title: Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors: a Department of Immunology , UConn Health , Farmington , CT , USA.
authors: Joseph M
authors: JM
authors: Ryan
authors: b Department of Medicine , UConn Health , Farmington , CT , USA.
authors: Jeffrey S
authors: JS
authors: Wasser
authors: a Department of Immunology , UConn Health , Farmington , CT , USA.
authors: Adam J
authors: AJ
authors: Adler
authors: a Department of Immunology , UConn Health , Farmington , CT , USA.
authors: Anthony T
authors: AT
authors: Vella
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D056747:Immunomodulation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D061025:Costimulatory and Inhibitory T-Cell Receptors
keywords: Accessory cell; Fc; Fc receptor; FcR; adverse events; antibody; antitumor; biologic; cancer; checkpoint inhibitor; costimulatory agonist; cytotoxic; effector; efficacy; immunomodulatory; immunosuppression; immunotherapy; irAE; mAb; monoclonal; side effects; tolerance; toxicity; tumor microenvironment; tumoricidal