Targeting Activated Platelets in the Tumor Microenvironment for Localized Delivery of Antibody-drug Conjugates to Tumors and Metastases
ISTH Academy. McFadyen J. Jul 10, 2019; 273990; OC 79.5 Topic: Platelets Beyond Hemostasis
James McFadyen
James McFadyen
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OC 79.5

Targeting Activated Platelets in the Tumor Microenvironment for Localized Delivery of Antibody-drug Conjugates to Tumors and Metastases

M.L. Yap1,2, J. McFadyen1,3,4, X. Wang1,3, M. Ziegler1, Y.-C. Chen1, A. Willcox1,3,4, C. Nowell3, A. Scott5, E. Sloan3, M. Hogarth2,3,6, G. Pietersz1,3,6, K. Peter1,3
1Baker Heart and Diabetes Institute, Melbourne, Australia, 2University of Melbourne, Melbourne, Australia, 3Monash University, Melbourne, Australia, 4The Alfred Hospital, Melbourne, Australia, 5Austin Health, Melbourne, Australia, 6Burnet Institute, Melbourne, Australia

Main Topic: Platelets and Megakaryocytes
Category: Platelets Beyond Hemostasis

Background: Apart from their classical role in hemostasis, platelets are increasingly recognized as important mediators of tumor growth and metastasis. Experimental studies have demonstrated that tumor cells release inflammatory mediators which may provide a pro-thrombotic environment, promoting platelet activation.
Aims:
1. To confirm if activated platelets are present and abundant in the tumor microenvironment.
2. To determine the utility of a single-chain antibody which binds to the activated integrin GPIIb/IIIa for targeted cancer diagnosis and therapy.
Methods: We developed a theranostic agent based on a single-chain antibody which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets (scFvGPIIb/IIIa). The scFvGPIIb/IIIa was conjugated to 1) A highly potent microtubule inhibitor, monomethyl auristatin E (MMAE), incorporated with a cathepsin B cleavable linker for drug release, for therapy, and 2) Cyanine7 for in vivo imaging.
Results: In vivo fluorescence imaging demonstrated that scFvGPIIb/IIIa-Cy7-MMAE localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a particularly difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Next, we demonstrated that the scFvGPIIb/IIIa-Cy7-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects.
Conclusions: Overall, we confirmed the utility of a novel theranostic based antibody-drug conjugate that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique double targeting mechanism holds major promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack a specific molecular surface epitope for drug targeting.

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