Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases

• Published in: Theranostics 2019-01, Vol.9 (4), p.1154-1169
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - metabolism; Blood Platelets - metabolism; Disease Models, Animal; Immunoconjugates - administration & dosage; Immunoconjugates - metabolism; Mice; Molecular Targeted Therapy - methods; Neoplasm Metastasis - drug therapy; Neoplasm Transplantation; Oligopeptides - administration & dosage; Oligopeptides - metabolism; Platelet Glycoprotein GPIb-IX Complex - immunology; Platelet Glycoprotein GPIIb-IIIa Complex - immunology; Research Paper; Single-Chain Antibodies - immunology; Transplantation, Heterologous; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Tumor Microenvironment
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.29146

: 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 (scFv ) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). : 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 scFv -MMAE was first conjugated with Cyanine7 for imaging. The therapeutic efficacy of the scFv -MMAE was then tested in a mouse metastasis model of triple negative breast cancer. : studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. 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 scFv -MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. : 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.