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

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.

• Authors: May Lin Yap, James D McFadyen, Xiaowei Wang, Melanie Ziegler, Yung-Chih Chen, Abbey Willcox, Cameron J Nowell, Andrew M Scott, Erica K Sloan, P Mark Hogarth, Geoffrey A Pietersz, Karlheinz Peter
• Journal: Theranostics (Theranostics) Vol. 9 Issue 4 Pg. 1154-1169 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 30867822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Immunoconjugates
• Oligopeptides
• Platelet Glycoprotein GPIIb-IIIa Complex
• Platelet Glycoprotein GPIb-IX Complex
• Single-Chain Antibodies
• glycoprotein receptor GPIb-IX
• monomethyl auristatin E

Topics

• Animals
• Antineoplastic Agents (administration & dosage, metabolism)
• Blood Platelets (metabolism)
• Disease Models, Animal
• Immunoconjugates (administration & dosage, metabolism)
• Mice
• Molecular Targeted Therapy (methods)
• Neoplasm Metastasis (drug therapy)
• Neoplasm Transplantation
• Oligopeptides (administration & dosage, metabolism)
• Platelet Glycoprotein GPIIb-IIIa Complex (immunology)
• Platelet Glycoprotein GPIb-IX Complex (immunology)
• Single-Chain Antibodies (immunology)
• Transplantation, Heterologous
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy)
• Tumor Microenvironment