Cambridge Healthtech Institute’s Inaugural
Bispecific Antibody Case Studies & Clinical Relevance
Improving Performance in the Clinic
August 22 - 23, 2018
CHI’s Bispecific Antibody Case Studies & Clinical Relevance conference will bring together clinicians, regulators, and industry experts in the field to discuss and exchange ideas on promising bispecific candidates. We will showcase all crucial
topics from understanding the biology behind different bispecific constructs to mitigating challenges in advancing novel platforms to the clinic. Other applications of bispecifics beyond oncology will also be discussed.
Final Agenda
WEDNESDAY, AUGUST 22
7:45 am Registration and Morning Coffee
8:30 NEW: Chairperson’s Opening Remarks
Peter Pavlik, PhD, Principle Scientist, Aptevo Therapeutics
8:35 Functional Optimization of Agonistic Antibodies to OX40 Receptor with Novel Fc Mutations to Promote Antibody Multimerization
Mark
L. Chiu, PhD, Associate Director, Process Analytical Sciences, Janssen R&D
Immunostimulatory receptors belonging to the tumor necrosis factor receptor (TNFR) superfamily are emerging as promising targets for cancer immunotherapies. To optimize the agonism of therapeutic antibodies to these receptors, Fc engineering of antibodies
was applied to facilitate the clustering of cell surface TNFRs to activate downstream signaling pathways. This study elucidated a novel Fc engineering approach to promote antibody multimerization on a cell surface, which could enhance agonism and
improve effector function for anti-TNFR antibodies as well as other therapeutic antibodies.
9:05 Activating the Immune System with Bispecific Antibodies
John Haurum, CEO, F-star Biotechnology Ltd.
Cancer proliferates through numerous evasion strategies and re-engaging the immune system is key in the control of tumor growth. In recent years, checkpoint immunotherapies and their combinations have rapidly progressed from being a promising therapeutic
opportunity to a robust clinical reality. In this presentation, we will discuss how checkpoint-binding bispecific antibodies have the potential to go beyond combinations, by reversing down-regulation of the immune system and promoting tumor elimination.
9:35 Development of Bispecific DART® and TRIDENT™ Molecules for Tumor Anchored Immune Co-Stimulation
Gundo Diedrich, PhD, Director, Antibody Engineering, MacroGenics
Agents that influence immune recognition and elimination of malignant tumor cells generally fall into two classes: those that antagonize immune inhibitory pathways (checkpoint inhibitors) and those that induce immune stimulatory pathways. A limitation
of either mechanism is unwanted immune effects on normal tissues. It is thus highly desirable to limit the immune modulatory activity to the tumor site, while sparing effects on normal cells. To accomplish this in the immune stimulatory context,
we have generated bispecific molecules using our Fc-bearing DART and TRIDENT platforms that combine a tumor-specific recognition unit (anti-HER2, EphA2 or other tumor-associated antigen) with a T cell costimulatory molecule binder (anti-CD137
or other) such that the agonistic activity of the latter is dependent on tumor recognition by the former. A case study on the data-driven process for one such molecule will be presented, on this process leading to both a clinical candidate as
well as a “plug-and-play” format for facile integration with other tumor antigens.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Cell-Type Specific Potent Wnt Signaling Blockade by Bispecific Antibody
Bin Liu,
PhD, Professor, Anesthesia, University of California, San Francisco
We found that the bispecific antibody inhibits Wnt-induced reporter activities with over one hundred-fold enhancement in potency, and in a cell type-selective manner. Potency enhancement is dependent on the expression level of the guide antigen on
the target cell surface and the apparent affinity of the anti-guide antibody. Both internalizing and non-internalizing guide antigens can be used, with internalizing bispecific antibody being able to block signaling by all ligands binding to the
target receptor due to its removal from the cell surface. It is thus feasible to develop bispecific-based therapeutic strategies that potently and selectively inhibit signaling pathways in a cell type-selective manner, creating opportunity for
therapeutic targeting.
11:15 ATOR-1015, a Next-Generation, Bispecific CTLA-4 x OX40 Targeting Antibody for Tumor Directed Immunotherapy of Cancer
Eva Dahlén, PhD, Senior Director, Business Development, Alligator Bioscience
ATOR-1015 is a next-generation CTLA-4 x OX40 bispecific immune activating antibody developed for tumor-directed immunotherapy. ATOR-1015 binds both targets simultaneously, promoting cell-cell interactions expected to enhance the immuno-stimulating
effect of the compound. The mode of action of ATOR-1015 is a combination of regulatory T cell (Treg) depletion and effector T cell activation. ATOR-1015 is currently in preclinical development and clinical trials will start in the second half
of 2018.
11:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:35 Chairperson’s Remarks
Rakesh Dixit, Vice President, Global Head, MedImmune, Inc.
1:40 Introduction and Overview of Bispecific Antibodies in the Clinic
Rakesh Dixit, Vice President, Global Head, MedImmune, Inc.
This talk will provide an introduction and overview of leading bispecific antibodies along with other combinations that are currently in the clinic.
2:10 Clinical Applications of the Bispecific DART® Platform to Enhance Antitumor Responses
Paul A. Moore, PhD, Vice President, Cell Biology & Immunology, MacroGenics, Inc.
This talk will cover case examples of DART molecules for redirected T cell killing of both liquid and solid tumors, and those designed to simultaneously block two immune checkpoint pathways.
2:40 Preclinical and Clinical Development of ZW25, a Novel HER2-Targeted Biparatopic Antibody
Nina Weisser, PhD, Principle Scientist, Therapeutics Research, Zymeworks
ZW25 is a novel, bispecific antibody directed against two distinct epitopes, ECD2 and ECD4, on the HER2 receptor. It has been engineered on the Azymetric™ IgG1 antibody scaffold which uses complementary mutations in the Fc CH3 domain interface
to enable bispecific antibody assembly. Clinically, ZW25 has been well-tolerated with promising single-agent anti-tumor activity in patients with heavily pretreated HER2-expressing cancers that have progressed after standard of care, including
multiple HER2-targeted regimens. ZW25 is the first unconjugated biparatopic antibody to enter clinical development for oncology. The anti-tumor activity observed as a single agent in heavily pretreated patients highlights the potential of its
unique bispecific mechanisms of action to overcome mechanisms of resistance to other HER2-targets agents. I intend to discuss the experiments we performed to understand the mechanism of biparatopic binding and its contributions to ZW25’s
mechanisms of action. I will share our experience in exploring alternative bispecific formats during lead optimization to optimize activity and compare ZW25’s preclinical activity with our early clinical observations of safety, pharmacokinetics
and anti-tumor activity through Phase I dose escalation and cohort expansion.
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Problem Solving Roundtable Discussions
These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the
topics and moderators are below. Please click here for full details on all breakouts.
Bispecific Antibodies in Cancer Immunotherapy
Moderator: Eva Dahlén, PhD, Senior Director, Business Development, Alligator Bioscience
- Tumor-targeting immunomodulating compounds; pros and cons of various approaches
- Dual immunomodulators vs combination therapy with monospecifics to corresponding targets
- Target indication / patient population considerations for various modes of action
- Affinity/valency considerations in relation to target expression pattern and target combination
Target Selection for Bispecific Antibodies and Related Biologics
Moderator: Rakesh Dixit, Vice President, Global Head, MedImmune, Inc.
- Biology of the targets and their combinability
- What targets to avoid in bispecific
- Effector function enhancement
- Bispecific ADCs: pros and cons
- Managing the safety, PK-PD risks with antibody engineering
Bispecific Ab Engineering
Moderator: Mark L. Chiu, PhD, Associate Director, Process Analytical Sciences, Janssen R&D
- Optimizing affinities for targets
- Inclusion of Fc engineering
- Target selection for chronic vs acute indications
- Manufacturing
4:45 End of Day
THURSDAY, AUGUST 23
8:00 am Morning Coffee
8:30 Chairperson’s Remarks
Rakesh Dixit, Vice President, Global Head, MedImmune, Inc.
8:35 KEYNOTE PRESENTATION: Case Studies of Bispecific Antibodies from a Regulatory Perspective
Deborah Schmiel, PhD, Microbiologist, Biologics CMC, Product Development, and Vaccinology, FDA
The FDA has licensed two bispecific antibodies (BsAbs) and the number in clinical development has steadily increased in recent years. Case studies relating product quality attributes to clinical concerns will be provided based on our experience with
the licensed BsAbs and others in clinical development
9:05 An Adaptable Bispecific Platform to Deliver Immunotherapy
Lawrence Lum, MD, DSc, Director, Cellular Therapy, University of Virginia School of Medicine
Anti-CD3 activated T cells (ATC) armed with bispecific antibodies (BATs) directed at HER2, EGFR, GD2, or CD20 for solid and liquid tumors will be presented. BATs exhibit clinical activity and immune activity in both solid and liquid tumors. The presentation
will focus on the use of BATs for targeting of solid tumors in clinical trials.
9:35 Redirecting T Cells to Hematological Malignancies with Bispecific Antibodies
Mireya Paulina Velasquez, MD, Assistant Member, Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital
Bispecific antibodies (BsAbs) are an attractive immunotherapy strategy. They have the potential to be an easily scalable, “off-the-shelf” product that can redirect T cells to hematological malignancies. The BsAb field is currently active
with preclinical and clinical studies. We will review the successes and challenges of T cell-targeted BsAbs targeting hematological malignancies, focusing on conducted clinical studies and strategies to improve their efficacy.
10:05 Networking Coffee Break
10:25 Chairperson’s Remarks
Yuxing Li, PhD, Associate Professor, Microbiology and Immunology, University of Maryland School of Medicine, Institute for Bioscience and Biotechnology Research
10:30 Multispecific Antibodies for Cross-Neutralization of Filoviruses
Elisabeth K. Nyakatura, PhD, Senior Scientist, Biochemistry, Albert Einstein College of Medicine
Monoclonal antibodies (mAbs) against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections. However, mAbs that exhibit neutralization or protective properties against multiple filoviruses are rare. Here, we examined a panel of engineered bi- and trispecific antibodies, whereby variable fragments of mAbs that target epitopes from multiple filoviruses were combined, for their capacity to neutralize viral infection across filovirus species. We found that bispecific combinations targeting EBOV and Sudan virus (SUDV, another ebolavirus), provide potent cross-neutralization and protection in mice. Furthermore, trispecific combinations, targeting EBOV, SUDV, and MARV, exhibited strong neutralization potential against all three viruses. These results provide important insight into multispecific antibody engineering against filoviruses and will inform future immunotherapeutic discovery.
11:00 A Hormone-Mimetic Bispecific Antibody for the Treatment of Metabolic Disease
Junichiro Sonoda, PhD, Senior Scientist, Cancer Immunology, Genentech, Inc.
FGF21 analogs belong to a new class of therapeutic candidates that improve insulin sensitivity, ameliorate hepatosteatosis, and induce weight loss. We have engineered a humanized effectorless bispecific anti-FGFR1/βKlotho antibody that acts as
a long-acting FGF21-mimetic. We will present the antibody discovery, the mechanism of action, together with the results from the first-in-human single ascending dose study performed with obese human subjects.
11:30 Trispecific Broadly Neutralizing HIV Antibodies Mediate Potent SHIV Protection in Macaques
Zhi-yong Yang, PhD, Director, North America Breakthrough Laboratory, Sanofi US
We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited
higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates,
in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.
12:00 pm Multispecific Antibodies Targeting HIV-1 Envelope Glycoproteins
Yuxing Li, PhD, Associate Professor, Microbiology and Immunology, University of Maryland School of Medicine, Institute for Bioscience and Biotechnology Research
Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two HIV-1 broadly neutralizing antibodies (bNAbs) combined with a third bNAb by “knobs-into-holes” technology resulting in a trispecific bNAb, which
targets three distinct HIV Env epitopes and has nearly pan-isolate neutralization breadth with high potency. Thus, multispecific antibodies combining functional moieties of bNAbs could achieve outstanding neutralization capacity with augmented
avidity.
12:30 End of Congress