Engineering Bispecific Antibodies

 

The world of bispecific strategies, formats and clinical results has been gearing up over the past several years. Now in its tenth year, the Engineering Bispecific Antibodies conference was the first one in the community to address the vast challenges and exciting new engineering and manufacturing advances that are enabling the next generation of improved bispecific antibodies. Come see for yourself why this field is leading a transformation beyond oncology to many other areas of medicine.

Final Agenda

Scientific Advisory Board

Mahiuddin Ahmed, PhD, CSO, Y-mAbs Therapeutics

Christian Klein, PhD, Roche Pharmaceutical Research & Early Development, Oncology Discovery & Translational Area, Cancer Immunotherapy Discovery, Roche Innovation Center Zurich, Roche Glycart AG

Robert Mabry, PhD, Lead, Biologics Research Group, Takeda

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

THURSDAY, APRIL 11

12:00 pm Registration (Commonwealth Hall)

12:35 Luncheon in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

BISPECIFICS FOR CNS AND COMPARTMENTAL DELIVERY
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1:40 Chairperson’s Opening Remarks

Mahiuddin Ahmed, PhD, CSO, Y-mAbs Therapeutics

1:50 Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy across the Blood–Brain Barrier

Danica Stanimirovic, PhD, Research Director, Translational Bioscience, National Research Council Canada

2:20 Co-Targeting EphA2 and EphA3 in Cancer Stem Cells Reduces Growth of Recurrent Glioblastoma

Singh_SheilaSheila K. Singh, MD, PhD FRCS(C), Pediatric Neurosurgeon, McMaster Children’s Hospital, Interim Division Head, Neurosurgery, Hamilton Health Sciences; Director, McMaster Surgeon Scientist Program, Professor of Surgery, McMaster University; Principal Investigator, Stem Cell and Cancer Research Institute, McMaster University; Senior Canada Research Chair in Human Cancer Stem Cell Biology, Michael DeGroote Centre for Learning and Discovery

Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by GBM stem cells (GSC), which have been implicated in resistance to GBM therapy. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in recurrent GBM (rGBM) that was enriched in GSC marker expression. Treatment of rGBM with a novel bispecific antibody against EPHA2 and EPHA3 reduces tumor burden. Strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM. 

2:50 BBB Transport Vehicle (TV): A Novel Brain Delivery Platform

Dennis_MarkMark Dennis, PhD, Fellow, Denali Therapeutics

The BBB Transport Vehicle (TV) enables the delivery of large molecule therapeutics to the brain for the treatment of neurological diseases. The TV platform contains an engineered Fc domain that binds the transferrin receptor and utilizes receptor-mediated transcytosis to cross the BBB. This platform can be formatted for efficient delivery of both antibodies (ATV) and enzymes (ETV) across the BBB.

3:20 The Journey to 'the' Antibody: Accessing a Versatile Toolbox

María González Pajuelo, CSO, FairJourney Biologics

To maximize the possibility to select “the” antibody, at FJB we have taken antibody discovery to an unprecedent level by creating a versatile toolbox that allows the selection by phage display of antibody fragments of different species from large naïve and immune repertoires. Ultimately these fragments can be engineered and converted to mono- and bi-specific formats that are produced in CHO cells.

3:50 Networking Refreshment Break (Harbor & Mezzanine Level)

4:20 T Cell Engineering to Overcome Tumor Heterogeneity and Microenvironment Inhibition in Brain Tumors

Joseph_SujithSujith K. Joseph, PhD, Scientist, Pediatrics Hematology-Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine

Successful T cell immunotherapy depends on overcoming tumor heterogeneity and microenvironment inhibition. Use of multivalent CAR T-cells demonstrate advantage when targeting highly heterogeneous brain tumors. Additionally, grafting an intrinsic checkpoint reversal receptor (CPR) to CAR T-cells can help them overcome the inhibitory effects of brain tumor microenvironment.

4:50 Tissue-Specific Delivery of Antibodies: Improving Efficacy by Putting Antibodies at the Site of Action

Borrok_JackMartin Jack Borrok, PhD, Scientist II, AstraZeneca

Upon vascular administration, bio-therapeutics become broadly distributed throughout the body with only a fraction of dosed drugs reaching the intended organ or tissue target. By targeting existing transport systems in the lungs (and other organs), we can improve both the delivery and efficacy of therapeutics that act within these tissues while concurrently reducing unintended interactions in tissues not being targeted.

5:20 End of Day

5:20 Registration for Dinner Short Courses (Commonwealth Hall)


Recommended Dinner Short Course*

SC12: Design Strategies and Development of ADCs

Robert Lutz, PhD, Principal Consultant, Crescendo Biopharma Consulting

 

*Separate registration required.

FRIDAY, APRIL 12

8:00 am Morning Coffee (Harbor Level)

BISPECIFIC ANTIBODIES FOR IMMUNOTHERAPY: SEEING CLINICAL RESULTS
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8:30 Chairperson’s Remarks

Ertan Eryilmaz, PhD, Senior Scientist, Takeda

8:35 Blockade of Multiple Checkpoint Receptors with Bispecific DART® Molecules

Diedrich_GundoGundo Diedrich, PhD, Director, Antibody Engineering, MacroGenics

Therapeutic blockade of immune checkpoint pathways with monoclonal antibodies has provided remarkable anti-tumor activity, translating to a significant improvement in overall survival in subsets of cancer patients. Dual blockade of checkpoint pathways with bispecific antibodies may further enhance clinical benefits. The development of two bispecific DART molecules targeting PD-1 and LAG-3 (MGD013) or PD-1 and CTLA-4 (MGD019) will be presented.

9:05 Tumor-Localized Activation of the Immune System Using Antibody-Anticalin® Fusion Proteins

Marina Pavlidou, PhD, Project Leader, Discovery, Pieris Pharmaceuticals

4-1BB (CD137), a key costimulatory immunoreceptor, is a highly promising therapeutic target for the treatment of cancer. We utilized the Anticalin technology to develop 4-1BB-bispecific fusion proteins for tumor-localized activation of the immune system to overcome toxicity and efficacy limitations of current 4-1BB-targeting antibodies. We describe the characterization of PRS-343, a 4-1BB/HER2-targeting bispecific, and the in vitro and in vivo preclinical data supporting the ongoing first-in-patient trial of this drug candidate. Beyond PRS-343, the versatility of the Anticalin platform allows for the generation of a wide range of bispecifics for localized T-cell activation, including a high level of flexibility in molecular geometry and target valency to optimize good drug-like properties and superior efficacy of drug candidates generated within this therapeutic protein class.

Amunix 9:35 XPAT-T Cell Engagers – A Novel Format to Mitigate the On-Target, Off-Tumor Problem

Volker Schellenberger, PhD, CTO, Research & Discovery, Amunix Pharmaceuticals, Inc.

Amunix developed a novel format of highly-selective bispecific T cell engagers based on our proprietary XPAT platform (XTENylated Protease Activatable in Tumor). XTENylation provides long in vivo half-life and universal masking applicable to any antibody. T cell activation is >10,000 fold reduced prior to local proteolysis in the tumor microenvironment. In vivo studies in xenografts and non-human primates demonstrate >100x improved therapeutic window relative to conventional T cell engagers such as BiTEs.

10:05 Networking Coffee Break (Harbor & Mezzanine Level)

INFECTIOUS DISEASE APPLICATIONS
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10:30 Chairperson’s Remarks

Ertan Eryilmaz, PhD, Senior Scientist, Takeda

10:35 Rational Design of a Trispecific Antibody Targeting the HIV-1 Env with Elevated Anti-Viral Activity

Zhi-Yong Yang, PhD, Director, Synthetic & Immune Biology, Sanofi

We engineered trispecific antibodies that allow a single molecule to interact with three independent HIV-1 envelope determinants. These trispecific antibodies exhibited higher potency and breadth than any single anti-HIV-1 antibody and showed protective efficacy in an animal model of HIV-1 infection. Trispecific antibodies thus constitute a platform to engage multiple therapeutic targets through a single protein and could be applicable for diverse diseases including infections, cancer and autoimmunity.

11:05 Beyond Blinatumomab: Antiviral Activity of BiTE® Antibody Constructs Targeting HIV

Brozy_JohannesJohannes Brozy, PhD, Senior Associate Scientist, BiTE® Technology, Amgen Research (Munich) GmbH

HIV is a chronic infection well controlled with the current cART. However, a cure for HIV is still lacking. Here, we show in vitro and ex vivo data that a BiTE antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE antibody constructs display efficient killing of gp120-expressing cells and inhibited replication in ex vivo HIV-infected PBMCs or macrophages.

11:35 Human and Bispecific Antibodies as Immunotherapies for Chikungunya Virus

Lai_JonathanJonathan R. Lai, PhD, Professor, Department of Biochemistry, Albert Einstein College of Medicine

Chikungunya virus (CHIKV) is a widespread mosquito-borne alphavirus that causes a severe and persistent arthralgia. We describe the use of single B-cell sorting to identify protective monoclonal antibodies that target the two envelope glycoproteins, E1 and E2, from convalescent CHIKV patients. Viral escape studies revealed the sites of susceptibility on both E1 and E2. This information was then used to engineer novel bispecific antibodies that enable simultaneous targeting of multiple epitopes in a single agent. These antibodies have strong potential for use as immunotherapies to prevent or treat CHIKV infection. 

12:05 Attend Concurrent Track or Enjoy Lunch on Your Own

1:05 Networking Refreshment Break (Harbor & Mezzanine Level)

ENGINEERED FCs IN BISPECIFICS: DRIVING DESIRED PK, ACUTE ACTIVITY AND LONG-TERM BIOLOGICAL CONSEQUENCES
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1:25 Chairperson’s Remarks

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

1:40 The Astonishing Diversity of Fc Domain Functions and the Development of Novel Fc Engineered IgG Variants

Stylianos Bournazos, PhD, Research Assistant Professor, Laboratory of Molecular Genetics and Immunology, Rockefeller University

2:10 Engineering Fc of BiSAbs to Restore and Extend Half-Life

Sachs_CliffordClifford William Sachs, PhD, Director, Research and Development, Toxicology, AstraZeneca

A systematic evaluation of pharmacokinetics (PK) of Bispecific IgG scaffolds and parental monoclonal antibodies (mAbs) in cynomolgus monkeys identified sites of ScFv attachment and immunogenicity of parental mAbs as key determinants of PK. Across scaffolds, introduction of half-life extension mutations in the Fc portion of the BiS increased half-life by 2 to 5-fold. Collectively, these data identified structural considerations and engineering approaches to facilitate development of Bispecific IgG scaffolds.

2:40 Modulating Functionality in Bispecifics – Towards Better Therapeutics

Steegmaier_MartinMartin Steegmaier, PhD, Head of Discovery, Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich

Therapeutic performance of recombinant antibodies relies on two independent mechanisms: antigen recognition and Fc-mediated antibody effector functions. Interaction of Fc-fragment with different FcR triggers antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity and determines pharmacokinetic half-life. Engineered hIgG Fc domains with completely abolished FcγR and C1q interactions, and with unaffected FcRn interactions and Fc stability have been previously described by us. The impact of antibody Fc engineering, however, goes beyond the modulation of the affinity or functionally of the interaction with various FcRs or the neonatal Fc receptor (FcRn). Specifically in the context of bispecific antibody engineering, the Fc functionality needs to be matched with the often-unique mode of action of the bispecific therapeutic to provide a unique PK profile or to match the requirement for effector function according to biological needs and safety requirements. Antagonistic antibodies can also be turned into agonists by switching the format and functionality of the Fc moiety. Examples of tailoring Fc functionality will be given for bispecific molecules currently being developed for immunological, ophthalmological and neuroscience indications.

3:10 NEW: EAGLE, A Novel Bispecific-Like Platform and Immunomodulatory Strategy

James Broderick, MD, CEO and Founder, Palleon Pharmaceuticals Inc.

Glyco-immune checkpoints have emerged as a novel mechanism of immune regulation of both innate and adaptive immunity and cancer immune escape. We have developed a novel bispecific-like platform named EAGLE (Enzyme-Antibody Glyco-Ligand Editing) with robust anti-tumor efficacy (~50% complete regression) in syngeneic EMT6 tumor models as a monotherapy. Here we reported how different bispecific-like configurations impact biological activity, pharmacokinetics, and toxicity of EAGLEs preclinically.

3:40 End of Conference

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