Cambridge Healthtech Instituteの第24回年次
2023年5月16 - 17日 ALL TIMES EDT
- 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.
Dessert Break in the Exhibit Hall with Poster Viewing1:40 pm
ENGINEERING FOR IMPROVED FC FUNCTION
Engineering the Antibody Fc for Conditional Activity in the Solid Tumor Microenvironment
Antibody-based therapeutics enjoy considerable successes as cancer treatments, but can cause serious toxicities due to recognition of tumor-associated antigens in non-cancerous tissues. We will discuss recent efforts to develop advanced antibody therapeutics with Fc-mediated activities that are restricted to the acidic solid tumor microenvironment. With the intent of decreasing toxicities and expanding therapeutic windows, protein engineering strategies can render antibody activity sensitive to multiple tumor-specific characteristics.
The Role of the Fc Domain in Immunity and Disease Outcomes
The antibody Fc domain shapes protective immunity against many different viral pathogens. We will present a Systems Serology approach to define antibody Fc features associated with protection from Ebola virus and describe how we have used antibody engineering approach to validate and mechanistically dissect the role of distinct Fc-mediated functions in protection. Further, we will discuss how to translate these approaches to other pathogens, such as SARS-CoV-2.
We present a method for modeling antibodies and performing pH-dependent conformational sampling, which can enhance property calculations. Structure-based charge descriptors are evaluated for their predictive performance on recently published antibody pI, viscosity, and clearance data. From this, we devised four rules for therapeutic antibody profiling which address developability issues arising from hydrophobicity and charged-based solution behavior, PK, and the ability to enrich for those that are approved by the FDA.
Refreshment Break in the Exhibit Hall with Poster Viewing3:50 pm
Identification of Rare Binders to Challenging Targets from a Phage Display Library Using Flow Cytometry and Biolayer Interferometry
In vitro biopanning platforms have expanded the field of antibody identification beyond immunization. However, applying these strategies to identifying binders against challenging targets remains a challenge. Here, we present a new pipeline, RAPID (Rare Antibody Phage Isolation and Discrimination), for the identification of rare high-affinity antibodies against challenging targets. RAPID is enabled by fluorescent labeled phage displayed antibody libraries, and fluorescent activated sorting allows for the isolation of promising binder populations. A Biolayer Interferometry method allows for candidate clones to be discriminatorily screened. We introduce this method with a well characterized Antigen-Antibody pair, and applications of RAPID biopanning are presented.
Activating and Modulating Antibody Therapeutics for Difficult Membrane Protein Targets
Antagonist antibodies for membrane protein targets like GPCRs and ion channels are difficult to discover. Agonist and modulating antibodies are even more challenging. Here I will discuss the challenges in the field and strategies for discovering and developing antibodies that access the full spectrum of activities against membrane protein targets.
Multi-Scale Simulations Reveal Antibody Reach and Energetics of Binding
Molecular simulation techniques can help solve the inverse problem of what antibody structures give rise to an experimental observable and provide valuable insight into the biophysical origin of antibody properties. Here, we use coarse-grain and all-atom molecular dynamics to accurately model how far antibodies can reach to bind antigens at both arms and to reveal differences in how TCR-mimetic antibodies bind pMHC targets in comparison to TCRs.
Close of Day6:00 pm
Dinner Short Course Registration6:00 pm
Recommended Dinner Short Course6:30 pm
SC6: Developability of Bispecific Antibodies
*Separate registration required. See short courses page for details.
Registration and Morning Coffee7:30 am
ENGINEERING FOR TARGETED DELIVERY AND IMPROVED SPECIFICITY
Intracellular Delivery of Antibodies for Cancer Applications
A significant barrier to cancer treatment is that although small molecule drugs easily enter cells, many intracellular oncoproteins lack suitable binding pockets, and so are unresponsive to them. Antibodies can act across a broad surface, so inhibiting protein-protein interactions, but unfortunately do not naturally enter cells. We have developed multimeric, cyclised cell-penetrating peptides that transfer functional antibodies efficiently across the cell membrane, allowing the targeting of previously “undruggable” intracellular molecules.
Development of T Cell Engagers Selective for Cells Co-Expressing Two Antigens
For the development of safe and effective T Cell Engagers (TCEs) for solid tumors, it is highly desirable to expand the number of available target antigens and also to increase the precision with which a TCE can differentiate tumors from healthy tissue. I will present a strategy to reduce on-target, off-tumor TCE activity by targeting co-expression of two tumor-associated antigens and describe engineering of trispecific antibodies with this selectivity.
KEYNOTE PRESENTATION: Inhibition of Key Intracellular Targets via the Cytosolic Delivery of Antibodies and Proteins
A limitation of biologics is their inability to cross the cell membrane. Conversely, small molecules readily cross cell membranes, but many intracellular proteins lack pockets for small molecule binding. We developed a method to deliver antibodies into the cytosol, which enabled us to inhibit cancer-associated proteins. We also delivered small, protein scaffolds intracellularly for therapeutic inhibition of conventionally-undruggable targets. Major themes to be covered include: a) modification of antibodies and proteins with anionic polypeptides for complexation with cationic lipids and efficient intracellular delivery; b) photoreactive antibody binding domains for efficient, site-specific labeling of antibodies; and c) antibody/protein-mediated inhibition of "undruggable" intracellular targets.
Multi-pass integral membrane proteins compose the largest therapeutically relevant group of proteins that have so far not been effectively targeted with antibody-based molecules. Icosagen has developed a wide array of expertise and technologies in protein production, antibody development, protein engineering and analytics over the past 10 years and here we present the integration of these technologies by launching our therapeutic antibody development pipeline to specifically target those proteins.
Coffee Break in the Exhibit Hall with Poster Viewing10:30 am
Transition to Plenary Keynote Session11:10 am
PLENARY KEYNOTE SESSION
Advancing Innovative Biologics Modalities from Research to Clinical Application - Novel Platforms, Automation, and Computation
Addressing disease biology in the clinic with protein therapeutics has become increasingly complex. Turning to innovative and novel scaffolds offers opportunities to tailor therapeutics not previously possible due to advances in host cell engineering and protein design approaches. Designing and developing these modalities requires a next-generation approach as we exploit increased potential design space and also growing data sources to leverage as we invent the next wave of therapeutics.
YOUNG SCIENTIST KEYNOTE
Engineering Prime Editor Proteins for Therapeutic Applications
Precision gene editing technologies have the potential to address a wide range of genetic diseases. Prime Editing is a recently developed “search-and-replace” gene editing approach that can precisely perform a wide variety of DNA sequence edits at programmed target sites in human genomes without requiring double-strand DNA breaks or donor DNA templates. I will describe advances to prime editing technology that improve its efficiency, specificity, and capabilities for therapeutic applications.
Session Break1:00 pm
Launched only a few years ago, the Leap-In Transposase platform has rapidly become an industry standard technology for the generation of CHO cells for the manufacturing of antibodies and other biologics. This presentation will highlight achievements and case studies of the platform including high titer mAb manufacturing, rapid anti-COVID responses, and some novel, next generation, applications.
Engineered proteins, therapeutic antibodies, and mRNA vaccine candidates are constructed via gene assembly or mutagenesis and cloned into a vector for expression and scale up. R&D groups either construct sequences of shorter oligos synthesized with phosphoramadite chemistry, or order chemically synthesized fragments from third-party gene synthesis companies. Both approaches create a bottleneck and delays identifying lead candidates which diminish R&D budget for vaccine and therapeutics development. Learn how to synthesize enzymatic oligos and assemble 1-2 KB genes in a day.
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.
TABLE 1: Implementation Challenges for Machine Learning as a Tool for Antibody Discovery - IN-PERSON ONLY
- Current successes
- Experimental validation and POC
- Bottlenecks and challenges
- Needs from IT and solution providers
TABLE 2: Would Increasing In Vivo Data Generation Increase Probability of Clinical Success? - IN-PERSON ONLY
- What preclinical in vivo data are most often predictive of clinical success
- What are some ways we could increase in vivo throughput
- How can AI and machine learning be utilized in conjunction with in vivo data
- How to improve the in vitro to in vivo drug development process by supplementing with early in vivo discovery workflows
- Unbiased in vivo based therapeutic discovery and the required in vivo throughput
ACCELERATING AND OPTIMIZING PROTEIN ENGINEERING
Computational Methods to Complement, Enrich, and Accelerate Antibody Discovery Programs
In the eternal race to make better biotherapeutics faster, GSK Biopharm discovery pipelines are continuously revamped by a tight collaboration among different departments. This presentation will focus on the computational methods that help select better targets, design and enrich screening libraries, and accelerate the multiobjective optimization of lead candidates through the analysis of NGS data with developability criteria.
Multiplexed In Vivo Drug Discovery Using a Novel Protein Barcoding Technology
When engineering therapeutics, in vivo validation remains the primary bottleneck to program advancement. We invented a novel method that enables multiplexed quantification of 100s of protein therapeutics in vivo. We have leveraged our in vivo data with machine learning to perform in vivo molecule design. Further, we show that in vitro assay results are often poorly predictive of downstream in vivo results, highlighting the importance of increased in vivo throughput.
Ice Cream Break in the Exhibit Hall with Poster Viewing4:35 pm
PEGS BOSTON COMMON: SPEED NETWORKING
How Many New Contacts Can you Make? - IN-PERSON ONLY
Bring yourself, your business cards or e-cards, and be prepared to share and summarize the key elements of your research in a minute. PEGS-Boston will provide a location, timer, and fellow attendees to facilitate the introductions.
STRUCTURAL MODELING IN ANTIBODY DISCOVERY AND ENGINEERING
GYST Platform: A Computational Sherpa for Augmented Exploration of Antibody Landscapes in Discovery and Engineering
Effective navigation and distillation of large structural datasets necessitates programmatic approaches. We describe the custom structural informatics platform (GYST) we are developing and its application to study thousands of fab interfaces for opportunities to engineer novel polyvalent fab formats. This platform allows expansion to other protein families within and beyond large molecule drug discovery. We also discuss how the amassed, pre-computed annotations are suited for training deep learning models.
VHH CDR-H3 Conformation Correlates with Germline Usage: Implications for VHH Ontogeny and Engineering
VHHs or nanobodies are single antigen binding domains originating from camelid heavy-chain antibodies. Analyzing variable domain structures from llama and alpaca we found that VHHs can be classified into structural clusters based on their CDR-H3 conformation. The clusters have distinct functional properties in how they interact with the antigen. VHHs from the two clusters originate from different VH germlines, demonstrating a previously undescribed impact of germline usage on CDR3 conformation.
Modeling with Rosetta to Guide Library Design of Antibodies
Therapeutic antibodies have played a critical role in healthcare for over three decades, yet the rate of discovering novel antibodies remains outpaced by the need for treatment options. This is particularly true for challenging glycan targets such as tumor-associated carbohydrate antigens (TACAs). In this work, we use Rosetta software to optimize affinity and specificity among a large collection of natively-paired, immune-evolved antibodies.
Networking Reception in the Exhibit Hall with Poster Viewing6:40 pm
PEGS BOSTON COMMON: WOMEN IN SCIENCE MEET UP
Women In Science Meet Up - IN-PERSON ONLY
The Women in Science Meet Up celebrates women trailblazers who are setting their own course in science. We invite women and men to come celebrate the successes of these women in breaking down barriers and inspiring future generations of female leaders. Come join fellow scientists and share your personal and professional journey.
- Who or What inspires you to explore a career in science?
- What fuels your imagination and spirit when you’re faced with challenges?
- What is your proudest moment?
- What can each of us do to improve things further?
Close of Engineering Antibodies Conference7:40 pm