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Complementing Immunity: Targeted Therapies and the Complement System Nexus

December 19, 2023
Abdul Rafae, MD, (@a_rafaemd), Samer Al Hadidi, MD, MS, (@HadidiSamer)
Myeloma Ctr, Winthrop P. Rockefeller Cancer Inst., U of Arkansas for Medical Sciences, Little Rock

The complement system plays a pivotal role in the intricate symphony of the human immune system. The dynamic orchestra of the complex network of proteins that work in a concert to protect the human body from different pathogens has now been recognized, and recent advancements have underscored the astonishing capabilities of this system. While many details of the complement system were elucidated half a century ago, the last two decades have been instrumental in recognizing the complement cascade’s vital role in shaping adaptive immunity, changing the traditional concepts of its role in innate immunity only. Notably, it was also found that the dysregulated complement system is a principal driver of many human diseases including cold agglutinin diseases, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, thrombotic microangiopathies, and others. A deeper comprehension of this intricate system has led to the development of targeted drugs for what was previously thought to be untreatable, revolutionizing the management and prognosis of these conditions. 

This year’s Presidential Symposium, chaired by Robert A. Brodsky, MD, reviewed the complement system with special focus on the canonical extracellular complement cascade, intracellular complement, and targeted complement inhibitor drugs that have changed the natural history of complement-driven diseases. Lubka T. Roumenina, PhD, from Cordeliers Research Center, Paris, discussed the canonical extracellular complement cascade and its role in the body’s innate immune defense against pathogens. Dr. Roumenina introduced the concept of “double-edged sword” functioning of the complement cascade against pathogens and accompanying host cell damage. Moreover, Dr. Roumenina reviewed the pathological aspect various complementopathies due to dysregulation of the complement system by demonstrating the mechanistic aspects of paroxysmal nocturnal hemoglobinuria (PNH) and cold agglutinin disease (CAD) for alternative and classical pathway activation, respectively. This was followed by the discussion on the intracellular component of the complement cascade by Claudia Kemper, PhD. Dr. Kemper focused on the non-canonical roles of the complement and discussed the role of intracellular complement in training adaptive immunity. Dr. Kemper also explored the role of intracellular complement activation in human diseases and its function in cell metabolism and autophagy.  

The stage was then set for Eleni Gavriilaki, MD, PhD, who covered the exciting journey of complement inhibition in the treatment of various complement-regulated diseases. Focusing primarily on PNH, Dr. Gavriilaki discussed various established as well as newer complement inhibitors that have been approved or are under development to treat PNH and other complementopathies. Complement inhibitors blocking C5, C3 and C1s and the alternate pathway, from IV infusions to subcutaneous injections and now oral inhibitors, and their advantages and disadvantages were also highlighted in Dr. Gavriilaki’s talk. Dr. Gavriilaki concluded by highlighting the involvement of complement in other complementopathies and reviewing the proper selection of patients who would benefit from complement inhibition. 

As our comprehension of the intricacies of the human immune system advances, new frontiers emerge. Dedicated researchers persist in unraveling their complexities, leading to targeted approaches in combating various pathologies. The nuanced role of the complement system in both innate and adaptive immunity has become a focal point, not only in auto-immune conditions but also in cancer treatment. The escalating interest in this system and ongoing drug development signal a promising future where its clinical applications could revolutionize the treatment of a wide array of conditions, including the range of hematologic disorders we treat on a daily basis. 

 

Drs. Rafae and Al Hadidi indicated no relevant conflicts of interest. 

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