Human Immunoglobulin G2 Has Agonistic Properties

Monoclonal antibodies (mAb) that bind agonistically to immunostimulatory coreceptors such as CD40, 4-1BB, and CD28 have shown promising clinical activity alone or in combination with other mAbs that directly target proteins expressed by cancer cells, but because only a small subset of patients experience durable responses, further optimization of these agents is needed. An emerging concept is that the therapeutic efficacy of immunostimulatory mAbs can be affected by variations in their heavy and light chain constant regions, collectively known as the immunoglobulin isotype, which can modulate interactions with Fcγ receptors (FcγR) expressed on the surface of immune cells. White and colleagues observed that chimeric antibodies had greater immunostimulatory activity in vitro and stimulated greater T cell and antibody responses in vivo when they included the IgG2 constant region compared with other human immunoglobulin isotypes. Notably, the response to IgG2 was FcγR independent, as FcγR inhibition or deletion did not prevent induction of immune cell activation and proliferation by an anti-CD40 antibody engineered to have an IgG2 isotype. The agonistic activity of IgG2 required both its CH1 and hinge domains, which are unique among human IgGs because they can adopt a range of disulfide bond configurations. Unlike the flexible IgG2A conformation, the more rigid, compact IgG2B conformation conferred FcγR-independent agonistic activity and induced greater immune responses, suggesting that the precise disulfide bond conformation of IgG2 dictates its immunostimulatory activity. Indeed, mutation of the IgG2 residues involved in disulfide bonds resulted in a range of agonistic activity, with a mutation locking IgG2 in the IgG2B conformation leading to greater activity than native IgG2. In addition to providing insight into the biologic activity of IgG2, these findings provide a framework for optimizing immunostimulatory mAbs to maximize their clinical efficacy.

White AL, Chan HT, French RR, Willoughby J, Mockridge CI, Roghanian A, et al. Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory cancer antibodies. Cancer Cell 2015;27:138–48.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.