Molecular pharmacology in complement‐mediated hemolytic disorders

Abstract

In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement‐targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement‐mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long‐acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti‐C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first‐line. However, recently FDA and EMA approved the anti‐C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti‐C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.

Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management

“…Other investigational agents such as FcγRn inhibitors (nipocalimab), Syk kinase inhibitors (fostamatinib), BTK kinase inhibitors (rilzabrutinib), or PI3 kinase inhibitors are being explored [57][58][59][60][61][62][63][64]. If complement-mediated hemolysis is suspected, treatment may include inhibitors of the complement pathway such as sutimlimab (anti-C1s) or eculizumab (anti-C5) [58,60,63,65]. There continues to be active research on new therapies for wAIHA [58,[63][64][65][66][67][68].…”

“…If complement-mediated hemolysis is suspected, treatment may include inhibitors of the complement pathway such as sutimlimab (anti-C1s) or eculizumab (anti-C5) [58,60,63,65]. There continues to be active research on new therapies for wAIHA [58,[63][64][65][66][67][68]. Although splenectomy was used for years with immense success, it is rarely used today [3,60].…”

“…CAD is a more difficult-to-treat AIHA, as the antibody is usually associated with a chronic disease and the monoclonal antibody produced can cause more severe anemia than in CAS [79][80][81][82][83][84][85][86]. Therefore, treatment can consist of rituximab or anti-complement therapies such as sutimlimab to block the classical complement activation pathway [58,65,[79][80][81][82] or eculizumab to block the membrane attack complex of complement activation pathway [58,78,83,84]. To limit the production of the causal antibody and to diminish the cellular biomass of the driving condition, rituximab with or without strong immunosuppressive drugs such as fludarabine or bendamustine may be prescribed [58,78,83,84].…”

The Production of Complement Inhibitor Proteins in Mammalian Cell Lines—Light at the End of the Tunnel?

“…The growing number of diseases, pathogenetic states, and clinical conditions associated with complement dysfunction fuel a strong interest in therapeutic options to modulate this host defense pathway. Among the various types of drug candidates, natural complement inhibitor proteins and derived molecules seem to be outshined by novel innovations in the current boom [ 1 , 2 ]. However, particularly in diseases in which a complement factor function is missing (lacking or mutated; for, e.g., factor H and aHUS), there is hardly any other option than replacement.…”

Editorial: Practical recommendations and consensus for the management of immune mediated hematologic diseases

“…The latter encompass autoimmune cytopenias, namely autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), autoimmune neutropenia as well as bone marrow failures including paroxysmal nocturnal hemoglobinuria (PNH). A deeper understanding of the pathogenic mechanisms led to the development of several novel target therapies ( 1 – 3 ). The latter represent an opportunity but also a challenge for the treating physician, given the scarcity of practical recommendations and guidelines.…”