John D. Lambris

John D. Lambris is a Greek-American biochemist and an academic. He is a professor in the Department of Pathology and Laboratory Medicine as well as Dr. Ralph and Sallie Weaver Professor of Research Medicine at the University of Pennsylvania.

Lambris' research encompasses complement structure, function, evolution and biology, with a focus on identifying roles of complement in immunity and disease. He has contributed to complement drug discovery by developing therapies that target unwanted complement activation in diseases. His lab has discovered a new class of peptide-based drugs, termed compstatins, and findings in the therapeutic modulation of complement, which validated C3 as a therapeutic target and supported the clinical approval of the first compstatin-based C3 inhibitors for various conditions. He has been included in the list of highly cited researchers identified by Clarivate/ISI. His works have been published in academic journals, including Nature Immunology and Nature Medicine. He has also edited publications, including books such as Structural Biology of the Complement System and Current Topics in Complement II.

Education Lambris completed his Bachelor of Science in Biology from the University of Patras in 1976. Later in 1979, he obtained a Ph.D. in Biochemistry from the same institution.

Lambris holds patents on complement inhibitors for therapeutic applications. His inventions include the first C3-targeted cyclic peptide inhibitor. This class comprises third and fourth generation compstatin derivatives with enhanced pharmacokinetic profiles and pharmacologic activities (including compounds like AMY-101 and AMY-106).

Research Lambris' research has focused on drug discovery and complement biology. Using complement as a model system, his group applied concepts to study the evolutionary history, structure, and functions of the complement system in both disease and health. His research group was among the first in exploring the roles of the third complement component (C3), providing insights into its activation and regulatory mechanisms. They identified key interactions between C3 and various natural ligands, viral immune evasion proteins, regulatory molecules and complement receptors. His approach led to the development of complement-targeted immunotherapies focused on C3. This included the discovery of Compstatin, the first small-molecule inhibitor of C3, and the subsequent refinement of this inhibitor family through structure-based design. These efforts resulted in the creation of therapies, such as Empaveli and Syfovre, used to treat paroxysmal nocturnal hemoglobinuria (PNH), and geographic atrophy. Additionally, his 1988 publication, co-authored with Y. Frei and B. Stockinger, detailed the creation of the first monoclonal antibody targeting C5.

Lambris' lab has also made contributions to innate immunology by questioning established paradigms and researching the role of the complement system in tissue homeostasis, innate immunity, and inflammation. The lab's research has identified functions of complement-modulated pathways in tissue regeneration and revealed tumor-promoting activities of complement, which present potential therapeutic targets for enhancing cancer immunotherapy. The lab has uncovered complement-mediated networks that influence synaptic plasticity during brain development and drive neuroinflammatory responses linked to cognitive decline in neurodegenerative diseases.

In collaboration with George Hajishengallis and other researchers, Lambris' lab also demonstrated the role of complement in driving dysbiosis of the oral microbiota, leading to periodontal inflammation and bone loss. These findings supported the development of C3 inhibition as a promising host-targeted therapy for periodontal disease, culminating in the Phase II trial of the compstatin-based inhibitor AMY-101 for treating periodontal inflammation.

Through a partnership with the Department of Medicine at Democritus University of Thrace, Lambris' lab was the first to demonstrate that complement activation induces thrombogenic responses in neutrophils, promoting tissue factor expression and the release of neutrophil extracellular traps (NETs). This work was extended to studies on severe COVID-19, where the lab and its collaborators showed that C3 activation amplifies interactions between platelets and neutrophils, driving TF-enriched NET release and immunothrombosis associated with the disease. These findings led to Phase II trial of the C3 inhibitor AMY-101 in severe COVID-19 patients.

Additionally, Lambris has advanced the understanding of the evolutionary biology of the complement system by discovering multiple isoforms of complement proteins in teleost fish. These findings highlight how these species compensate for their relatively limited adaptive immune systems by enhancing the capabilities of their innate immune recognition.

Awards and honors 1991 – M.S. (Honorary), University of Pennsylvania 2006 – Honorary Doctorate, Linnaeus University 2013 – Honorary Doctorate, Uppsala University 2012 – Hans Kupczyk Guest Professor, University of Ulm, Germany 2015 – Class of Sciences Awards, Academy of Athens 2023 – Honorary professor, Democritus University of Thrace