PEOPLE

John D. Lambris, PhD

Dr. Ralph and Sallie Weaver Professor of Research Medicine
Perelman School of Medicine at the University of Pennsylvania

Contact InformationPerelman School of Medicine at the University of Pennsylvania
Department of Pathology and Laboratory Medicine
Stellar-Chance Laboratories, Rm. 401
422 Curie Boulevard
Philadelphia, PA 19104
Tel: 215-746-5765
Fax: 215-573-8738
Email: lambris@pennmedicine.upenn.edu

Specialty Division

Cancer and Immunobiology

Research Expertise

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

Research Summary:
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.

The Lambris 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 >136, citations >67,154) 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.

For updated information about the work of Dr. Lambris, please visit his personal website at www.lambris.com

Education

BS (Biology), University of Patras, Greece, 1976
PhD (Biochemistry), University of Patras, Greece, 1979

Specialty Certification

Postgraduate Training

Awards and Honors

Scholarship from the State Scholarship Institute for progress as a student in the Department of Biology, 1973-76
Award from the Lawyer's Association of Patras as having ranked first among the three-year students of the Biological Department, 1974-75
Fellowship, National Research Foundation, Athens, Greece, 1977-78
Fellowship, Alexander von Humboldt Foundation (This fellowship was declined in favor of the EMBO long-term fellowship), 1982-83
Long-term Fellowship, European Molecular Biology Organization ALTF 121-1982, 1982-83
M.S. (Honorary), University of Pennsylvania, 1991
Honorary Doctorate, Linnaeus University, Kalmar, Sweden, 2006
Hans Kupczyk Guest Professor, University of Ulm, Ulm, Germany, 2012
Honorary Doctorate, Uppsala University, Uppsala, Sweden, 2013
Class of Sciences Awards, Academy of Athens, Athens, Greece, 2015
Inventor of the Year Award, Penn Center of Innovation, 2017
Patent Award, Penn Center of Innovation, 2018
Clarivate Highly Cited Researcher, 2018-23
Honorary Professor, Democritus University of Thrace (DUTH), Greece, 2023

Memberships and Professional Organizations

American Association of Immunologists, 1982-present
Biochemical Society (UK), 1984-90
American Association of Microbiologists, 1985
Aegean Conferencers, 1990-present
Protein Society, 1990-95
American Association for Advancement of Science, 1990
American Society for Biochemistry and Molecular Biology, 1991-95
International Society of Developmental & Comparative Immunology, 1991-95
Panepirotic Federation of America, Canada, & Australia, 1995-97
National Science Foundation, Greece, 1997-2000

Web Links


Selected Publications

A guide to complement biology, pathology and therapeutic opportunity

Mastellos DC, Hajishengallis G, Lambris JD. Nat Rev Immunol 2023 Sep 5. doi: 10.1038/s41577-023-00926-1. Epub ahead of print. PMID: 37670180.

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Complement-targeted therapeutics: An emerging field enabled by academic drug discovery

Lamers C, Ricklin D, Lambris JDAm J Hematol 98 Suppl 4:S82-S89, May 2023. doi: 10.1002/ajh.26875. PMID: 36755352.

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Complement-regulatory biomaterial coatings: Activity and selectivity profile of the factor H-binding peptide 5C6

Bechtler C, Koutsogiannaki S, Umnyakova E, Hamid A, Gautam A, Sarigiannis Y, Pouw RB, Lamers C, Rabbani S, Schmidt CQ, Lambris JD*, Ricklin D*. Acta Biomater 155:123-138, Jan 2023. doi: 10.1016/j.actbio.2022.10.055. Epub 2022 Nov 1. PMID: 36328123.  *Shared supervision.

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Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

Lamers C, Xue X, SmieŇ°ko M, van Son H, Wagner B, Berger N, Sfyroera G, Gros P, Lambris JD*, Ricklin D*. Nat Commun 13(1):5519, Sep 2022. doi: 10.1038/s41467-022-33003-7. PMID: 36127336; PMCID: PMC9488889.  *Shared supervision.

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Considering innate immune responses in SARS-CoV-2 infection and COVID-19

Diamond MS, Lambris JD, Ting JP, Tsang JS. Nat Rev Immunol 22(8):465-470, 2022 Aug. doi: 10.1038/s41577-022-00744-x. Epub 2022 Jul 4. PMID: 35788185; PMCID: PMC9252555.

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Complement C3 inhibition in severe COVID-19 using compstatin AMY-101

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 JDSci Adv 8(33):eabo2341, Aug 2022. doi: 10.1126/sciadv.abo2341. Epub 2022 Aug 17. PMID: 35977025; PMCID: PMC9385148.

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Recent developments in C3-targeted complement therapeutics

Mastellos DC, Lambris JDSemin Immunol 60:101645, Mar 2022. doi: 10.1016/j.smim.2022.101645. Epub 2022 Jul 29. PMID: 35915008.

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Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation

Hasturk H, Hajishengallis G; Forsyth Institute Center for Clinical and Translational Research staff; Lambris JD, Mastellos DC, Yancopoulou D. J Clin Invest 131(23):e152973, Dec 2021. doi: 10.1172/JCI152973. PMID: 34618684; PMCID: PMC8631591.

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Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and immunosuppression

Magrini E, Di Marco S, Mapelli SN, Perucchini C, Pasqualini F, Donato A, Guevara Lopez ML, Carriero R, Ponzetta A, Colombo P, Cananzi F, Supino D, Reis ES, Peano C, Inforzato A, Jaillon S, Doni A, Lambris JD, Mantovani A, Garlanda C. Nat Cancer 2(2):218-232, Feb 2021. doi: 10.1038/s43018-021-00173-0. Epub 2021 Feb 18. PMID: 34505065; PMCID: PMC8425276.

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Complement as a target in COVID-19?

Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, Lambris JD. Nat Rev Immunol 20(6):343-344, Jun 2020. doi: 10.1038/s41577-020-0320-7. Epub 2020 Apr 23. Erratum in: Nat Rev Immunol. 2020 Jul;20(7):448. PMID: 32327719; PMCID: PMC7187144.

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