Infusion Reactions Associated with the Medical Application of Monoclonal Antibodies: The Role of Complement Activation and Possibility of Inhibition by Factor H

Abstract

Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as "nanomedicines", can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then focus on the reactions caused by mAb therapy. Because the alternative pathway of complement activation may amplify such adverse reactions, we highlight the potential use of complement factor H as an inhibitor of CARPA.

Keywords: CARPA; complement; complement activation; factor H; hypersensitivity; infusion reaction; monoclonal antibody therapy; pseudoallergic reaction.

Figure 1

Complement activation as an essential mechanism of the therapeutic action of rituximab, an anti-CD20 antibody. Rituximab recognizes CD20 on the surface of pre- and mature B cells. After binding, the complement activation cascade is initiated by the classical pathway leading to the cleavage of C3 into C3a and C3b. C3b can cause complement-dependent cytotoxicity (CDC) by promoting the assembly of the membrane attack complex (MAC), while complement receptors on phagocytic cells, such as complement receptor type 3 (CR3) on macrophages, can mediate complement-enhanced antibody-dependent cell-mediated phagocytosis (ADCP). Surface-bound rituximab can trigger natural killer (NK) cells and macrophages by complement-independent mechanisms, via antibody-dependent cell-mediated cytotoxicity (ADCC), ADCP and, to a lesser degree, the induction of programmed cell death (PCD).