Cambridge Healthtech Instituteの第25回年次
Display of Biologics
Scientific Advisory Board
Andrew R.M. Bradbury, MB BS, PhD, CSO, Specifica, Inc.
Jennifer R. Cochran, PhD, Shriram Chair of Bioengineering; Professor of Bioengineering, and (by courtesy) Chemical Engineering,
Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Whiting School of
Engineering, Johns Hopkins University
E. Sally Ward, PhD, Director, Translational Immunology; Professor, Molecular Immunology, Centre for Cancer Immunology,
University of Southampton
Gregory A. Weiss, PhD, Professor, Chemistry, Pharmaceutical Sciences, Molecular Biology & Biochemistry, University of California,
K. Dane Wittrup, PhD, J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
- 5:00 pm Main Conference Registration1:00 pm
Recommended Pre-Conference Short Course2:00 pm
SC4: An Introduction to Protein Degraders: A Focus on PROTACs
*Separate registration required. See short courses page for details.
Registration and Morning Coffee7:00 am
CHALLENGES OF COMPUTATIONAL ANTIBODY DESIGN
Opportunities & Challenges in Computational Antibody Design
Despite decades of research, the ability to generate effective antibodies completely on the computer is elusive, and antibody discovery and optimization continue to rely on iterative and time-consuming high-throughput screening. I will review the prerequisites for effective and universally applicable antibody design methods, the opportunities in developing methods for computational antibody optimization, and the underlying factors that explain why completely computational antibody design remains challenging.
Computational Design or in vitro Evolution…Better Together
Computational protein design has become a key tool in protein engineering. It is however clear that often computationally designed proteins are often suboptimal and require further optimization. Frequently, such optimization is performed by in vitro evolution techniques which are equally powerful and have been transformative in protein engineering. During my talk, I will discuss the strengths and weaknesses of each approach and their synergistic usage to solve hard problems in protein engineering that become accessible by the use of hybrid approaches. Lastly, I will discuss some of the potential applications of ML-driven approaches to enable both computational design and in vitro evolution.
AbCheck has developed a number of technologies for efficiently discovering high-quality MAbs for next-generation protein therapeutics. Our drug discovery platform offers modular solutions to overcome target-specific challenges and improve success rates for drug discovery campaigns. Our proprietary microfluidics approach enables direct one-step sorting for function and/or other critical criteria with high throughput of millions of droplets per day for the discovery of antibodies to both known and emerging functional targets.
Networking Coffee Break10:00 am
EMERGING PLATFORMS FOR PROTEIN DISCOVERY AND ENGINEERING
Isolation of Binding Proteins Using Magnetized Yeast Cell Targets
The isolation of binding proteins from combinatorial libraries has typically relied on the use of a soluble, recombinantly expressed form of the target protein when performing magnetic selections or fluorescence-activated cell sorting. Appropriate target protein expression and subsequent purification represents a significant bottleneck in this process. As an alternative, the use of target proteins expressed on the surface of magnetized yeast cells in combinatorial library screening is discussed.
Systems Biologics: Large-Scale Engineering of Modulators of Protein Networks
We have developed an approach that we call “systems biologics”, which combines large-scale systems biology with the development of new antibody drugs. The efficient pipeline extends from basic research through translational science, and it constitutes a new model for research and drug development. Through this model, cutting-edge systems biology basic research can be seamlessly translated into systems biologics: novel, multi-functional drugs, and diagnostics that take advantage of the complexities of human biology revealed by genomics data.
Single-domain antibodies (sdAbs) are desirable targeting arms in cell therapies and multispecifics due to their small size, modularity, and favorable binding properties, without needing VH/VL pairing. In this presentation, we will present the key features of a human sdAb discovery platform utilizing semi-synthetic VH libraries and in vitro display, augmented by bioinformatics, as well as case studies that showcase the successful discovery of sdAbs for potential therapeutic applications.
DESIGNING BIOLOGICS FOR NON-ONCOLOGY APPLICATIONS
Using Yeast Display for Non-Oncology Applications
The growing need for antibodies with customized specificity provides a rich environment for engineering efforts. By leveraging the unique properties of neural networks, we developed a generative model for immunoglobulin 3D structures, with which diverse structures can be modeled with unprecedented speed. This "Generative Design" strategy explores dynamic structures and our preliminary experimental results on multiple targets support the plausibility of in silico design of epitope-specific antibodies.
Designing Ultrapotent DARPins for Rapid Allergic Desensitization
Using yeast display and structure-based engineering, we have generated potent IgE inhibitors built from designed ankyrin repeat proteins (DARPins). These fast-acting inhibitors employ multiple distinct anti-IgE domains to disrupt highly stable IgE receptor complexes at low nanomolar potencies. This dynamic mechanism of action desensitizes allergic effector cells in minutes by stripping allergen-reactive IgE from the high affinity IgE receptor and enables new therapeutic avenues for the anti-IgE inhibitor class.
Session Break1:35 pm
Phage-Displayed Noncanonical Amino Acids for Drug Discovery
Using the amber suppression-based noncanonical amino acid mutagenesis technique, we showed that a number of noncanonical amino acids with unique chemical functionalities can be genetically encoded in phage-displayed peptides. These unique chemical functionalities allowed simultaneous cyclization with a nearby cysteine for the generation of phage-displayed cyclic peptide libraries and directly targeting the active sites of therapeutic targets for improved and accelerated drug discovery. Successful demonstrations have been done with therapeutic targets including SIRT1, HDAC8, ENL, and BRD9.
Reversible Covalent Ligand Discovery via Chemically Enhanced Phage-Display
Chemoselective and site-selective modification of phage coat proteins allows facile incorporation of designer functional groups into phage-displayed peptide libraries, thereby extending the power of phage display to cover non-natural peptide libraries. This presentation will discuss our work on the development and evaluation of phage libraries that carry a reversible covalent warhead, which can greatly enhance a peptide's binding to its target protein.
- Design and properties of lysine-targeting warheads
- Phage-displayed libraries of novel macrocyclic peptides
- Covalent "binding" peptide macrocycle as inhibitors for difficult-to-target proteins
The Pioneer Library is one of the largest functional phage display Fab libraries ever made and it takes advantage of a novel selection system termed SpyDisplay. With its more than 200 billion different antibodies, this new library enables Bio-Rad to rapidly generate high affinity human antibodies for therapeutic development. Example data for anti-TIGIT antibodies will be shown.
Networking Refreshment Break3:20 pm
Transition to Plenary Keynote Session3:50 pm
PLENARY KEYNOTE SESSION
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
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
PEGS BOSTON COMMON: YOUNG SCIENTIST MEET UP
Young Scientist Meet Up - IN-PERSON ONLY
The young scientist meet up is an opportunity for scientists entering the field to develop connections across institutions, and for established leaders to come build relationships with the next generation of scientists. The meet-up will pave the way for mentorships, professional opportunities, and scientific discovery.
- Get to know fellow peers and colleagues
- Make connections and network with other institutions
- Inspire others and be inspired!
Close of Day7:00 pm
Registration and Morning Coffee8:00 am
Pirating Biology to Degrade Extracellular Proteins
In contrast to intracellular PROTACs, approaches to degrade extracellular proteins are just emerging. I’ll describe our recent progress to harness natural mechanisms such as transmembrane E3 ligases and chemokine receptors to degrade extracellular proteins using fully genetically encoded bi-specific antibodies we call AbTACs and KineTACs, respectively.
Biodegrader Optimization and Design Principles
bioPROTACs are expressable protein-based degraders that redirect ubiquitination to a target of interest. The design rules for such agents have yet to be fully worked out - what binder properties (affinity, epitope, stability) are critical, what linker properties (rigidity, length) are best, and which E3 ligase adaptors drive the greatest degree of target degradation? And in lieu of hard rules, what is the most efficient strategy for bespoke bioPROTAC optimization?
Proteome-Scale Degrader Screens
An unbiased discovery of proximity-dependent degraders and stabilizers will be reviewed and characterization of unexpected protein degraders and stabilizers will be discussed. The functional assessment of 300 E3 ligases and 50 DUBs for proximity-dependent degradation and stabilization will be covered and discovery of highly potent and broadly active E3 ligases for targeted protein degradation will be reviewed.
Coffee Break in the Exhibit Hall with Poster Viewing10:30 am
Targeting Tumors with Bicycle Conjugates
Bicycle Therapeutics is developing a unique class of chemically synthesized medicines based on its proprietary bicycle peptide (Bicycle) phage display platform. These bicyclic peptides, or Bicycles, are a class of highly constrained peptides characterized by the formation of two loops when the linear peptide is cyclized around a trivalent scaffold. Bicycles have broad utility and may confer several advantages over existing modalities - namely their small size, modularity for conjugation, and favorable pharmacokinetics. Bicycles are currently being explored in the clinic as Bicycle toxin conjugates (BTCs) for targeted delivery of cytotoxic payloads into tumors, and Bicycle tumor-targeted immune cell agonists (Bicycle TICAs). In the talk, I will share our research progress in the development of Bicycle conjugates.
Therapeutic Applications Based on the DARPin Platform - From Small Size Single Domain to Hexavalent and Multi-Specific Binding Molecules
The DARPin technology enables the exploration of new therapeutic designs on multiple disease pathways. Based on DARPin properties (small size, high affinity, excellent stability), we can generate single-domain DARPin agents for fast-in/fast-out radio ligand therapies (RLT) with high tumor accumulation - OR - generate multi-specific DARPin therapeutics such as MP0533, a half-life extended CD3-based T cell engager targeting simultaneously CD33, CD123, and CD70 to selectively target malignant AML cancer cells.
Merck Synthetic Single-Domain Antibody Libraries and the Phage-to-Yeast Workflow for Rapid VHH Discovery and Affinity Maturation
Single-domain antibody fragments known as VHH have emerged in the pharmaceutical industry as useful biotherapeutics. Here we describe the development of synthetic VHH libraries and a phage-to-yeast affinity maturation workflow for rapid in vitro selection of high affinity single domain binders. The phage VHH libraries have 10^11 unique CDRH3 diversity. After 2 rounds of phage panning, the yeast display libraries are then built to introduce additional CDRH1 and CDRH2 diversity. High affinity VHH binders are selected from yeast libraries. We show this platform is able to generate high affinity and potent antibodies with broad sequence diversity and epitope coverage.
Twist Biopharma, a division of Twist Bioscience, combines HT DNA synthesis technology with expertise in antibody engineering to provide antibody discovery solutions - from gene synthesis to antibody optimization. The result is a make-test cycle that yields better antibodies against challenging targets from immunization, libraries, and machine learning. We will continue to expand discovery, library synthesis and screening capabilities with others to further utilize their make-test cycle.
The Specifica Generation-3 Library Platform is based on highly developable clinical scaffolds, into which natural CDRs purged of sequence liabilities are embedded. The platform directly yields highly diverse, high affinity, developable, drug-like antibodies, as potent as those from immune sources, with minimal need for downstream optimization. This talk will discuss extension of the Platform to VHH libraries and lead antibody improvement, with simultaneous enhancement of both affinity and developability.
Close of Display of Biologics Conference1:40 pm
Recommended Dinner Short Course6:30 pm
SC6: Developability of Bispecific Antibodies
*Separate registration required. See short courses page for details.