Engineering Bispecific Antibodies

 

二重特異性抗体のエンジニアリング

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, CEO, Oriole Biotech, Inc.

THURSDAY, APRIL 11

12:00 pm Registration

12:35 Luncheon in the Exhibit Hall with Poster Viewing

中枢神経系とコンパートメントへのデリバリーに対応する二重特異性抗体

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 Ephrin Receptor Tyrosine Kinases A2 and A3 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

Recurrent glioblastoma (rGBM) remains vastly understudied with few biological targets for therapeutic development. In our present study, we identify that co-expression of EphA2 and EphA3 functionally marks a potent glioblastoma stem cells (GSC) population in rGBM. We developed a EphA2/EphA3 bispecific-antibody (BsAb) and demonstrate that treatment with the BsAb reduces rGBM tumor burden. Therefore, we present the development of rational therapeutic approaches against biologically relevant targets in 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 Talk Title to be Announced

María González Pajuelo, CSO, FairJourney Biologics

3:50 Networking Refreshment Break

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, MedImmune

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


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

免疫療法に対応する二重特異性抗体:臨床研究の成果

8:30 Chairperson’s Remarks

Robert Mabry, PhD, Lead, Biologics Research Group, 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

Rothe_ChristineChristine Rothe, PhD, Vice President & Head Discovery & Alliance Management, Pieris Pharmaceuticals GmbH

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 Presentation to be Announced

10:05 Networking Coffee Break

感染性疾患への応用

10:30 Chairperson’s Remarks

Robert Mabry, PhD, Lead, Biologics Research Group, 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 pm MEDI3902 Correlates of Protection against Severe Pseudomonas aeruginosa Pneumonia in Rabbits

DiGiandomenico_AntonioAntonio DiGiandomenico, PhD, Principal Scientist, Microbial Sciences, MedImmune

Pseudomonas aeruginosa is a major challenge for new antimicrobial drug discovery efforts because of its versatile lifestyle and ability to develop antibiotic resistance. This rise in resistance coupled with the dearth in discovery of new antibiotic classes requires development of alternative antimicrobials such as pathogen-specific monoclonal antibodies (mAbs). In this presentation, I will introduce a novel anti-Pseudomonal bispecific mAb and discuss the correlates of protection in rabbit models of acute pneumonia and ventilator-associated pneumonia.

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Networking Refreshment Break

二重特異性抗体の改変されたFc領域:望ましい薬物動態、急速な活性、長期的な生物学的影響の促進

1:25 Chairperson’s Remarks

G. Jonah Rainey, PhD, CEO, Oriole Biotech, Inc.


1:40 KEYNOTE PRESENTATION: Modulating Immunity through Selective Fc Interactions: Strategies for Inducing Durable Anti-Tumor Responses

Ravetch_JeffreyJeffrey V. Ravetch, MD, PhD, Theresa and Eugene M. Lang Professor, Immunology, Virology, and Microbiology, Rockefeller University


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

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

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 EAGLE, A Novel Bispecific-Like Platform and Immunomodulatory Strategy

Peng_LiLi Peng, PhD, Vice President, Biotherapeutics Discovery, Palleon Pharmaceuticals

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

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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