The Role of Complement in the Mechanism of Action of Therapeutic Anti-Cancer mAbs

Abstract

Unconjugated anti-cancer IgG1 monoclonal antibodies (mAbs) activate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages, and these activities are thought to be important mechanisms of action for many of these mAbs in vivo. Several mAbs also activate the classical complement pathway and promote complement-dependent cytotoxicity (CDC), although with very different levels of efficacy, depending on the mAb, the target antigen, and the tumor type. Recent studies have unraveled the various structural factors that define why some IgG1 mAbs are strong mediators of CDC, whereas others are not. The role of complement activation and membrane inhibitors expressed by tumor cells, most notably CD55 and CD59, has also been quite extensively studied, but how much these affect the resistance of tumors in vivo to IgG1 therapeutic mAbs still remains incompletely understood. Recent studies have demonstrated that complement activation has multiple effects beyond target cell lysis, affecting both innate and adaptive immunity mediated by soluble complement fragments, such as C3a and C5a, and by stimulating complement receptors expressed by immune cells, including NK cells, neutrophils, macrophages, T cells, and dendritic cells. Complement activation can enhance ADCC and ADCP and may contribute to the vaccine effect of mAbs. These different aspects of complement are also briefly reviewed in the specific context of FDA-approved therapeutic anti-cancer IgG1 mAbs.

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells

“…Alternatively (or in addition), a pathogen-derived protein, which would be apparent on the surface of infected cells [80], would be a suitable antigen, inducing the production of antibodies that recognize infected cells, and trigger classical complement activation [81] or antibody-dependent cytotoxicity [82]. A nano-vaccine applied for tumor therapy should be decorated with a tumor-associated/specific surface protein in order to obtain antibodies that recognize malignant cells and confer antibodymediated cytotoxic effects [83,84]. Targeting of B-1 cells by a nano-vaccine via CR1/2 may result in a profound generation of IgM antibodies [56].…”

Monoclonal antibodies for cancerous conditions in essential medicine list: An experience from a tertiary hospital in Bengaluru, India

“…As described in the previous literatures, monoclonal antibodies are prescribed for patients with many cancerous conditions either as a single drug or in combinations with other drugs. 9 Though, there are no specified DDD and PDD for many of the drugs used in these situations. 8 The study findings have following programmatic implications.…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…The Fc region recruits the complement cascade via interacting with C1q, ultimately leading to the targeted cells’ apoptosis. These Fc-dependent effector mechanisms are crucial for many marketed antibodies, especially for anti-tumor antibodies [ 231 ]. Although broadly evidenced in vitro, these mechanisms have incompletely understood participation in efficacy in vivo, which vary across antibodies, target antigens, tumor types, and patient populations [ 229 , 232 , 233 , 234 , 235 ].…”