Sutimlimab for the Treatment of Cold Agglutinin Disease

Abstract

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia and a bone marrow clonal lymphoproliferative disorder. Hemolysis in CAD is complement-dependent and mediated by the classical activation pathway. Patients also frequently suffer from fatigue and cold-induced circulatory symptoms. Although not all patients need treatment, the symptom burden has previously been underestimated. Effective therapies target the clonal lymphoproliferation or the complement activation. Sutimlimab, a humanized monoclonal IgG4 antibody that binds and inactivates complement protein C1s, is the most extensively investigated complement inhibitor for the treatment of CAD. This review addresses the preclinical studies of sutimlimab and the studies of pharmacokinetics and pharmacodynamics. We then describe and discuss the prospective clinical trials that established sutimlimab as a rapidly acting, highly efficacious, and low-toxic therapeutic agent. This complement inhibitor does not improve the cold-induced circulatory symptoms, which are not complement-mediated. Sutimlimab is approved for the treatment of CAD in the US, Japan, and the European Union. A tentative therapeutic algorithm is presented. The choice of therapy for CAD should be based on an individual assessment, and patients requiring therapy should be considered for inclusion in clinical trials.

Graphical abstract

Figure 1.

Complement-mediated hemolysis in CAD. IgM-cold agglutinin bound to its cell surface antigen initiates the classical complement activation pathway by binding and activating the C1qrs complex. Activated C1s cleaves C4 and C2 in turn; C4 and C2 split products combine to form C3 convertase on the cell surface, followed by fixation and cleavage of C3. C3b-opsonized erythrocytes are phagocytosed by the mononuclear phagocytic system, predominantly in the liver (extravascular hemolysis). To some degree, in particular in severely affected patients and acute exacerbations, C3b can also combine with C4b and C2a, thereby forming C5 convertase and activating the terminal complement cascade. If this pathway is triggered, C5 convertase binds and splits C5, resulting in formation of the MAC, and intravascular hemolysis. Lightning symbols denote anaphylotoxin properties of soluble split products. Only relevant pathways are shown. CAD = cold agglutinin disease; MAC = membrane attack complex.

Figure 2.

In vitro inhibition of cold agglutinin-induced, complement-mediated phagocytosis and C3 fragment deposition on erythrocytes by TNT003 (anti-C1s mouse monoclonal antibody). Plasma samples from CAD patients were used as a source of cold agglutinin and normal human serum as a source of complement. Based on data from Shi et al. Figure previously published by Berentsen et al, reused under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Copyright (2022): Berentsen et al. CA = cold agglutinin; CAD = cold agglutinin disease; EDTA = ethylene diamine tetraacetic acid; IC = internal control; NHS = normal human serum; RBC = red blood cell.

Figure 3.

Improvement of hemolytic anemia in the randomized CADENZA study of sutimlimab in patients with CAD. Rapid normalization of hemoglobin levels (A) and bilirubin levels (B) were observed in the treatment arm. In the placebo arm, no significant improvement was observed during the first 26 wk (Part A). After 26 wk (Part B), patients randomized to the placebo arm were shifted to sutimlimab, followed by rapid improvement of hemolytic anemia very similar to that observed initially in the treatment arm. Remissions were sustained throughout the study period (≥79 wk). Figure first published in Blood by Röth, Berentsen, Barcellini et al, reused under general permission. Copyright (2022): the American Society of Hematology. BL = baseline; CAD = cold agglutinin disease; Hb = hemoglobin; LV = last available on-treatment value; PBO = placebo; SE = standard error; SUT = sutimlimab; ULN = upper limit of normal.

Figure 4.

Treatment algorithm for CAD.