Harnessing the therapeutic potential of IgG3 through molecular engineering

About This Grant

ABSTRACT Monoclonal antibodies have found enormous clinical utility for treatment of infectious diseases, autoimmunity and cancer. While there are four human IgG subclasses, only IgG1, 2 and 4 have been deployed as therapeutics. IgG1 is the most abundant subclass and is the go-to molecule when target cell killing is desired, i.e the cancer drugs anti-HER-2 (trastuzumab) that kills breast cancer cells and anti-CD20 (rituximab) that depletes B cell tumors. IgG2 in contrast has very low affinity for FcgR, is a poor activator of complement and cell mediated killing, and is often used for receptor blocking or neutralizing mAbs, ie the EGFR blocker panitumumab. IgG4 is used for chronic diseases and for immune check-point inhibitors, such as nivolumab (PD1 blockade). IgG4 does not activate complement and binds poorly to FcgR making it a preferred choice when cell death or inflammation is not the goal. In contrast, IgG3 has not found widespread use clinically, with only one human trial of an IgG3 antibody exist in the literature. The paucity of interest in IgG3 for development of therapeutics, despite its potency with regards to antibody effector functions, and optimal ability to engage antigens through its flexible hinge region, mainly stems from its very short in vivo half-life. There are some additional technical challenges such as the existence of multiple allotypes, practical obstacles to effective purification, and pH stability. Due to its superior range of effector mechanism potency, and flexible binding properties, we propose that revisiting IgG3 as a therapeutic agent is warranted. Herein we will employ protein engineering to optimize the FcRn interaction of IgG3 to expand its in vivo half-life, and the FcR interactions to define the full range of effector mechanism activation that can be achieved through IgG3. We propose that if harnessed appropriately, IgG3 can be developed for therapeutic clinical use, with the benefits of improved binding profiles and a broader dynamic range of effector function potency.