Complementopathies and precision medicine

Abstract

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

Figure 1. Targets of complement inhibitors in various stages of clinical development for complement-mediated disorders.

Complement-targeting compounds are shown in red and indicate the step of the complement pathway they target. From left to right: sutimlimab inhibits C1s of the classical pathway; narsoplimab inhibits mannose-binding protein-associated serine protease 2 (MASP-2) of the lectin pathway; pegcetacoplan (formerly APL-2) and AMY-101 inhibit C3 and C3 convertase activity; IONIS-FB-LRx and LPN023 inhibit factor B; lampalizumab and danicopan inhibit factor D; mini-FH/AMY-201 inhibits alternative pathway C3 convertase; CLG561 inhibits properdin; MicroCept inhibits C3 and C5 convertases; eculizumab, ravulizumab, crovalimab, ABP959, tesidolumab, REGN3918, mubodina, coversin, RA101495, cemdisiran, and zimura inhibit C5; and avacopan inhibits C5a receptor; and IFX-1 inhibits C5a.

Figure 2. Mutations in complement regulators involved in complement-mediated diseases.

Complement activation leads to C3 activation and C3 convertase formation on C3-opsonized surfaces, culminating in pronounced C3 fragment deposition on complement-targeted surfaces (proximal complement). In the presence of increased surface density of deposited C3b, the terminal complement is triggered, leading to membrane attack complex (MAC) formation on the surface of target cell. Complement pathway dysregulation results from loss-of-function mutations in regulatory factors (i.e., factor H [FH], factor I [FI], thrombomodulin [THBD], and vitronectin [VTN]) shown in red, gain-of-function mutations (i.e., C3 and factor B [FB]) shown in blue, and DGKE mutations in purple, indicating their unknown effect on complement cascade.

Figure 3. Complementopathies in the clinic.

(A) Model of the modified Ham (mHam) test. PIGA^null (PNH-like) TF1 cells do not express CD55 and CD59 and are therefore susceptible to complement-mediated killing. Cells are incubated with patient and control sera, then with a WST-1 cell proliferation dye reagent (Roche). Nonviable cells do not release dye because of complement-mediated killing, resulting in differences in measured absorbance. The percentage of live cells is calculated as the ratio of sample absorbance relative to its heat-inactivated control, multiplied by 100. The percentage of nonviable cells is a measure of complement activation. (B) Proposed model for APS and CAPS. Recent studies suggest that aPLs induce complement activation in patients with complement-amplifying trigger(s), such as infection, surgery, or autoimmune disease, and cause thrombosis in APS. Patients who also have a pathogenic loss-of-function mutation in a complement-inhibitory factor (e.g., CFH, CFI, CD46, or THBD) or a gain-of-function mutation of a complement-activating factor (e.g., CFB, C3) are likely to be predisposed to uncontrolled complement activation. In the setting of a complement-amplifying trigger, aPL-induced complement activation could lead to disseminated thrombosis and ischemic multiorgan failure in CAPS. PIGA, phosphatidylinositol N-acetylglucosaminyltransferase subunit A; PNH, paroxysmal nocturnal hemoglobinuria; APS, antiphospholipid syndrome; CAPS, catastrophic antiphospholipid syndrome; aPL, antiphospholipid antibody.