiliation | College of Health and Biomedicine, Victoria University, Melbourne, 3021, Australia | en |
dc.identifier.affiliation | Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia | en |
dc.identifier.affiliation | Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia | - |
dc.identifier.affiliation | Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia | - |
dc.identifier.doi | 10.7150/thno.29146 | - |
dc.identifier.orcid | 0000-0002-6656-295X | - |
dc.identifier.pubmedid | 30867822 | - |
dc.type.austin | Journal Article | - |
local.name.researcher | Scott, Andrew M | |
item.grantfulltext | none | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.languageiso639-1 | en | - |
item.openairetype | Journal Article | - |
item.cerifentitytype | Publications | - |
item.fulltext | No Fulltext | - |
crisitem.author.dept | Clinical Haematology | - |
crisitem.author.dept | Molecular Imaging and Therapy | - |
crisitem.author.dept | Olivia Newton-John Cancer Research Institute | - |
Appears in Collections: | Journal articles |
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