Antibody‐mediated complement activation in pathology and protection

Abstract

Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/ epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.

Antibodies Inhibiting the Type III Secretion System of Gram-Negative Pathogenic Bacteria

“…Abs can bind to the displayed pathogen protein fragments and be recognized by natural killer (NK) cells. The NK cells then induce apoptosis of the infected host cell [35]. For clarity within this review, Abs that attach to antigens presented on the host cell will be considered marked for ADCC.…”

Isotype selection for antibody-based cancer therapy

“…Importantly, mutations that potentiate CDC can be combined with ADCP and ADCC-enhancing mutations in a single IgG1 31 , thus broadening the effector function of these antibodies. Finally, the mutations that favour IgG hexamer formation also significantly enhance C1q fixation and thus CDC 32,33 . However, currently it remains to be seen whether these Fc mutations that enhance CDC in in vitro and inex vivo studies translate into improved clinical efficacy.…”

“…Nevertheless, if larger and better designed studies confirm the negative correlation between lower affinity FcRs variants and response to IgG antibody treatment, these patients may benefit more from IgE, IgA or mAbs optimised for complement activation. When it comes to complement optimised mAbs it may further be important to consider tumour microenvironment (TME) factors such as pH that can affect CDC 62 or the expression level of complement regulatory proteins which allow complement evasion by cancer cells 63 . Furthermore, it has been shown that C reactive protein (CRP) shares its binding site on FcγRs (I and II) and FcαRI with IgG and IgA, respectively, whereas it can also bind to C1q 64,65 .…”

Multifaceted roles of antibody Fc effector functions: from protection to pathology

“…While the benefits of antibodies are undeniable, it is also important to acknowledge that antibodies can contribute to dysregulation of immunity and disease pathology, including autoimmunity and even enhancement of infection or promotion of tumorigenic microenvironments as highlighted by Goldberg and Ackerman 6 …”