Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life

Abstract

Purpose of review: A wealth of recent animal model data suggests that as exciting possibilities for the use of antibodies in passive immunotherapy strategies continue to develop, it will be important to broadly consider how antibodies achieve anti-HIV-1 effect in vivo.

Recent findings: Beyond neutralization breadth and potency, substantial evidence from natural infection, vaccination, and studies in animal models points to a critical role for antibody Fc receptor (FcR) engagement in reducing risk of infection, decreasing postinfection viremia, and delaying viral rebound. Supporting these findings in the setting of HIV, the clinical maturation of recombinant antibody therapeutics has reinforced the importance of Fc-driven activity in vivo across many disease settings, as well as opportunely resulted in the development and exploration of a number of engineered Fc sequence and glycosylation variants that possess differential binding to FcRs. Exploiting these variants as tools, the individual and concerted effects of antibody effector functions such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement-dependent cytotoxicity, antibody half-life, and compartmentalization are now being explored. As exciting molecular therapies are advanced, these studies promise to provide insight into optimal in-vivo antibody activity profiles.

Summary: Careful consideration of recent progress in understanding protective antibody activities in vivo can point toward how tailoring antibody activity via Fc domain modification may enable optimization of HIV prevention and eradication strategies.

FIGURE 1

Structural diversity of IgG and IgA. Structurally, IgG (a) and IgA (b) differ in valency, size, and extent of glycosylation. (a) IgG antibodies may be further divided into four subclasses (recently reviewed in [19]). Structurally, the most notable distinction among subclasses is the significantly extended hinge of IgG3, which contains a variable number of repeating units. Other structural differences include the ability of IgG4 molecules to undergo Fab arm exchange, which results in naturally bispecific but functionally monovalent antibodies [20]; and among all subclasses, varying numbers and formation of disulfide bonds in the hinge region have been observed [21]. Although IgG has traditionally not been thought to oligomerize, recent evidence suggests otherwise, with observations of ordered IgG1 hexamers [22^▪] and confirmation of covalent IgG2 dimers [23]. (b) IgA1 and IgA2 subclasses, whose prevalences vary among serum and various secretions, primarily differ structurally in terms of their hinge region, which is extended and extensively O-glycosylated in IgA1. Although this extension may offer advantages in accommodating bivalent antigen binding across greater physical distances, it is also thought to sensitize IgA1 to proteolytic degradation, and to be relatively rigid, potentially constraining the geometry of bivalent antigen binding. IgA molecules may be covalently dimerized via disulfide bond formation with the J chain, a 15 kDa immunoglobulin fold family protein that can also covalently polymerize immunoglobulin M. dIgA, dimeric IgA; IgA, immunoglobulin A; IgG, immunoglobulin G; dIgA, dimeric IgA; sIgA, secretory IgA; mIgA, monomeric IgA.

FIGURE 2

Properties of FcR. (a) There are multiple FcγR receptors, including FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb found on a spectrum of effector cells including macrophages, neutrophils, NK cells, eosinophils, basophils, dendritic cells—all exhibiting differential receptor expression patterns and activity profiles. Each receptor and its allotypic variants have differential binding to IgGs based on subclass, glycosylation, and avidity. Beyond their structural and cellular diversity, functional relationships are complex as differential engagement between activating and inhibitory FcRs dictates their effector function [24], and certain receptors have additional roles in antigen presentation [25] and B-cell activation [26]. Cumulatively, they are responsible for mediating functions as diverse as ADCC, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement-dependent cytotoxicity, and trapping in mucus. FcRn, the IgG transporter, binds to IgG in a pH-dependent manner to permit shuttling across epithelial boundaries via endosomal trafficking. (b) IgA receptors include polymeric immunoglobulin receptor, FcαR, and Fcα/μR found on a number of cell types following binding of systemic dIgA, polymeric immunoglobulin receptor is cleaved at the apical membrane, leaving a fragment known as the SC bound. The resulting dIgA with the J chain and SC is known as secretory IgA, a hydrophilic and negatively charged molecule repelled by mucosal surfaces thought to act as a relatively passive pathogen trap. SC is thought to occlude FcαR binding, and thus partially account for the striking activity difference between plasma and mucosal IgA species. ADCC, antibody-dependent cellular cytotoxicity; FcR, Fc receptor; FDC, follicular dendritic cell; IgA, immunoglobulin A; IgG, immunoglobulin G; NK, natural killer; ORF, open reading frame; PMN, polymorphonuclear leukocyte; SC, secretory component.