Académie royale de Médecine de Belgique

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Résumé de John D. Lambris


THE COMPLEMENT SYSTEM AT THE FOREFRONT OF NOVEL IMMUNOTHERAPIES    

par John D. LAMBRIS (University of Pennsylvannie – USA), invité.

The complement system is an evolutionarily conserved arm of the innate immune response with key roles in pathogen elimination, tissue homeostasis and immunosurveillance. Our work has helped illuminate many aspects of complement’s evolution and at the same time has laid the foundation for understanding the broad landscape of interactions forged between key complement components and other inflammatory and immunomodulatory pathways in health and disease. Over the years we have leveraged this knowledge for the rational, structure-guided design of novel complement therapeutics that can broadly inhibit complement activation in a wide spectrum of clinical indications. Along this frame we have developed and characterized the first series of potent peptidic C3 inhibitors of the compstatin family. These inhibitors have been extensively tested in preclinical NHP models of disease, revealing new pathologies that can benefit from complement modulation at the level of C3. Applying C3 inhibition we have revealed previously elusive pathogenic roles of complement in diverse pathologies ranging from cancer and transplantation to hematological, renal and ocular inflammatory diseases. Our compstatin-based C3 inhibitors have advanced through clinical development and are currently evaluated in Phase II/III studies for different indications. Of note, clinical experience from ongoing trials with C3 inhibitors has largely dismissed hypothetical assertions about the safety of clinical C3 intervention. I discuss key therapeutic concepts in the complement field with an emphasis on the current state of play of C3 therapeutics in the clinical stage. I will emphasize on target and disease selection, and the potential benefits or disadvantages of targeting different components of the cascade. Undoubtedly, complement drug discovery has gained a lot of traction in the past few years, and the sheer number of clinical-stage complement therapeutics is a testament to this increasing interest. A critical yet fair and evidence-based appraisal of these novel immunotherapies is essential for the benefit of the entire field.