Cambridge Healthtech Instituteの第4回年次
Emerging Indications for Therapeutic Antibodies
(抗体医薬の新規適応症)
非がん療法の新たなターゲット、経路、および戦略
2023年5月15〜16日 EDT(東部夏時間)
5月14日(日)
- 5:00 pm Main Conference Registration1:00 pm
Recommended Pre-Conference Short Course2:00 pm
SC1: Antibody Drug Discovery: From Target to Lead
*Separate registration required. See short courses page for details.
Monday, May 15
Registration and Morning Coffee7:00 am
AUTOIMMUNITY AND INFLAMMATION
自己免疫と炎症
Optimizing C7 Antibodies for High Affinity, Developability, and Functionality for Treatment of Myasthenia Gravis
Ruud M. De Wildt, PhD, Senior Director & Head of Antibody Lead Discovery, GlaxoSmithKline
Engineering and selecting an antibody for high affinity and potency can sometimes come at the expense of a desirable developability profile. In this presentation, we will describe complementary methods to improve affinity and developability whilst maintaining function in a panel of C7 antibodies. We identified antibodies that had desired human, cynomolgus monkey, and/or rat cross-reactive profiles and each had a distinct, novel mechanism of C7 inhibition. The lead antibody was effective in preventing experimental Myasthenia Gravis in rats in both prophylactic and therapeutic dosing regimens, and this provides therapeutic options for treatment of MG patients.
Antibody-Based Inhibition of Proteases to Target Inflammatory Diseases
James T. Koerber, PhD, Distinguished Scientist and Group Leader, Antibody Engineering, Genentech, Inc.
Proteases play an essential role in maintaining tissue homeostasis and aberrant activation leads to cancer or inflammatory diseases. The development of selective and potent protease inhibitory antibodies offers tremendous therapeutic potential. I will outline two case studies where we develop inhibitory antibodies with picomolar affinities and new modes of action. We leverage these antibodies to reveal the role of proteases as primary drivers of inflammatory disease in several mouse models.
Sponsored Presentation (Opportunity Available)9:30 am
Networking Coffee Break10:00 am
Engineering Non-competitive Inhibitors of the TNF Receptor Family with Synthetic Protein Scaffolds
Benjamin J. Hackel, PhD, Professor, Chemical Engineering & Materials Science, University of Minnesota
Aberrant signaling of the tumor necrosis factor receptor family has significant detrimental effects in multiple disease states. Ligand competition impacts multiple pathways, causing an array of side effects, and is challenged by native potency and high local concentrations. Synthetic scaffolds were engineered to bind receptors (separately TNFR1 and DR5) and inhibit signaling and downstream processes without competing for native ligand binding. Mechanistic impacts of receptor conformation were evaluated.
The State of the Science in Disease Modeling across Diverse Indications
Alex Zhavoronkov, PhD, Founder & CEO, Insilico Medicine
In this talk, we will present the combinations of several AI approaches for target discovery, protein structure prediction using AlphaFold, and generative chemistry for rapid design of novel drugs. We will present the case of hit identification for CDK20 with no experimentally-derived crystal structure.
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:30 am
INTERACTIVE DISCUSSIONS
インタラクティブディスカッション
Interactive Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the Interactive Discussions page on the conference website for a complete listing of topics and descriptions.
INTERACTIVE DISCUSSION: Future Directions in Antibody Development
Ahuva Nissim, PhD, Professor, Antibody and Therapeutic Engineering, William Harvey Research Institute, Queen Mary University of London
- How can we address the challenges of difficult targets?
- Can we still improve the next generation of repertoires?
- What are the Impacts of machine learning and bioinformatics?
- What is the niche for academic vs. industry research?
INTERACTIVE DISCUSSION: Antibodies vs Small Molecules: Can Artificial Intelligence Help with Target Annotation and Commercial Tractability Analysis?
Session Break1:30 pm
NEUROLOGY INDICATIONS
神経学的適応症
Development of ARGX-119, an Agonistic Antibody Targeting MuSK
Karen Silence, PhD, Head, Preclinical Product Development, ArGEN-X
ARGX-119 is an agonistic anti- muscle-specific kinase (MuSK) antibody, derived from the SIMPLE antibody platform, with broad potential in neuromuscular diseases. Congenital myasthenia (CM) is a devastating neuromuscular disease and mutations in DOK7 are a major cause of CM. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in mouse model for DOK7 CM.
Strategies for Selective Targeting of Metalloproteinases Responsible in Neurodegenerative Diseases
Maryam Raeeszadeh-Sarmazdeh, PhD, Assistant Professor, Graduate Program Director, Chemical and Materials Engineering, University of Nevada
There is a significant need for targeting new pathological proteins to develop novel therapies for neurodegenerative diseases. Metalloproteinases (MPs) play key physiological and pathological roles in the central nervous system by regulating signaling pathways during neuroinflammation, blood-brain barrier disruption, or synaptic dysfunction which makes them great targets for developing therapeutics for neurodegenerative diseases. Due to multifaceted role of MPs in cellular function, it is desired to use protein engineering and design approaches to generate MP inhibitors that inhibit specific MPs upregulated in the brain tissue and other related tissues of AD patients.
Sponsored Presentation (Opportunity Available)2:50 pm
Networking Refreshment Break3:20 pm
Transition to Plenary Keynote Session3:50 pm
PLENARY KEYNOTE SESSION
プレナリーセッション・基調講演
Advances in CAR T Therapy
Carl H. June, MD, Richard W. Vague Professor in Immunotherapy; Professor of Medicine; Director, Center for Cellular Immunotherapies; Director, Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine
Advances in the understanding of basic immunology have ushered in two major approaches for cancer therapy over the past 10 years. The first is checkpoint therapy to augment the function of the natural immune system. The second uses the emerging discipline of synthetic biology and the tools of molecular biology and genome engineering to create new forms of engineered cells with enhanced functionalities. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Barriers to therapy of solid tumors will be discussed.
The Next Frontier in Machine Learning and Biologics: "Lab in a Loop" Large Molecule Drug Discovery, From Optimization to de novo Discovery
John Marioni, PhD, Senior Vice President and Head of Computation, Research and Early Development, Genentech
A key opportunity in applying machine learning to augment biologic drug discovery and development is through constant iteration - a process we call "lab in a loop." By developing integrated methods for optimizing affinity and multiple developability parameters, as well as a close integration of antibody engineering, machine learning, and structural biology, we have the potential to more rapidly identify and test novel candidate molecules. Sophisticated machine learning frameworks allow us to integrate later stages of optimization into the earliest stages of discovery, while high-throughput experimental systems allow rapid improvement of all methods and molecules. This process starts with the integration of people and scientific culture and ends with tightly integrated computational and experimental systems.
Welcome Reception in the Exhibit Hall with Poster Viewing5:40 pm
Close of Day7:00 pm
5月16日(火)
Registration and Morning Coffee8:00 am
OTHER EMERGING INDICATIONS
その他の新たな適応症
Discovery and Characterization of a Ligand-Selective Anti-Notch2 Antibody for Muco-Obstructive Pulmonary Disorders
Adel ElSohly, PhD, Group Leader, Protein Chemistry, Genentech, Inc.
The Notch pathway is conserved in all metazoans, but safely drugging this target has remained an elusive challenge. Herein we describe the discovery and characterization of a Jag-ligand selective anti-Notch2 antibody that binds a unique epitope on Notch2. We demonstrate this selectivity via systemic administration of this antibody, which causes selective transdifferentiation of the mouse airway without causing DLL-dependent systemic phenotypes.
Autoantibody and T Cell Responses to Oxidative Post-Translationally Modified Insulin Neoantigenic Peptides in Type 1 Diabetes
Ahuva Nissim, PhD, Professor, Antibody and Therapeutic Engineering, William Harvey Research Institute, Queen Mary University of London
Antibodies specific to oxidative post-translationally modified insulin (oxPTM-INS) are present in most individuals with type 1 diabetes (T1D), even before the clinical onset. We investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in T1D. We combined size-exclusion chromatography, LC-MS/MS, ELISA, and T cells proliferation assays to identify the oxPTM-INSPs that are involved in the immunopathogenesis of T1D.
Novel Yeast Display Platform Optimizes for Multiple Characteristics in Parallel
Eric Furfine, PhD, Co-CEO & CSO, Mosaic Biosciences, Inc.
We have optimized three separate antibodies for increased potency and other beneficial characteristics. A poorly-expressed p95-binding mouse mAb was optimized for nearly an order of magnitude improvement in potency and nearly two orders of magnitude increased expression. A humanized tyrosine kinase receptor (TKR) agonistic antibody with modest cross-reactivity to the murine TKR was improved in potency by nearly two orders of magnitude against both species. Finally, a mouse mAb against an undisclosed soluble extracellular protein was humanized and optimized for potency using a designed yeast display library and by approximately two orders of magnitude but maintained the relevant selectivity.
Sponsored Presentation (Opportunity Available)10:00 am
Coffee Break in the Exhibit Hall with Poster Viewing10:30 am
Monoclonal Antibodies, Small Interfering RNAs, and Anti-Sense Oligonucleotides to Treat Hyperlipidemia
Nicholas Marston, MD, Assistant Professor, Medicine, Brigham and Women's Hospital
PCSK9 and ANGPTL3 are two targets that have FDA-approved monoclonal antibodies against them, both causing significant reductions in LDL cholesterol and triglycerides. RNA therapies, including small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), work intracellularly to inhibit protein translation. This prevents key proteins of interest, such as PCSK9, ANGPTL3, APOC3, or Lp(a), from being produced in the cell, reducing serum levels by as much as 95%.
A Novel GIPR Antagonist Antibody and GLP-1 Peptide Conjugate (AMG 133) for Treatment of Obesity
Yuan Cheng, PhD, Senior Principal Scientist, Therapeutic Discovery, Amgen, Inc.
AMG 133 is a novel gastric inhibitory polypeptide receptor (GIPR) antagonistic antibody and GLP-1 peptide conjugate that exhibited remarkable body weight loss and significant improvement of metabolic parameters in preclinical models. In human Phase 1 trial AMG 133 demonstrated weight loss and tolerability. The design, conjugation process, and preclinical activity will be discussed.
In silico Design of a Highly Protective Anti-Malarial Antibody
Reda Rawi, PhD, Staff Scientist & Co-Head, Structural Bioinformatics Core, NIH NIAID
A single administration of CIS43 can protect against malaria infection for up to 9 months. Here, we developed an in silico pipeline to improve the potency of CIS43 antibody variants by optimizing the binding energy to its target antigen PfCSP. Designed variants showed increased affinity and superior protective efficacy to an in vivo mouse challenge model. The best-designed variant, antibody P3-43, showed ~10-fold improvement in protection relative to CIS43. This novel in silico pipeline provides a generally applicable approach to improve antibody functionality and lead to novel variants to be used for passive prevention against malaria.
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:40 pm
Close of Emerging Indications for Therapeutic Antibodies Conference1:40 pm
Recommended Dinner Short Course6:30 pm
SC6: Developability of Bispecific Antibodies
*Separate registration required. See short courses page for details.
* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。
2023年 プログラム
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