Cambridge Healthtech Instituteの第11回年次
Advancing Bispecific Antibodies and Combination Therapy to the Clinic
Scientific Advisory Board
Frank Comer, PhD, Associate Principal Scientist, AstraZeneca
Eric Smith, PhD, Senior Director, Bispecifics, Regeneron Pharmaceuticals, Inc.
Nathan D. Trinklein, PhD, Co-Founder and President, Rondo Therapeutics
- 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
NON-T CELL ENGAGERS AND OTHER BISPECIFIC MECHANISMS
Antibody-Lectin Bispecifics for Glyco-Immune Checkpoint Blockade
PROTABs for Targeted Degradation of Transmembrane Proteins
PROteolysis TArgeteing Bispecifcs (PROTABs) are antibodies that colocalize transmembrane E3 ubiquitin ligases with target receptors to induce their ubiquitination and degradation. We will describe the discovery of PROTABs targeting ligases overexpressed in colorectal cancer and their activities in vitro and in vivo. We further demonstrate applicability of PROTABs for multiple ligases and receptors and describe protein engineering rules for maximizing the efficiency of degradation.
Microfluidic chips can be used to sort and clone CHO cells, perform miniaturized assays, and recover top performers. This automated process reduces the number of clones that must be expanded and characterized, while simultaneously increasing the likelihood of finding a cell line producing a high percentage of bispecific heterodimer. Here, I will present data demonstrating how miniaturized quality assays enable selection of top performing clones within five days of cloning.
Refreshment Break in the Exhibit Hall with Poster Viewing3:50 pm
Surrogate Cytokine Agonists (SCAs): Unlocking Natural and Novel Cytokine Signals with Nanobody-Based Therapeutics
At Synthekine, we have generated a series of functional synthetic cytokine agonists (SCAs) that mimic and modulate natural signals or create new ones. These molecules are expected to provide therapeutic immunomodulation while exhibiting antibody-like druggability.
PD1-IL2v: PD-1-Cis IL-2Rbg Agonism Yields Better T Cell Effectors from Stem-Like CD8+ T Cells
This talk will describe a new generation of PD1-cis-targeted IL-2R agonists resulting from the fusion of a high-affinity PD-1 antibody to an IL-2Rbg agonist. Such agonists maintain the advantages of IL-2Rbg-biased agonists for systemic immunotherapy, but in addition allow the expansion of a unique subset of less exhausted and more cytotoxic effector T cells when acting on antigen-experienced stem-like CD8+ T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.
Surface Proteomics for Target Discovery: Finding Target Combinations That Improve Tissue Specificity and Therapeutic Index
- Why and how multi-targeting can help
- How best to find cell surface targets
- How to combine and prioritize targets based on therapeutic goals
- Examples of multi-targeting advances
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
KEYNOTE PRESENTATION: Triggered Bispecifics
Tissue-restricted immune modulators may provide better therapeutic approaches to autoimmune disease. We are developing bispecifics consisting of a high affinity targeting domain fused to a PD-1 agonist moiety to inhibit autoreactive T cells for the treatment of skin diseases such as vitiligo and atopic dermatitis. These molecules, once bound to target cells, activate the PD-1 pathway potently inhibiting inflammatory cytokine production and cytotoxic activity. In the absence of target cell binding, they are unable to inhibit T cells. These immune-modulating bispecifics have the potential to deliver skin-restricted T cell inhibition while avoiding systemic immunosuppression.
Design Meets Biology - Engineering Immune Engagers with Potentially Improved TI
T cell engagers are highly potent anti-cancer immunotherapeutic molecules. However, on-target, off-tumor toxicity and cytokine release syndrome (CRS) limit the broad application of these drug modalities. Through several case studies, we’ll showcase the development of next generation immune engagers that can better engage and modulate T cell reactivity with the aim to decouple tumor cell killing from systemic toxicity.
Bispecific antibodies (BsABs) represent an emerging class of immunotherapy but inefficiency in the current BsAB discovery paradigm has limited their broad clinical availability. Here we report a high throughput, single-cell- and combinatorial library-based BsAB functional screening pipeline. This platform can not only significantly increase the development speed of high-quality BsAB therapeutics, but also shed light on their generalizable design principles.
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
We are presenting a showcase of discovering common light chain antibodies against a NK cell target. OmniDeep is a suite of in silico tools for antibody therapeutic discovery and optimization. Deep screening and high-throughput expression/characterization were used to seed information on top of NGS data sets. Our results demonstrate the power of this approach in corralling diverse OmniAb antibody repertoires and accelerating the development of effective therapeutics.
HCAb Harbour Mice®, the first fully human Heavy Chain only Antibody (HCAb) transgenic platform in the world, efficiently produces soluble, high affinity, and functional HCAbs with excellent physicochemical characteristics for CMC development. VHs from this platform do not have the hallmark residues present in camelid VHHs, predicting a low immunogenicity in human and evidenced by anti-CTLA4 HCAb Porustobart in phase 2 clinical trials. Fully human VH domains have great potential to generate a multitude of modalities for therapeutic and diagnostic uses.
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 5: Therapeutic Platforms for Antibody-Mediated Protein Degradation - IN-PERSON ONLY
- Review the multiple technologies have recently emerged to induce targeted degradation of cell surface or secreted proteins including LyTACs, PROTAbs/AbTACs, and KineTACs
- Discuss pros and cons of targeted degradation vs. inhibition, and where targeted degradation may be most applicable
- Compare different antibody-mediated degradation technologies and discuss where they may be optimally used
- Discuss what protein-engineering approaches might be applicable to enhance degradation efficiency
CO-STIMULATION AND COMBINATIONS
Combining Signals 1, 2, and 3 for Optimal T Cell Activation against Tumors
Xencor is developing a growing pipeline of CD3 and CD28 T cell engagers, together with several potency-optimized cytokine-Fc fusions, including IL15, IL12, and IL18. We will discuss preclinical data exploring combination of these various agents with themselves and PD1 inhibition to promote optimal T cell activation in the tumor microenvironment.
Targeted Therapies for the Enhancement of Anti-Tumor T Cell Responses
This presentation will describe key pre-clinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell targeted enhancement strategies in pre-clinical development will be discussed.
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.
T Cell Activation via Co-Stimulatory CD28 Bispecific Antibodies
Antibodies CD28 bispecific antibodies (bsAbs) were generated to co-stimulate T cells in the presence expressing a selected tumor-associated antigen (TAA) or by co-engaging PD-L1 on cancer cells or antigen-presenting cells. Using our κλ body antibody platform, CD28 bsAbs targeting multiple TAAs were designed for tumor-specific activation of the immune system. CD28-engaging κλ bodies enhance the antitumor response via stimulation of T cell proliferation and activation, increased cytokine secretion, and directed cytotoxicity. Desired characteristics of the anti-CD28 arm, approaches to drive selective co-engagement, and TAA-dependent co-stimulation versus immune checkpoint-dependent co-stimulation will be discussed.
Partners-in-Crime: Co-Stimulation via 4-1BB or CD28 to Boost the Efficacy of T Cell Bispecifics
The presentation will cover an overview and update on preclinical properties of solid and heme tumor co-stimulators including FAP-4-1BBL, CD19-4-1BBL, and CD19-CD28 in active clinical development in combination with cibisatamab and glofitamab, respectively.
Strength in Partnerships: Duobody CD40x41BB (GEN1042) Therapeutic for Advanced Solid Tumor Treatment
Duobody GEN1042 is a conditional activator of co-stimulatory molecules 4-1BB and CD40 which has shown early promise in the treatment of advanced solid tumors. Preclinical data shows enhanced priming and anti-tumor activity inclusive of T cell proliferation and effector functions. Furthermore, monotherapy and combination data from our FIH, open-label, phase I/II trial (NCT04083599) reveal a manageable safety profile, clinical activity, and pharmacodynamics consistent with the mechanism of action.
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 Advancing Bispecific Antibodies and Combination Therapy to the Clinic Conference7:40 pm