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