Engineering Bispecific Antibodies

- 双特异性抗体工程 -


The universe of bispecific antibody platforms, combinations, strategies and chemistry is growing exponentially and the application of bispecific constructs in immunotherapy is proving to be an extremely effective combination. Fine tuning specificity, calibrating potency while minimizing safety risk are all top priorities of antibody engineers for targets in oncology, immuno-oncology and infectious disease. Early results with new platforms and evolving techniques will be shared. Plan to take part in the premier event in the bispecific antibody community and learn what is next for tackling the biggest challenges facing the field and how to overcome them.

Final Agenda

Scientific Advisory Board

Mahiuddin Ahmed, PhD, CSO, Y-mAbs Therapeutics
Christian Klein, PhD, Head, Oncology Programs & Depart Head Cancer Immunotherapy Discovery 3, Roche Innovation Center Zurich, Roche Pharma Research & Early Development
G. Jonah Rainey, PhD, Vice President, Antibody Therapeutics, Gritstone Oncology, Inc.
Eugene Zhukovsky, PhD, Chief Scientific Officer, Biomunex Pharmaceuticals

5月7日(四)

12:00 pm Registration

12:35 Luncheon in the Exhibit Hall with Poster Viewing

BISPECIFIC ANTIBODIES FOR CO-STIMULATION AND CANCER IMMUNOTHERAPY

1:40 Chairperson’s Opening Remarks

Jonathan H. Davis, PhD, Head, Innovation, Invenra, Inc.


1:50 KEYNOTE PRESENTATION: Co-Stimulatory Bispecific Antibodies for Combination Cancer Immunotherapy

Skokos_DimitrisDimitris Skokos, PhD, Director, Immune & Inflammatory Diseases, Regeneron Pharmaceuticals

Although tumor-specific antigen (TSAxCD3) bispecifics have demonstrated promising anti-tumor efficacy in cancer patients, the opportunity to optimize T cell activity further remains. Herein we introduce a novel class of bispecific antibodies that mimic “signal 2”, by bridging a TSA to a co-stimulatory receptor on T cells. Combining this novel class of co-stimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, “off-the-shelf” antibody therapies with potentially enhanced anti-tumor efficacy.

2:20 Simultaneous Multiple Interaction T Cell Engagers (SMITEs): Improving Bispecific Therapies through T Cell Co-Stimulation

Correnti_ColinColin Correnti, PhD, Senior Scientist and Director of Protein Sciences, Fred Hutchinson Cancer Research Center

We are developing pairs of synergistic T cell engagers that simultaneously bind two cancer antigens and two T cell coreceptors. Importantly, each singleton is selected to be inactive until paired, providing T cell co-stimulation and improved cancer specificity. In this presentation I’ll describe our approach for generating silent and synergistic T cell engagers, highlighting our use of the Trianni™ mouse and automated methods for protein expression and T cell assays.

2:50 Trispecific Antibodies Enhance the Therapeutic Efficacy of Tumor-Directed T Cells through T Cell Receptor Co-Stimulation

Yang_Zhi-YongZhi Yong Yang, PhD, Director, Synthetic & Immune Biology, Sanofi

CD38/CD3xCD28 trispecific Ab demonstrated desired in vitro functions, including the capabilities of inducing robust T cell activation, up-regulating anti-apoptotic protein Bcl-xL expression in primary human T cells, supporting T cell proliferation, and exhibiting potent tumor killing activity. It stimulated memory/effector T cell proliferation and reduced regulatory T cells and was well tolerated at efficacious dose showing anti-tumor activity in non-human primates. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

3:20 Dealing with the Combinatorial Complexity of Protein Engineering: Bi- and Multi-Specifics, TCRs and CAR Ts

Fitzgerald_AmandaAmanda Fitzgerald, PhD, Senior Scientific Consultant, Biologics, Genedata

We present a new technology platform to fully automate both molecular design, as well as the integrated assessment of potency, efficacy, and developability profiling of large panels of bispecific candidates. We will present use cases showing how the platform allows for the systematic cloning, expression, purification, and characterization of complex multi-specific, CAR T and TCR modalities, with a focus on immuno-oncology applications.

3:50 Networking Refreshment Break

4:20 T Cell Engaging Bispecific Antibodies: Comparing Pfizer’s Platforms

Chaparro-Riggers_JavierJavier Chaparro-Riggers, PhD, Executive Director, Biomedicine Design, Pfizer Inc.

T cell engaging bispecific antibodies are a promising therapeutic approach for the treatment of multiple cancer types. A variety of formats are currently being tested in the clinic. Pfizer has developed several Fc-containing T cell engaging bispecific antibody platforms, which increase the half-life and allow for conventional dosing. These platforms are currently evaluated in the clinic. Here, we will compare these platforms and the challenges and opportunities of each platform will be highlighted.

4:50 A Bispecific SNIPER™ Demonstrates Preclinical Efficacy through the Selective Elimination of Tumor Tregs

Davis_JonathanJonathan H. Davis, PhD, Head, Innovation, Invenra, Inc.

Antibodies for immune checkpoint blockade have revolutionized cancer therapy but their use is oftentimes limited by toxicity, particularly when used in combination. The next generation of immunotherapies must address these toxicities to enable more potent combination therapies. Here, we describe a bispecific SNIPER™ antibody that selectively targets intratumoral regulatory T cells (Treg), diminishing the immunosuppressive tumor microenvironment without the toxicity associated with systemic Treg depletion. In vitro functional characterization of the engineered human SNIPERs™ identified a lead candidate that selectively binds Tregs localized in human tumors over those in systemic circulation. In vivo studies using a mouse surrogate SNIPER™ in CT26 tumor models revealed a dramatic reduction in Tregs in the tumors, with no change in the periphery. In an early CT26 model, a strong majority of mice receiving single agent therapy showed complete response and recovery. Combinations with immune stimulating agents against more advanced tumors led to similar efficacy.

5:20 End of Day

5:15 Registration for Dinner Short Courses

*Separate registration required.

5月8日(五)

8:00 am Registration and Morning Coffee

MULTISPECIFICITY AND COMBINATION STRATEGIES

8:30 Chairperson’s Remarks

Mahiuddin Ahmed, PhD, CSO, Y-mAbs Therapeutics

8:35 Rational Combinatorial CAR Designs for Effective Immunotherapy

Hamieh_MohamadMohamad Hamieh, PhD, Research Associate, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center

Chimeric antigen receptors (CARs) are synthetic receptors for antigen that reprogram T cell specificity, function, and persistence. Despite remarkable complete response rates observed with patients suffering from B cell malignancies, relapses occur in a large fraction of patients, some of which are antigen-negative and others antigen-low. We explored multiple strategies of antigen dual targeting to improve CAR design with target-adapted co-stimulatory domains to prolong functional CAR T cell persistence and mitigate the risk of antigen escape.

9:05 Novel Insights into Immune Cell-Mediated Killing of Tumor Cells

Demarest_StephenStephen Demarest, PhD, Senior Research Fellow, Eli Lilly and Company

Using computational modeling and protein engineering, we generated novel agents to redirect T cells to fight cancer. The designs provide for robust production of these novel agents. Impacts on epitope, affinity, and geometry will be discussed.

9:35 Platformization of Multi-Specific Protein Engineering

Dietmar-Hoffmann_DietmarDietmar Hoffmann, PhD, Associate Director, Section Head Molecular, Expression and Screening Technologies Group, Biologics Research US, Sanofi

The success rate to identify a multi-specific lead molecule (e.g. a tri-specific antibody) increases with the number of variants tested. Therefore, systematic screening of a large panel of multi-specific variants in a high throughput approach is critical to identify candidates with drug like properties early in the discovery process. We have automated both the molecular biology and the protein production increasing our capability for medium-scale production of multi-specific antibodies facilitating more functional and developability assays.

10:05 Networking Coffee Break

CLINICAL VALIDATION OF PLATFORMS

Chairperson’s Remarks

G. Jonah Rainey, PhD, Vice President, Antibody Therapeutics, Gritstone Oncology, Inc.


10:35 KEYNOTE PRESENTATION: Trends in Bispecific Antibody Development

Reichert_JaniceJanice Reichert, PhD, Executive Director, The Antibody Society

Bispecific antibodies hold substantial potential for treatment of numerous human diseases. Nearly 90 bispecific antibodies are currently in clinical studies, with most of these entering studies in the past 3 years. These molecules are thus of substantial interest to the biopharmaceutical industry, but only limited efficacy data is available because few have completed late-stage clinical studies. Dr. Reichert will discuss the bispecific antibody pipeline and future prospects for their approval.

11:05 The Dual Variable Domain Ig (DVD-Ig) Platform: Lessons Learned from the Clinic and Future Directions

Ghayur_TariqTariq Ghayur, PhD, Distinguished Research Fellow, Foundational Immunology, AbbVie

Three DVD-Ig molecules, two (ABT 981 and ABT 122) in autoimmune and one (ABT 165) in oncology indications, have now been evaluated in humans (Phase I/II). The results suggest that these molecules behave like monoclonal antibodies and the DVD-Ig format per se may not be immunogenic. However, in some instance, target biology may play a role in ADA response. This presentation will discuss these data and the future directions.

11:35 T Cell Therapeutics to Address Hematological Malignancies and Solid Tumors

Arvedson_TaraTara Arvedson, PhD, Executive Director, Oncology and Inflammation Research, Amgen

T cell therapeutics have demonstrated clinical benefit in hematological malignancies and there is growing evidence of activity in solid tumors. This presentation will describe key findings from recent trials along with observations from nonclinical studies that inform on mechanism of action and approaches to address clinically observed challenges.

12:05 pm PANEL DISCUSSION

12:35 LUNCHEON PRESENTATION: Unique in vitro Technologies for R&D of Biologics Including scFv, Fab, IgG, Cyclic Peptide and Bispecific

Ebihara_TakashiTakashi Ebihara, PhD, COO, GeneFrontier Corporation

Our unique platform technology called PUREfrex is a fully reconstituted cell-free protein expression system. PUREfrex can effectively express scFv, Fab and full IgG as well, which is useful for high-throughput screening. In addition to that, we established robust ribosome display with PUREfrex called PUREfrexRD, which has great advantage in screening of highly diversified library and developing new antibodies or cyclic peptides. We’ll also present unique bispecific format based on those cyclic peptide and antibodies.

1:05 Networking Refreshment Break

TUNING SPECIFICITY – BALANCING POTENCY VS. SIDE-EFFECTS

1:35 Chairperson’s Remarks

Eugene Zhukovsky, PhD, CSO, Biomunex Pharmaceuticals

1:40 Immunological Synapses in Human Health and Disease

Valitutti_SalvatoreSalvatore Valitutti, MD, Director, Research, INSERM; Head, Laboratory Molecular Dynamics of Lymphocyte Interactions, Cancer Research Center of Toulouse

I will summarize our contribution to the field of human cytotoxic T lymphocyte (CTL) biology and, in particular, to the notion of the high sensitivity, rapidity and efficacy of CTL responses. I will introduce the concept of lytic versus stimulatory synapse dichotomy in CTL. I will then expose our recent findings on the molecular mechanisms of tumor cells defense from CTL attack at the lytic synapse.

2:10 A Novel Bispecific Antibody Platform that Elicits Efficient Tumor Lysis with Minimal Cytokine Release in Liquid and Solid Tumors

Trinklein_NathanNathan Trinklein, PhD, CTO, Discovery, Teneobio

Using a unique sequence-based discovery approach along with proprietary transgenic rats, we have created a large collection of fully human anti-CD3 antibodies with diverse T cell agonist activities. Using machine learning tools, we were able to rapidly establish sequence-activity relationships and identify key residues in antibody sequences that had desired agonist behavior. The CD3 antibodies identified by our platform show diverse in vitro T cell activation profiles measured by CD69 upregulation, IL2, and IFNg production. We also generated human domain antibodies targeting a variety of tumor antigens that we combined with our unique CD3 antibodies to create bispecific molecules that mediate redirected T cell killing of tumor cells. In one particular example, we have created a panel of aCD3:aBCMA bispecific antibodies for the treatment of multiple myeloma that stimulate different levels of T cell activity. Using a multiple myeloma tumor cell line along with primary human PBMCs, we demonstrate a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release using our bispecific molecules with diverse CD3 binding activities. Our lead program, TNB383B (BCMAxCD3) is currently in Phase I clinical studies. In summary, we have created a platform for tunable immune activation at the site of the tumor that works with a variety of tumor antigens.

2:40 Optimizing Cytolytic Activity and Cytokine Release via Affinity Modulation of CD3-Engaging DART® Molecules for Redirected T Cell Killing

Diedrich_GundoGundo Diedrich, PhD, Director, Antibody Engineering, MacroGenics, Inc.

CD3-engaging bispecifics mediate potent redirected T cell killing in vitro and anti-tumor activity in vivo. However, their dosing is often limited by systemic cytokine release. While cytokine release effects can be mitigated through dosing strategies and anti-cytokine antibodies, an expansion of the therapeutic window of CD3-engaging bispecifics is desirable. Our studies suggest that modulating the affinity of CD3 engagement can reduce systemic cytokine secretion without compromising anti-tumor efficacy, and therefore might improve the activity and safety profile of the next-generation CD3-engaging DART molecules.

3:10 Activating and Recruiting T Cells with Bispecific Antibodies and Potency-Optimized Cytokines

Desjarlais_JohnJohn Desjarlais, PhD, CSO, Xencor

Xencor has developed a robust platform for the creation of bispecific antibodies that recruit and activate immune cells to destroy tumors. This platform, importantly, includes the ability to explore different valencies and CD3 affinities to maximize selectivity and therapeutic index. Alternatively, checkpoint bispecific antibodies (e.g., PD1 x CTLA4) have been optimized to more safely target multiple checkpoint receptors, with potential to selectively activate endogenous tumor-reactive T cells. Finally, we have also applied our platform to create novel, reduced-potency IL15-Fc fusions with superior pharmacodynamic properties and improved therapeutic index.

3:40 End of Conference

* 活动内容有可能不事先告知作更动及调整。

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