Review
Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future

https://doi.org/10.1016/j.smim.2016.05.001Get rights and content

Highlights

  • Eculizumab is the current anti-complement treatment agent approved for the treatment of PNH and atypical HUS.

  • The complement system is identified as a key pathogenic factor in other hemolytic anemias, eventually benefiting from anti-complement treatment.

  • A second-generation of complement inhibitors is under development, targeting distinct key steps of the complement cascade.

  • Targeted inhibitors of early steps of complement activation represent promising agents for anti-complement treatment in PNH and other diseases.

Abstract

The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias, trying to identify the most promising approaches for each individual disease.

Introduction

The complement system is a key component of the innate immunity which is finely regulated in humans. As for the adaptive immunity, the physiologic role of complement includes protection from foreign dangers, mostly infectious agents, as well as from self-triggers, like damaged tissues [1], [2]. The complement system also represents a broad effector mechanism which may play a role in several human diseases (e.g., paroxysmal nocturnal hemoglobinuria [PNH], hemolytic-uremic syndrome [HUS], kidney disorders, age-related macular degeneration) and conditions (e.g., sepsis, ischemia/reperfusion injury, allograft rejection) [2], [3], [4]. These diseases may affect basically all human organs or systems; here we focus on disorders characterized by a common hematological presentation, which is hemolysis. Hemolytic anemias are a heterogeneous group of disorders which may have completely different causes; nevertheless, the complement system has been implicated as possible pathogenic mechanism in many of them. However, since the possible involvement of complement encompasses diseases which traditionally have been considered largely independent, a systematic classification of complement-mediated hemolytic anemia is missing. A tentative classification (see Table 1) may discriminate between forms caused by a primary impairment of endogenous complement regulation (primary forms), as compared with forms characterized by hyperactivation of complement secondary to other pathogenic events (secondary forms). Sometimes this distinction is not easy, because primary and secondary complement derangements may lead to similar disorders (see for instance the broad chapter of thrombotic microangiopathies, TMA), as well as primary dysregulation may work as a permissive environment where further secondary events are needed for the development of the disease. Primary forms include the most typical complement-mediated hemolytic anemia – namely PNH – as well as inherited diseases such as atypical HUS (aHUS) and a rare congenital deficiency of CD59. While in PNH the impairment of complement regulation is restricted to affected blood cells, eventually accounting for the typical hemolysis (see below), in aHUS such impairment is systemic, mostly in the fluid phase, and it results in possible microangiopathy (aHUS can be considered a primary, inherited microangiopathy). Secondary forms can be divided in two subgroups with different pathophysiology, according to the event triggering complement: (i) auto-immune antibody-mediated hemolytic anemia (AIHA), and (ii) secondary thrombotic microangiopathies. Antibody-mediated hemolytic anemia include cold agglutinine disease (CAD), cold paroxysmal hemoglobinuria (CPH) and other warm or mixed auto-immune hemolytic anemias; these conditions differ for the intrinsic features of the pathogenic immunoglobulin (e.g., antigen specificity, thermal range and mostly capability of activating the complement cascade), which eventually account for the contribution of the complement system to the mechanisms of hemolysis. TMAs are even more heterogeneous, and include the typical form of HUS (driven by bacterial toxins activating complement), as well as thrombotic thrombocytopenic purpura (TTP) and transplant-associated microangiopathies (TA-TMA), two conditions where the pathogenic role of complement has not yet been elucidated.

Here we briefly review the use of therapeutic complement inhibition in complement-mediated anemias, aiming to highlight how clinical interventions contribute to elucidate complement-mediated pathophysiology. Based on these finding we will also review the novel strategies of complement modulations which are currently under development, that eventually aim to improve the treatment of different complement-mediated anemias.

Section snippets

The history of complement inhibition in hemolytic anemias

Eculizumab (Soliris®, Alexion) [5] is the first complement inhibitor approved for clinical use in humans, initially for PNH and subsequently for aHUS. The experience with this anti-C5 humanized monoclonal antibody (mAb), which intercepts the complement cascade at the level of its terminal effector pathway, is extremely informative.

The present of complement inhibition: unmet medical needs

The introduction of eculizumab represented a major step in medicine, since for the first time clinicians where able to interfere with complement as the pathogenic mechanism of several diseases. Nevertheless, the availability of an effective therapy then raises additional medical needs, which include the possible extension of its use to other conditions, as well as the possibility to further improve the standard treatment. Indeed, different unmet clinical needs may be identified in the context

The future of complement inhibition

After the excellent results with the first complement inhibitor eculizumab, there is now a second generation of complement modulators which are starting their preclinical or clinical development [98], [99]. Table 1 includes the most relevant compounds, which are grouped according to their specific targets in the complement cascade (see also Fig. 1); roughly, novel complement inhibitors can be divided into inhibitors of the terminal complement effector pathway (i.e., targeting C5 or downstream

Concluding remarks

Thirteen years of therapeutic complement inhibition demonstrated that this treatment option was safe and potentially effective in different human diseases. The experience in PNH and aHUS led to dramatic clinical results, which have changed the natural history of these diseases. Thus, anti-complement treatment is a developing field which is now trying to address different unmet clinical needs. Maybe the most relevant issue is the access to anti-complement therapies; indeed, while complement is a

References (201)

  • S.R. Cataland et al.

    How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome

    Blood

    (2014)
  • A.M. Risitano et al.

    Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab

    Blood

    (2009)
  • Z. Lin et al.

    Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria

    Blood

    (2015)
  • A.M. Risitano et al.

    Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab

    Blood

    (2008)
  • A.M. Risitano et al.

    Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab

    Blood

    (2008)
  • R.A. Brodsky

    How I treat paroxysmal nocturnal hemoglobinuria

    Blood

    (2009)
  • L.S. Keir

    Shiga toxin associated hemolytic uremic syndrome

    Hematol. Oncol. Clin. North Am.

    (2015)
  • M. Michael et al.

    Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials

    Am. J. Kidney Dis.

    (2009)
  • X. Zheng et al.

    Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura

    J. Biol. Chem.

    (2001)
  • J.F. Dong et al.

    ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions

    Blood

    (2002)
  • N. Turner et al.

    Ultralarge von Willebrand factor-induced platelet clumping and activation of the alternative complement pathway in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndromes

    Hematol. Oncol. Clin. North Am.

    (2015)
  • X.U. Hu et al.

    Complement activation may trigger the onset of thrombotic thrombocytopenic purpura in patients with severe ADAMTS13 deficiency

    Blood

    (2014)
  • B.L. Laskin et al.

    Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy

    Blood

    (2011)
  • V.T. Ho et al.

    Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation

    Biol. Blood Marrow Transplant.

    (2005)
  • S. Jodele et al.

    Pulmonary arterial hypertension in pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy

    Biol. Blood Marrow Transplant.

    (2013)
  • J. El-Bietar et al.

    Histologic features of intestinal thrombotic microangiopathy in pediatric and young adult patients after hematopoietic stem cell transplantation

    Biol. Blood Marrow Transplant.

    (2015)
  • S. Jodele et al.

    A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury

    Blood Rev.

    (2015)
  • S. Jodele et al.

    Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

    Blood

    (2014)
  • S. Jodele et al.

    Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy

    Blood

    (2013)
  • S. Jodele et al.

    The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy

    Blood

    (2016)
  • D. Ricklin et al.

    TMA. beware of complements

    Blood

    (2013)
  • S. Jodele et al.

    Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy

    Biol. Blood Marrow Transplant.

    (2014)
  • S. Jodele et al.

    Variable eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation

    Biol. Blood Marrow Transplant.

    (2016)
  • S. Berentsen et al.

    Cold agglutinin-mediated autoimmune hemolytic anemia

    Hematol. Oncol. Clin. North Am.

    (2015)
  • P.L. Swiecicki et al.

    Cold agglutinin disease

    Blood

    (2013)
  • A. Roth et al.

    Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease

    Blood

    (2009)
  • A. Röth et al.

    Complement inhibition with eculizumab in patients with cold agglutinin disease (CAD): results from a prospective phase II trial (DECADE trial)

    Blood

    (2015)
  • S. Shanbhag et al.

    Paroxysmal cold hemoglobinuria

    Hematol. Oncol. Clin. North Am.

    (2015)
  • D. Wouters et al.

    C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia

    Blood

    (2013)
  • D. Ricklin et al.

    Complement: a key system for immune surveillance and homeostasis

    Nat. Immunol.

    (2010)
  • D. Ricklin et al.

    Complement in immune and inflammatory disorders: pathophysiological mechanisms

    J. Immunol.

    (2013)
  • V.M. Holers

    The spectrum of complement alternative pathway-mediated diseases

    Immunol. Rev.

    (2008)
  • R.P. Rother et al.

    Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria

    Nat. Biotechnol.

    (2007)
  • A.M. Risitano

    Paroxysmal nocturnal hemoglobinuria

  • L. Luzzatto et al.

    Paroxysmal nocturnal hemoglobinuria

  • C.J. Parker et al.

    Paroxysmal nocturnal hemoglobinuria

  • T. Miyata et al.

    The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis

    Science

    (1993)
  • A. Nicholson-Weller et al.

    Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system

    J. Immunol.

    (1982)
  • A. Nicholson-Weller

    Decay accelerating factor (CD55)

    Curr. Top. Microbiol. Immunol.

    (1992)
  • M.H. Holguin et al.

    Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria

    J. Clin. Invest.

    (1989)
  • Cited by (0)

    View full text