Professor, University of Pennsylvania
There is a growing awareness that complement plays an integral role in human physiology and disease, with an expanding list of pathologies that are linked to dysregulated complement activation. It has become evident that targeted modulation of complement opens new therapeutic opportunities, and the first complement-directed drugs have been successfully introduced in the clinic. However, there are still unmet clinical needs that may be best addressed by an expansion of therapeutic inhibitors acting at distinct levels of the cascade. As the convergence point of all activation routes and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement system. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. Studies in recent years have provided insight into the mode of action and structural determinants of this inhibitor class and allowed for the design of compstatin derivatives with largely improved affinity for C3 and favorable pharmacodynamic properties. Among them, the analog Cp40 has shown particular promise and has been successfully evaluated in a variety of clinically relevant models, ranging from C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, malarial anemia, and periodontal disease to hemodialysis-induced inflammation, xenotransplantation, hemorrhagic shock, oncolytic virus therapy and wound healing. Building on these strong preclinical results, a Cp40-based drug (AMY-101, Amyndas) has meanwhile entered clinical development. These initial clinical studies have already revealed a unique pharmacokinetic behavior that is expected to facilitate long-term administration, and indicated a favorable safety profile. This presentation highlights milestones in the recent development of compstatin AMY-101, showcases data from disease-related studies, and discusses First-in-Human (FIH) safety and PK data as well as general implications on therapeutic complement inhibition at the level of C3.
John D. Lambris, received his Ph.D. in Biochemistry in 1979. He is the Dr. Ralph and Sallie Weaver Professor of Research Medicine in the Department of Pathology & Laboratory Medicine at the University of Pennsylvania, Philadelphia, PA. Using complement as a model system Dr. Lambris applies ideas and methods embodied in engineering, computer science, physics, chemistry, biomedicine, and other fields to study the structure and functions of the complement system.
Dr. Lambris' laboratory was among the first to map the critical sites on C3 responsible for its diverse functions and also to define its complex binding dynamics to various C3 natural ligands, viral proteins, complement receptors, and regulators. His laboratory contributed in the development of complement-based anti-inflammatory therapeutics through the discovery of the first small-size complement inhibitor, termed Compstatin, which has exhibited consistent efficacy for use in a series of in vivo trials and shows great promise for the use in the clinic. His subsequent efforts to develop more potent compstatin analogues have laid the development of a novel platform for peptide-based drug design, integrating both rational and in silico approaches. In as series of elegant in vivo studies the Lambris lab. established an unprecedented association of complement components with non-inflammatory pathways by demonstrating the involvement of complement in the developmental processes, including liver and limb regeneration, hematopoietic development and stem cell engraftment.
Dr. Lambris has published over 450 papers in peer-reviewed journals and is the editor of several books and special journal issues. He has delivered invited lectures and served as a session chairperson at various national and international scientific conferences, organized workshops, and group discussion sessions. Dr. Lambris is the Founder and Executive Director of Aegean Conferences, an independent, nonprofit, educational organization and of Amyndas Pharmaceuticals, a company developing complement therapeutics. He also serves as an Editorial Board Member of several peer-reviewed journals, and has served as the President of the International Complement Society.
Dr. Lambris has received more than $50 million research funding from various institutions and agencies including the National Institute of Health (NIH), National Science Foundation (NSF), American Cancer Society, and European Union.
For further information about Dr. John D. Lambris, click here to visit his personal homepage at www.lambris.com