Novel Drug Discovery: Where Are We Now?
Among the various therapeutic strategies currently under development, few have managed to garner the interest of drug developers as quickly as modulating the immune system and proteostasis. Due to the remarkable clinical response of first-generation cancer immunotherapies, and success in harnessing the proteostasis machinery of the Ubiquitin Proteasome System (UPS) for targeted protein degradation, significant efforts are currently underway to explore the wealth of possibilities targeting immune and proteostasis pathways.
Discovery on Target's 2017 Plenary Keynote Program features lectures and discussion from two renowned and distinguished scientists: Dr. Jeffrey Ravetch, who will discuss his work on the diverse downstream pro-inflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors; and Dr. Raymond Deshaies, who will show for the first time that the activity of p97/VCP·Npl4·Ufd1 is enhanced by mutations that cause multisystem proteinopathy.
Wednesday, September 27
12:20 - 2:00 pm PLENARY KEYNOTE Program
12:20 pm Event Chairperson's Opening Remarks
Kip Harry, Senior Conference Director, Cambridge Healthtech Institute
12:25 Plenary Keynote Introduction
12:40 Diversification of Antibody Effector Function
Jeffrey V. Ravetch, M.D., Ph.D., Theresa and Eugene M. Lang Professor; Head, Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University
Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector molecules to which their constant regions (Fc domains) engage. Thus, while Fab-antigen interactions are crucial to the specificity of the antibody response, there is a crucial role for the Fc domain in mediating the diverse effector properties triggered by antigen recognition, even for processes traditionally attributed solely to recognition by the Fab, such as neutralization of toxins and viruses. Specific interactions of the IgG Fc domain with distinct receptors expressed by diverse immune cell types result in the pleiotropic effector functions for IgG, including the clearance of pathogens and toxins, lysis and removal of infected or malignant cells, modulation of the innate and adaptive branches of immunity to shape an immune response, and initiation of anti-inflammatory pathways that actively suppress immunity. The Fc domain mediates these diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the distinct conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. I will discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.
1:20 Ubiquitin- and ATP-Dependent Unfoldase Activity of p97/VCP·Npl4·Ufd1 Is Enhanced by Mutations that Cause Multisystem Proteinopathy
Raymond J. Deshaies, Ph.D., Senior Vice President, Discovery Research, Amgen
p97 is a 'segregase' that plays a key role in numerous ubiquitin-dependent pathways. p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the mechanistic basis for this activity. We developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate for the first time that wild type p97 can unfold proteins and that this activity is dependent on the p97 adaptor Npl4·Ufd1, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Remarkably, p97 mutants that cause disease in humans unfold substrate faster, suggesting that excess activity may underlie pathogenesis.
2:00 Close of Plenary Keynote Program
PLENARY KEYNOTE BIOGRAPHIES
Jeffrey V. Ravetch, M.D., Ph.D.
Theresa and Eugene M. Lang Professor; Head, Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University
Jeffrey V. Ravetch, M.D., Ph.D. is currently the Theresa and Eugene Lang Professor at the Rockefeller University and Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology. Dr. Ravetch, a native of New York City, received his undergraduate training in molecular biophysics and biochemistry at Yale University, earning his BS degree in 1973, working with Donald M. Crothers on the thermodynamic and kinetic properties of synthetic oligoribonucleotides. He continued his training at the Rockefeller University - Cornell Medical School M.D./Ph.D. program, earning his doctorate in 1978 in genetics with Norton Zinder and Peter Model, investigating the genetics of viral replication and gene expression for the single-stranded DNA bacteriophage f1. In 1979, he earned his M.D. from Cornell University Medical School. He pursued postdoctoral studies at the NIH with Phil Leder where he identified and characterized the genes for human antibodies and the DNA elements involved in switch recombination. From 1982 to 1996, Dr. Ravetch was a member of the faculty of Memorial Sloan Kettering Cancer Center and Cornell Medical College. His laboratory has focused on the Fc domain of antibodies and the receptors it engages, determining the mechanisms by which this domain enables antibodies to mediate their diverse biological activities in vivo. His work established the novel structural basis for Fc domain functional diversity and the pre-eminence of FcR pathways in host defense, inflammation and tolerance, describing novel inhibitory signaling pathways to account for the paradoxical roles of antibodies as promoting and suppressing inflammation. His work has been widely extended into clinical applications for the treatment of neoplastic, inflammatory and infectious diseases.
Raymond J. Deshaies, Ph.D.
Senior Vice President, Discovery Research, Amgen
Dr. Deshaies received his Ph.D. degree in biochemistry from UC-Berkeley and was a Lucille P. Markey Postdoctoral Scholar at UCSF. His honors include the American Society for Cell Biology-Promega Early Career Life Scientist of the Year Award for 1999, appointment as a Fellow of the American Association for the Advancement of Science, election to the American Academy for Arts and Sciences (2011), and election to the National Academy of Sciences (2016). Dr. Deshaies's lab at Caltech investigates the cellular machinery that mediates protein degradation by the ubiquitin-proteasome system. In addition to his academic work, Dr. Deshaies co-founded Proteolix in 2003. Proteolix initiated development of Kyprolis (approved by FDA, July 2012) and was acquired by Onyx in 2009. In 2011, Dr. Deshaies co-founded Cleave Biosciences. Cleave initiated Phase I clinical trials in 2014 with a molecular scaffold whose development was initiated in the Deshaies laboratory.