CHI’s Second Annual Bispecific 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. A companion diagnostic aspect for bispecific platforms will be examined for meaningful therapeutic selection based on patient identification, stratification, and the early assessment of treatment efficacies. An extension of bispecific applications in other diseases besides oncology will also be discussed.

Final Agenda

WEDNESDAY, AUGUST 21

1:00 pm Registration

CLINICAL PROGRESS FOR BISPECIFICS AND COMBINATIONS

1:35 Chairperson’s Opening Remarks

Rakesh Dixit, PhD, DABT, President & CEO, Bionavigen

1:40 FEATURED PRESENTATION: Introduction and Overview of Bispecific Antibodies in the Clinic: Learnings from Success and Failures

Rakesh Dixit, PhD, DABT, President & CEO, Bionavigen

This talk will provide an introduction and overview of leading bispecific antibodies along with other combinations that are currently in the clinic, including the learnings from successes and failures of bispecific antibodies.

2:10 M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGF-β in Advanced Solid Tumors

Julius Strauss, MD, Assistant Research Physician, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH

M7824 is a bifunctional fusion protein targeting PD-L1 and TGF-β. In Phase I/II trials, M7824 has shown evidence of clinical efficacy in a variety of tumor types, including NSCLC, gastric ca, biliary tract ca and HPV associated malignancies.

2:40 ZW49 – A Novel Bispecific Antibody-Drug Conjugate (ADC) Targeting HER2-Expressing Cancers

John Babcook, PhD, Senior Vice President, Discovery Research, Zymeworks

ZW49 is a bispecific anti-HER2 ADC currently being evaluated in a Phase I clinical trial. In preclinical studies, ZW49 demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient-derived xenografts, and promising efficacy in a model of breast cancer brain metastases at exposures tolerated in non-human primates. These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development.

3:10 Engineering Bispecific Antibodies for Clinical Success

Adam Zwolak, PhD, Senior Scientist, Multispecific Antibody Engineering, JBIO Therapeutics, Janssen R&D, LLC

Bispecific antibodies open new therapeutic mechanisms including T cell engagement and dual antigen-targeting. Clinical development of BsAbs presents unique challenges in both manufacturing and dosing.  The emergence of this clinical and manufacturing data from first-generation BsAbs has allowed upstream discovery efforts to engineer molecules designed to overcome these challenges. Here, we describe a series of BsAbs in clinical development and apply the observations from these efforts to design of next-generation BsAbs.

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

4:20 Leveraging Host Anti-Tumor Immunity through Bispecific DART® Molecule

Paul A. Moore, PhD, Vice President, Cell Biology & Immunology, MacroGenics, Inc.

This presentation will review MacroGenics clinical experience with redirected T-cell killing bispecific DART molecules, and approaches to maximize therapeutic responses through combination with checkpoint inhibitors and/or immune co-stimulators.

4:50 ABL001 (NOV1501): A Novel Bispecific Antibody Targeting VEGF & DLL4 for the Treatment of Solid Tumors

Sang Hoon Lee, PhD, CEO, ABL Bio

To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF, thereby significantly suppressing tumor angiogenesis. I will report the most recent data for this ongoing Phase 1a study. Phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody.

5:20 Problem Solving Roundtable Discussions

PK and Immunogenicity Analytical Strategy to Support Bispecific Antibody Clinical Development

Moderator: Kate Peng, PhD, Group Leader/Senior Scientist, BioAnalytical Sciences, Genentech

• PK method development considerations
• Immunogenicity assessment strategy

Safety of Bispecifics Based on CD3 Targeting on T Cells

Moderator: Rakesh Dixit, PhD, DABT, President & CEO, Bionavigen

• Advantages of CD3-based Bispecifics, meeting the deficiencies of the BITE molecules
• Discussion on CD3 bispecific formats? Target selection?
• Safety challenges of CD-3 bispecifics: Target related or format based?
• Risk mitigation through smart engineering approaches

6:15 End of Day

6:20 Get personal: Fun with your peers and colleagues at the Infamy Bar & Restaurant*

An informal gathering will be held in the Infamy Bar & Restaurant (located in the hotel lobby). We encourage you to turn to your neighbors during this gathering to shake hands, make conversations and get to know each other on a personal level. The best learning and relationship-building experiences are informal! Many surrounding restaurants are within walking distance to continue the conversations over dinner.

*This is not a CHI hosted event. Food and drinks will not be provided by the event organizers.

THURSDAY, AUGUST 22

8:00 am Morning Coffee

UNDERSTANDING THE BIOLOGY FOR ENHANCED SAFETY AND EFFICACY

8:30 Chairperson’s Remarks

Nazzareno Dimasi, PhD, Associate Director, R&D, AstraZeneca Biopharmaceuticals

8:35 KEYNOTE PRESENTATION: Bioassay Development for Bispecific Antibody from an FDA Standpoint

Wen Jin Wu, MD, PhD, Senior Investigator, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA CDER

Bispecific antibodies are the agents targeting two antigens, such as two receptors expressed on either the same or the different cells, two ligands, or one ligand and one receptor, and have the unique potential to mediate multiple biological effects and may kill the tumor cells more efficiently compared to monoclonal antibodies. Bispecific antibodies Investigational New Drug (IND) submissions have grown enormously in recent years. Therefore, to improve product manufacturing and testing to help ensure availability of high-quality bispecific antibodies during clinical study, it is essential to develop cell-based bioassay(s) that can characterize biological activity, demonstrate mechanism of action, detect structural changes, and function as a quality control release assay. The regulatory issues and the pitfalls in bioassays will be discussed.

9:05 Lessons Learned from the Bis4Ab Platform: From a Bispecific Engineering Concept to Clinical Investigation.

Nazzareno Dimasi, PhD, Associate Director, R&D, AstraZeneca Biopharmaceuticals

Over the past several years, we have generated several bispecific bivalent antibody formats. Amongst those formats, Bis4Ab is the most advanced format we have in clinical investigation. In this presentation, the Bis4Ab engineering design and development are presented. As an example of Bis4Ab, lessons learned during the preclinical and clinical investigation of MEDI3902, which is being investigated in Phase II trials as immunoprophylactic against Pseudomonas aeruginosa in mechanistic ventilated subjects are presented.

9:35 Design Meets Biology – Engineering a PD-1/CTLA-4 Bispecific Antibody to Improve Both Safety and Efficacy

Yariv Mazor, PhD, Senior Scientist, Antibody Discovery & Protein Engineering, AstraZeneca Biopharmaceuticals

MEDI5752 is a monovalent bispecific IgG1 antibody (DuetMab), targeting the two clinically validated receptors; PD-1 and CTLA-4. The bispecific antibody introduces novel MOAs that may provide an improved therapeutic index when compared to the two monotherapies and mAb combinations. MEDI5752 is currently being clinically evaluated for safety and efficacy.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:50 Bispecific γδ-T cell Engagers for Cancer Immunotherapy

Paul W.H.I. Parren, PhD, Executive Vice President and Head of R&D, Lava Therapeutics

Bispecific T cell engagers (bs-TCE) are a promising class of immune-oncology agents in targeted cancer immunotherapy. Classical bs-TCE designs consist of a tumor antigen-binding domain combined with a binding domain against the CD3 T-cell receptor-signaling complex. Irrespective of the bispecific antibody format used, CD3-based bs-TCEs have a number of disadvantages, which in part are explained by the fact that they activate all T-cells irrespective of lineage, which associates with serious adverse events as a result of exaggerated T cell activation and cytokine release in some patients, and limited efficacy due to T suppressor cell activation in others. The development of bs-TCEs with increased tumor selectivity to widen the therapeutic window has high potential. Lava Therapeutics’ platform is based on the selective recruitment of Vγ9Vδ2 T cells for tumor targeting. This gd T cell subset has been shown to display powerful innate anti-tumor immune effector activity with an ability to infiltrate human tumors in which its abundance in tumor-infiltrating lymphocytes has been shown to positively correlate with patient survival. This presentation will discuss a novel class of bsTCEs designed to engage Vγ9Vδ2-T cells for the development of efficacious and safe cancer immunotherapies.

11:20 Developing “Fit-for-Purpose” Bi- and Multi-Specific Biologics to Achieve Desired Functional Outcomes

Tariq Ghayur, PhD, Distinguished Research Fellow, Immunology Discovery, AbbVie

To achieve desired therapeutic outcomes multiple features need to be considered in a therapeutic modality, for example: (i) valency and geometry of target binding domains; (ii) glycosylation profile and (iii) PK. In this talk we will describe our efforts to engineer such functional properties in bi- & multi-specific biologics.

11:50 Enjoy Lunch on Your Own

CASE STUDY OF BISPECIFIC

1:30 Chairperson’s Remarks

Paul A. Moore, PhD, Vice President, Cell Biology & Immunology, MacroGenics, Inc.

1:35 A B-body™ Bispecific OX40 Agonist Antibody that Exhibits Superior Activity without Secondary Crosslinking

Bonnie Hammer, PhD, Vice President, Biologic Development, Invenra

OX40 is a costimulatory molecule found on T cells belonging to the tumor necrosis factor receptor superfamily (TNFR). TNFR superfamily members require high-order receptor clustering in order to achieve full activity. Traditional monoclonal antibodies require secondary cross-linking to achieve this high-order receptor clustering. We have developed a biparatopic antibody to OX40 that in the absence of cross-linking meets or exceeds the level of activation of a traditional monoclonal cross-linked antibody and exhibits potent in vivo efficacy in a mouse model.

2:05 A Novel Multi-Specific Antibody Targeting PD-L1-Overexpressing Cancers that Stimulates Antigen-Committed CD8+ T Cells Through Concomitant Engagement of 4-1BB

Christian Hess, PhD, Associate Director, Group Leader Protein Engineering, Numab Therapeutics AG 

Encouraging pre-clinical results achieved with combined PD-L1/PD-1 and 4-1BB regimens have not yet translated into durable clinical success, due to co-administration of 4-1BB-agonistic antibodies being either intolerable at effective doses or ineffective at all evaluated doses. To eliminate this safety/efficacy tradeoff, we engineered a novel, PD-L1/4-1BB/HSA trispecific scMATCH™3 immunomodulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon PD-L1-binding/-blockade and is equally effective as a αPD-L1 mAb + α4-1BB mAb combination at slowing tumor progression in vivo, while being better tolerated.

IMMUNOGENICITY AND CLINICAL PHARMACOLOGY CONSIDERATIONS

2:35 Chairperson’s Remarks

Paul A. Moore, PhD, Vice President, Cell Biology & Immunology, MacroGenics, Inc.

2:40 FEATURED PRESENTATION: Clinical Pharmacology Considerations of Bispecific Antibodies

Ping Ji, PhD, Pharmacologist, OCP, FDA

Bispecific antibodies as therapeutic agents are characterized by the ability to bind two different targets, either cell-surface receptors or soluble ligands, on the same or different cell(s). Their PK/PD properties, including their immunogenic potential, are closely related to their structural features such as molecular weight and physicochemical properties and binding affinity to the antigen. This presentation will describe the clinical pharmacology properties of bispecific antibodies and their clinical development strategy. The challenges of bioanalytical assay of bispecific antibodies will also be presented.

3:10 Immunogenicity Assessment of Bispecific Antibody Therapeutics in Clinical Studies

Kate Peng, PhD, Group Leader/Senior Scientist, BioAnalytical Sciences, Genentech

Bispecific mAbs (bsmAbs) are a novel class of mAbs that aim to improve drug efficacy by simultaneously working on two targets. This is a relatively new approach with limited experiences in clinical development. This presentation discusses our strategy for assessing the anti-drug antibody (ADA) responses to the bsmAb and summarizes the characterization results as well as the clinical impact of ADAs on drug exposure and safety.

3:40 End of Bispecific Antibody Pipeline Congress