Activated platelets and antibody opsonization as tumor markers: novel avenues for cancer diagnosis, targeted therapy and monitoring therapeutic outcomes

Abstract

With over 100 types of cancer known, the study presented in this thesis introduces novel means of targeting a wide range of cancers, rather than a specific cancer antigen. Here, unique cancer targets, such as components of the tumor microenvironment and monoclonal antibody opsonization are investigated as new approaches for cancer diagnosis and targeted therapy. The first part of the study investigates the possibility of targeting activated platelets in the tumor microenvironment as a novel cancer diagnostic target. I showed the feasibility of using a single-chain antibody, which targets the activated form of GPIIb/IIIa, the most abundant platelet-specific receptor on the platelet surface as a possible tool for cancer diagnosis using PET/CT, fluorescence imaging and ultrasound. The second part of the investigation aims to further expand the utility of the single-chain antibody as an antibody-drug conjugate for cancer therapy. Using a mouse metastasis model of triple negative breast cancer, I showed that the activated platelet targeting single-chain antibody, conjugated to Auristatin E, a clinically available chemotherapy agent, was successful in reducing tumor growth and preventing metastasis development. The final part of the thesis describes the development of an FcγRIIIa receptor dimer, which has been engineered to selectively bind avidly to multimeric Fc complexes. This binding mimics the engagement of FcγRIIIa on effector cells, such as on NK cells, with antibody-coated cells that leads to antibody-mediated target killing. Here, using a mouse xenograft model of B cell lymphoma treated with Rituximab and triple negative breast cancer adenocarcinoma, treated with an EGFR receptor antibody, I show that the FcγRIIIa receptor dimer, labeled with a near-infrared contrast agent, could be used to specifically image antibody opsonization of tumor cells in vivo.