Influence of immunoglobulin isotype on therapeutic antibody function

Abstract

Monoclonal antibody (mAb) therapeutics are revolutionizing cancer treatment; however, not all tumors respond, and agent optimization is essential to improve outcome. It has become clear over recent years that isotype choice is vital to therapeutic success with agents that work through different mechanisms, direct tumor targeting, agonistic receptor engagement, or receptor-ligand blockade, having contrasting requirements. Here we summarize how isotype dictates mAb activity and discuss ways in which this information can be used for the development of enhanced therapeutics.

Figure 1

Role of isotype and FcγR interactions in therapeutic mAb function. Multiple mechanisms can mediate mAb therapeutic efficacy, influenced differentially by mAb isotype and FcγR interactions. (A) Direct targeting (depleting) mAbs mediate clearance of cells expressing their Ag target by recruitment of activatory FcγR (FcγRIIA or FcγRIIIA)-expressing cytotoxic immune effectors. Interaction of the mAb Fc with inhibitory FcγRIIB can prevent this process. Thus, hIgG1 and Fc- or glyco-engineered forms of mAb with a high activatory:inhibitory FcγR binding ratio are optimal. (B) Agonistic mAbs are designed to stimulate signaling through their receptor targets, typically TNFR, through receptor clustering. This can be achieved either by crosslinking of the mAb Fc by FcγRIIB on adjacent cells enhanced by the SE/LF mutation in hIgG1 (top) or through the unique configuration of human IgG2(B) (bottom; see also Figure 2). (C) Blocking mAbs are designed to block receptor-ligand interactions mediating immune suppression (eg, CTLA4, PD-1) or required for tumor cell growth/survival (eg, HER2, epidermal growth factor receptor [EGFR]). Recent preclinical data suggest that optimal activity, at least for PD1 mAbs, is achieved in the absence of FcγR engagement. Isotypes with minimal FcγR binding, such as hIgG4 or “FcγR null” mAbs engineered to prevent FcγR engagement, may therefore be optimal. For each mechanism, example targets are listed on the left, with those in blue demonstrated to engage multiple mechanisms in preclinical models. The roles of FcγR (black, positive role; red, negative role) and optimal isotypes are listed on the right and are detailed in the text.

Figure 2

Disulphide shuffling in human IgG2 produces alternative hinge configurations. Disulphide bonds in the hinge and CH1 domains of hIgG2 can rearrange. hIgG2 is thought to be synthesized in its IgG2(A) format where all 4 hinge cysteines are involved in parallel inter-heavy chain disulphide bonds (left). Over time, as it circulates in the blood, these bonds can rearrange and the protein passes through a series of intermediates with a portion achieving a conformation [IgG2(B)] in which both Fab arms are disulphide linked to the hinge. IgG2(A) is thought to have a more open and flexible conformation than the more compact and rigid IgG2(B) (see main text for details and references).