Molecular imaging applications of antibody-based immunotherapeutics to understand cancer drug distribution

With the landscape-transforming arrival of cancer immunotherapy, such as drugs that block immune checkpoints, durable responses are observed for several different cancer types. Regrettably, only part of the patients initially respond, and once responded, resistance to immune checkpoint blockade may occur. Therefore, new treatment options are explored to enhance the immune system. These approaches include engaging T cells or inhibit immunosuppressive cell types like tumor-associated macrophages (TAMs). T-cell activating drugs include bispecific T cell engagers (BiTEs) and T cell-redirecting antibodies, both redirect T cells to a predefined tumor target for subsequent infiltration and cytotoxicity. Another approach are drugs that inhibit TAMs, resulting in an enhanced tumor immune response.

Limited information is available regarding the pharmacological behavior of these new molecular entities. Radiolabeling these types of drugs with positron emission tomography (PET) isotopes allows molecular imaging using PET to assess whole-body drug distribution and tumor targeting. Ex vivo, techniques like tissue autoradiography, radioactive gel electrophoresis of plasma or tissue lysate, and ex vivo biodistribution complement PET imaging.

The research described in this thesis aims to gain insight with molecular imaging in the pharmacological behavior of antibody-based immunotherapeutics using molecular imaging. We show the tumor targeting properties of BiTES in both the preclinical as clinical setting. In addition we preclinically studied the distribution of a T cell-redirecting antibody and a TAM-directed antibody. Overall, molecular imaging of new radiolabeled cancer drugs could provide information to support drug development.