Date of Completion

5-8-2020

Embargo Period

5-8-2020

Keywords

Cancer immunotherapy, Costimulation, CD134, OX40, CD137, 4-1BB, antibody, antitumor, irAE, Fc receptor, OrthomAb

Major Advisor

Adam J. Adler PhD

Co-Major Advisor

Anthony T. Vella PhD

Associate Advisor

Robert Clark MD

Associate Advisor

Carol Pilbeam MD, PhD

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Checkpoint-inhibiting antibodies targeting CTLA-4 and PD-1, along with costimulatory agonists, exhibit impressive anti-cancer efficacy and durable tumor regression. Despite this success, however, many patients fail to respond because of multiple immunosuppressive mechanisms used by cancer cells. Combination therapies designed to overcome this show promise, but strategies relying on multiple agents face logistical and regulatory challenges, as well as increased toxicity. This body of work begins with an in-depth review of antibody-based immunomodulatory cancer therapy, with an emphasis on efficacy, toxicity, and their interconnectedness. Following this background, an innovative approach to overcoming fundamental flaws in the current immunotherapy paradigm is presented. Click chemistry was utilized to fuse two TNFR family costimulatory agonists (anti-CD134 and anti-CD137) into a single biologic (OrthomAb) that harnesses the immunomodulatory effects of both antibodies, essentially functioning as a “single- agent combination therapy”. OrthomAb demonstrated potent costimulatory activity in vitro and antitumor efficacy in an aggressive mouse melanoma model. OrthomAb also elicited secretion of several unique cytokines and exhibited unexpected, possibly beneficial, effects on T cell proliferation. Expanding on OrthomAb as a platform revealed novel solutions to several issues hindering traditional combination therapy, such as the provocation of adverse events. This body of work concludes with an overview of more recent preliminary studies aiming to unravel the mechanism of OrthomAb, as well as that of unlinked anti-CD134 plus anti-CD137 dual costimulation (DCo). Using CD134/CD137 single- and double-knockout mice and additional click chemistry-derived antibody conjugates as controls, costimulatory receptor binding patterns and hybrid signaling mechanisms are explored. Bio-engineering techniques are also discussed as a means by which to alter the structures of antibody-derived conjugates in order to decrease toxicity but leave efficacy intact. These mechanistic studies serve to increase our understanding of T cell costimulation and immunomodulatory cancer therapy to inform strategies to improve upon current treatment options. In sum, this work establishes a new framework for encapsulating the benefits of combination tumor immunotherapy within a single agent, one which may improve treatment efficacy and tolerability, with the ultimate goal of saving more cancer patients while also enabling them to maintain higher quality of life.

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