Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

ABSTRACT

Introduction: Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy.

Areas covered: We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR).

Expert Opinion: Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.

KEYWORDS:

• Accessory cell
• adverse events
• antibody
• antitumor
• biologic
• cancer
• checkpoint inhibitor
• costimulatory agonist
• cytotoxic
• effector
• efficacy
• Fc
• Fc receptor
• FcR
• immunomodulatory
• immunosuppression
• immunotherapy
• irAE
• mAb
• monoclonal
• side effects
• tolerance
• toxicity
• tumor microenvironment
• tumoricidal

Article highlights.

• mAbs, including checkpoint inhibitors and costimulatory agonists, represent a promising new approach to cancer therapy.

• These mAbs work by enhancing immunity, thereby increasing antitumor activities. In doing so, however, a variety of irAEs can occur.

• Successful translation of these agents depends on selectively limiting the frequency and severity of irAEs without losing therapeutic efficacy.

• Although the mechanisms involving efficacy and irAEs have much overlap, evidence supports the idea that these effects can be isolated and fine-tuned.

• Interactions between Fc and FcR are essential in mediating biological activity, but are also implicated in the eliciting of adverse events.

• Modifying the structures of these mAbs so that they avoid Fc–FcR interactions, while still retaining therapeutic efficacy, might be a viable strategy for the future development of mAbs with more favorable therapeutic indices.

Acknowledgment

Authors thank Dr James Buturla (UConn Health) for his critical comments and editorial contributions.

Declaration of interests

A Vella and A Adler received grants from the NIH (AI094640 and CA109339). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.