John D. Lambris

faculty photo
Dr. Ralph and Sallie Weaver Professor of Research Medicine
Department: Pathology and Laboratory Medicine

Contact information
401 Stellar-Chance Laboratories
422 Curie Blvd.
Philadelphia, PA 19104
Office: (215) 746-5765
Fax: (215) 573-8738
Education:
B.S. (Biology)
University of Patras, Greece, 1976.
Ph.D. (Biochemistry)
University of Patras, Greece, 1979.
Permanent link
 
> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

Research Interests

Complement, Inflammation, Cancer, Systems Biology, Therapeutics, Peptides, Innate Immunity, liver regeneration, sepsis

Research Summary

Using complement as a model system we apply ideas and methods embodied in engineering, computer science, physics, chemistry, and other fields to address today’s challenges in biomedical research.

The complement system has been long appreciated as a major effector arm of the innate immune response. It consists of a complex group of serum proteins and glycoproteins and soluble or membrane-bound receptors, which play an important role in host defense against infection. Complement, a phylogenetically conserved arm of innate immunity, functions together with the adaptive immune response by serving as an important inflammatory mediator of antigen-antibody interactions. It also provides an interface between the innate and adaptive immune response by contributing to the enhancement of the humoral response mounted against specific antigens. 

In an era that nurtures the integrated study of biological systems as the prevalent concept in contemporary scientific thinking, complement research is being revisited and our current knowledge of this innate immune system is enriched by findings that point to novel functions that do not strictly correlate with immunological defense and surveillance, immune modulation or inflammation.

Departing from traditional hallmarks of molecular biology such as the genome and the transcriptome and beginning to appreciate more the “proteome” as the dynamic expression profile and unique ‘fingerprint’ of all organisms, novel associations between biochemical pathways and apparently unrelated biological processes are constantly revealed. In this respect, recent evidence produced by our laboratory (and others) suggests that complement components can modulate diverse biological processes by closely interacting with other intra- and intercellular networks.

Furthermore, the structure and functions of several complement proteins as well as the protein-protein interactions that underlie these functions are now being investigated with the aid of cross-disciplinary approaches ranging from mathematics and biophysics to comparative phylogenesis, in silico studies, mimetics and proteomics. Our laboratory, extending its research beyond the scope of traditional complement pathobiology, has embraced this global and combinatorial approach to biomedical research and has been actively engaged in defining the function of complement proteins in several biological contexts and pathophysiological states.

Our current research efforts focus on the structural-functional aspects of protein-protein interactions and the rational design of small-size complement inhibitors. We also study the viral molecular mimicry and immune evasion strategies, as well as the evolution of complement biology. In addition we study the involvement of various complement components with developmental pathways and the role of complement in tissue regeneration, early hematopoietic development and cancer.

Our laboratory invented the use of complement inhibitors for therapeutic purposes; I am the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogues such as AMY‑101) for clinical applications. Our laboratory also invented the compstatin technology licensed to Apellis Pharmaceuticals (4(1MeW)7W (also known as POT‑4 and APL‑1) and pegylated derivatives such as APL-9 and APL-2/Pegcetatoplan/Empaveli/Aspavelli/Syfovre which has been approved by FDA for paroxysmal nocturnal hemoglobinuria (PNH) and as the first treatment for Geographic Atrophy — an advanced stage of age-related macular degeneration that is a leading cause of blindness.

For updated information please visit WWW.LAMBRIS.COM

Description of Itmat Expertise

Our laboratory is widely recognized as one of the leading laboratories and pioneers in the field of complement biology and drug discovery. Using complement as a model system, our group applies concepts and methods embodied in bioengineering, computer science, physics, chemistry, biomedicine, and other fields to study the structure, evolutionary history and functions of the complement system in both health and disease.

Our laboratory was among the first to unravel the diverse functions of the third complement component (C3) and to define the complex binding dynamics that underlie its activation and regulation, dissecting key interactions with various natural C3 ligands, viral immune evasion proteins, complement receptors, and regulators. Our crossdisciplinary research spearheaded the development of complement-based immunotherapies targeting the central protein C3 through the discovery of the first small-sized complement C3 inhibitor, termed Compstatin, and the structure-guided refinement and expansion of this family of C3 inhibitory peptides which now includes the first clinically approved compstatin-based therapeutics, Empaveli and Syfovre, for the treatment of the rare hematological disorder PNH and the ocular inflammatory disease geographic atrophy (advanced stage of dry AMD) respectively. The C3-targeted inhibitors developed by our group have exhibited consistent therapeutic efficacy in proof-of-concept studies in various disease models and clinical trials in a range of clinical indications. Dr. Lambris publication in 1988 (in collaboration with Y. Frei and B. Stockinger) on the generation of the first monoclonal antibody to C5 spearheaded the development of therapeutic anti C5 antibodies such as eculizumab (Soliris).

Our lab has also made fundamental discoveries that shifted long-held paradigms in innate immunology reshaping our perception of the role of complement in innate immunity, tissue homeostasis and inflammation. Our research has established new and unconventional functions of complement-modulated pathways in tissue regeneration and revealed tumor-promoting activities of complement that can be targeted to enhance cancer immunotherapy. Our research has also contributed to uncovering complement-mediated networks that modulate synaptic plasticity in the developing brain and mediate early neuroinflammatory responses that drive cognitive impairment in neurodegenerative diseases. Together with Dr. George Hajishengallis and other collaborators, our lab has shown the crucial role of complement in promoting dysbiotic changes in the oral microbiota that drive periodontal inflammation and bone loss and has validated C3 inhibition as a promising host modulation therapy for treating periodontal disease. This research has led to the first successful Phase II trial of the compstatin-based inhibitor AMY-101 in patients with periodontal inflammation; coordinated by Dr. Hasturk at Forsyth Institute and sponsored by Amyndas Pharmaceuticlas. In a longstanding collaboration with the Department of Medicine, Democritus University of Thrace, our lab and our collaborators were the first to show that complement activation drives thrombogenic responses in neutrophils promoting Tissue Factor expression and NET release. These fundamental discoveries were recently extended to studies in patients with severe COVID-19, where we revealed that C3 activation potentiates reciprocal platelet and neutrophil interactions that fuel TF-enriched NET release and COVID-19-associated immunothrombosis. These mechanistic and translational studies formed the basis for the conduct of a multi-center Phase II trial of the complement C3 inhibitor AMY-101 in patients with severe COVID-19, which was coordinated by clinical investigators from the Department of Medicine, Democritus University of Thrace and sponsored by Amyndas Pharmaceuticlas.

Our laboratory has also made fundamental contributions to the evolutionary biology of complement by identifying multiple complement protein isoforms in teleost fish that expand the innate recognition capability of these species in lieu of an underdeveloped adaptive immune compartment.

Dr. Lambris has published 529 papers in peer-reviewed journals (google scholar H index >135, citations >66,626) and is the editor of several books and special journal issues. In recognition of the broad impact of his research on multiple disciplines he has been named from 2018-2023 on the Clarivate Highly Cited Researchers List. He has served as the first elected President of the International Complement Society. He is the inventor of patents and/or patent applications that describe the use of complement inhibitors for therapeutic purposes; the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogues such as AMY 101) for clinical applications, and the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (4(1MeW)7W (also known as POT 4 and APL 1) and pegylated derivatives such as APL-9 and APL-2/Pegcetatoplan/Empaveli/Aspavelli/Syfovre) the later of which has been approved for clinical use for PNH and Geographic Atrophy.

Selected Publications

Mastellos DC, Hajishengallis G, Lambris JD.: A guide to complement biology, pathology and therapeutic opportunity. Nat Rev Immunol Sep 2023.

Li X, Wang H, Schmidt CQ, Ferreira VP, Yancopoulou D, Mastellos DC, Lambris JD, Hajishengallis G.: The Complement-Targeted Inhibitor Mini-FH Protects against Experimental Periodontitis via Both C3-Dependent and C3-Independent Mechanisms. J Immunol 211: 453-461, Aug 2023.

Gerogianni A, Bal M, Mohlin C, Woodruff TM, Lambris JD, Mollnes TE, Sjöström DJ, Nilsson PH.: In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model. Front Immunol 14: 1101387, Apr 2023.

Kuhn A, Riegger J, Teixeira GQ, Huber-Lang M, Lambris JD, Neidlinger-Wilke C, Brenner RE.: Terminal Complement Activation Is Induced by Factors Released from Endplate Tissue of Disc Degeneration Patients and Stimulates Expression of Catabolic Enzymes in Annulus Fibrosus Cells. Cells 12: 887, Mar 2023.

Bechtler C, Koutsogiannaki S, Umnyakova E, Hamid A, Gautam A, Sarigiannis Y, Pouw RB, Lamers C, Rabbani S, Schmidt CQ, Lambris JD, Ricklin D.: Complement-regulatory biomaterial coatings: Activity and selectivity profile of the factor H-binding peptide 5C6. Acta Biomater 155: 123-138, Jan 2023.

Lamers C, Ricklin D, Lambris JD.: Complement-targeted therapeutics: An emerging field enabled by academic drug discovery. Am J Hematol 2023.

Wang H, Ideguchi H, Kajikawa T, Mastellos DC, Lambris JD, Hajishengallis G.: Complement Is Required for Microbe-Driven Induction of Th17 and Periodontitis. J Immunol 209: 1370-1378, Oct 2022.

Lamers C, Xue X, Smieško M, van Son H, Wagner B, Berger N, Sfyroera G, Gros P, Lambris JD, Ricklin D.: Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors. Nat Commun 13: 5519, Sep 2022.

Skendros P, Germanidis G, Mastellos DC, Antoniadou C, Gavriilidis E, Kalopitas G, Samakidou A, Liontos A, Chrysanthopoulou A, Ntinopoulou M, Kogias D, Karanika I, Smyrlis A, Cepaityte D, Fotiadou I, Zioga N, Mitroulis I, Gatselis NK, Papagoras C, Metallidis S, Milionis H, Dalekos GN, Willems L, Persson B, Manivel VA, Nilsson B, Connolly ES, Iacobelli S, Papadopoulos V, Calado RT, Huber-Lang M, Risitano AM, Yancopoulou D, Ritis K, Lambris JD.: Complement C3 inhibition in severe COVID-19 using compstatin AMY-101. Sci Adv 8: eabo2341, Aug 2022.

Mastellos DC, Lambris JD.: Recent developments in C3-targeted complement therapeutics. Semin Immunol Jul 2022.

back to top
Last updated: 11/19/2023
The Trustees of the University of Pennsylvania