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.

Keywords: Antibody-dependent complement activation; antibody engineering; cancer; complement; infectious disease.

Figure 1:. Overview of Complement Initiation Pathways & Possible Outcomes.

Figure reproduced with permission. (a) The complement cascade be initiated by three defined pathways, which commonly amplify through the C3 convertase, and terminate in target opsonization and/or membrane disruption. The classical pathway denotes activation of the complement cascade by the multi-functional C1q molecule, where C1q-mediated activation was classically defined by an initial recognition event by C1q of target-bound antibody. The Lectin pathway is initiated when specific polysaccharides are directly recognized by mannose-binding lectin (MBL), collectin-11 (CL-11), or by members of the ficolin family (Fcn). The alternative pathway is generally characterized by low levels of continual activation that is typically tempered by host regulatory proteins to protect from self-inflicted tissue damage. (b) Gradually, the products of this low-level activation build up on surfaces lacking host complement regulatory proteins and reach a crescendo, resulting in (c) exponential amplification and cascade progression leading to (d, e) soluble inflammatory molecule generation, target opsonization, lytic insertion of the membrane attack complex (MAC), destruction, adherence and trafficking, adaptive immune education, and host clearance. Ag: antigen; Ab: antibody; C1q: complement component 1q; C1r/s: complement component 1q-associated serine proteases r and s; MBL: mannose binding lectin; MASP: MBL-associated serine proteases; Fcn: ficolins; CL-11: collectin-11; PAMP: pathogen-associated molecular pattern; FP: factor P (properdin); C3(H₂O): hydrolyzed C3; FB: factor B, FD: factor D; RCA: regulators of complement activation; C4: complement component 4; C2: complement component 2; FI: factor I; CR1: complement receptor 1 (CD35); C3dg: complement fragment 3dg; C3aR: C3a receptor; C5aR1 and 2: C5a receptor 1 and 2 (CD88 and C5L2, respectively); CRIg: CR of the immunoglobulin family; MAC: membrane attack complex (C5b-9); TCR: T-cell receptor; BCR: B-cell receptor.

Figure 2:. Structural Determinants of Antibody-mediated Complement Activation (AMCA).

(a) IgG1 antibody structure denoting antigen-binding (Fab) and Fc Receptor-binding (Fc) domains and antibody-intrinsic factors known to affect the efficiency of AMCA. Boxed regions indicate the site of interactions with C1q globular heads (orange) and between Fc domains (purple). Amino acid residues known to impact Fc-C1q (orange) or Fc-Fc (purple) interactions in the context of IgG1 numbering are indicated. (b) Structure of C1q globular head (orange) and IgG1 Fc (purple) complex. (c). Structure of Fc-Fc dimer complex. (d). (Left) Top down view of Fc hexamer (purple) interacting with six C1q globular heads (orange). (Right) Side view of C1 complex C1r and C1s (blue). IgG1 Fc, PDB 1HZH. IgG1 Fc and gC1q co-complex, PDB 6FCZ. Cryo-EM reconstruction of C1-IgG1 complex, EMD-4232, reproduced with permission.