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

ACTIVATION OF THE IMMUNE SYSTEM

8:30 Chairperson’s Opening Remarks

Robert Mabry, PhD, Vice President, Protein Science, Cogen Therapeutics, Inc.

8:35 Functional Optimization of Agonistic Antibodies to OX40 Receptor with Novel Fc Mutations to Promote Antibody Multimerization

Mark_ChiuMark 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_HaurumJohn 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_DiedrichGundo 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_LiuBin 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_DahlenEva 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 Sponsored Presentation (Opportunity Available)

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Session Break

ADVANCING BISPECIFICS IN THE CLINIC

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_DixitRakesh 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_MoorePaul 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_WeisserNina 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 Sponsored Presentation (Opportunity Available)

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 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

5:15 End of Day

THURSDAY, AUGUST 23

8:00 am Morning Coffee

ADVANCING BISPECIFICS IN THE CLINIC (CONT.)

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_LumLawrence 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

Paulina_VelasquezMireya 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 Sponsored Presentation (Opportunity Available)

10:35 Networking Coffee Break

BISPECIFIC ANTIBODIES BEYOND ONCOLOGY

10:55 Chairperson’s Remarks

Yuxing Li, PhD, Associate Professor, Microbiology and Immunology, University of Maryland School of Medicine, Institute for Bioscience and Biotechnology Research

11:00 A Hormone-Mimetic Bispecific Antibody for the Treatment of Metabolic Disease

Jun_SonodaJunichiro 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_LiYuxing 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 Multispecific Antibodies for Cross-Neutralization of Filoviruses

Elisabeth_NyakaturaElisabeth 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.

1:00 End of Congress