Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

Abstract

Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans.

Non-neutralizing antibodies increase endogenous circulating Ang1 levels

“…26–32 In cynomolgus monkey studies, we demonstrated that non-neutralizing antibody mAB-NN wild type increased circulating Ang1 to 6.7 fold and mAB-NN YTE increased Ang1 to 8.7 fold, while keeping Ang2 level relatively unchanged. The level of Ang1 increase is clinically relevant.…”

“…However, immune complexes most likely form when antibody and antigen have the same molar ratio (e.g., 1 bivalent antibody vs 2 monomeric units of antigen). 32 In the cynomolgus monkey study with mAB-NN, the total Ang1 level stayed below 1.5 ng/mL (except one time point on day 25), which translated to below 27 pM for 56 kD Ang1 protein (Figure 4a). The antibody concentration stayed above 10 nM.…”

Persistent Circulating Immune Complexes: Potential Source of Epimutation and Cancer Poor Prognosis

“…The rate of immune complex removal in turn depends on the rate of removal by mononuclear phagocyte system (MPS), and on the deposition of immune complex on tissues [21]. In cases with inefficient clearance by the mononuclear phagocytes system (MPS) only, pathological consequences will be expected, in particular by immune complexes formed with moderate excess of antigen (soluble immune complexes [19]. Additionally, the fate of circulating immune complexes (CIC) has been examined by injection of preformed IC prepared with IgG class of antibodies [19].…”

“…In cases with inefficient clearance by the mononuclear phagocytes system (MPS) only, pathological consequences will be expected, in particular by immune complexes formed with moderate excess of antigen (soluble immune complexes [19]. Additionally, the fate of circulating immune complexes (CIC) has been examined by injection of preformed IC prepared with IgG class of antibodies [19]. These investigations have shown that removal of CIC by MPS depends on the lattice of the immune complexes (IC), the status of the MPS, the nature of the antigen in IC and characteristic of the antibody in IC [19,21].…”

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

“…Both CIC and DNA, complexed with circulating opsonins, are captured by macrophages through Fcγ-receptors, the former alongside with CR1 cleavage [70]. However, elimination of DNA by means of CIC is much slower compared to CRP-SAP-linked DNA [71].…”