Cambridge Healthtech Institute's Ninth Annual

Engineering Bispecific Antibodies

( 二重特異性抗体のエンジニアリング )

生物製剤の分野における研究の進展

2018年5月3-4日 | World Trade Center | マサチューセッツ州ボストン

 

The field of bispecific antibodies continues to be energized as applications in immuno-oncology show impressive and unprecedented results while emerging formats and delivery modes are expanding. The Ninth Annual Engineering Bispecific Antibodies meeting will showcase scientists presenting unpublished results and progress to date. Don't miss this seminal event for engineering bispecific antibodies that is transforming the industry, and ultimately, the clinic.

Scientific Advisory Board

Mahiuddin Ahmed, PhD, Assistant Attending Biologist, Assistant Member, Department of Pediatrics, Memorial Sloan Kettering Cancer Center

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, Director, Protein Sciences and Antibody Technology, Jounce Therapeutics

G. Jonah Rainey, PhD, Executive Director, Head of Antibody Research, MabVax Therapeutics Holdings, Inc.

 

Final Agenda

5月3日 (木)

二重特異性抗体とCAR-T細胞のアプローチ:直接比較

12:00 pm Registration

12:35 Luncheon in the Exhibit Hall with Poster Viewing

1:40 Chairperson's Remarks

G. Jonah Rainey, PhD, Executive Director, Head of Antibody Research, MabVax Therapeutics Holdings, Inc.

1:50 Preventing Antigen Escape with CD19/CD20 Bispecific Chimeric Antigen Receptors

Yvonne Y. Chen, PhD, Assistant Professor, Chemical and Biomolecular Engineering, University of California, Los Angeles

Antigen escape is a major cause of cancer remission in patients treated with CD19 chimeric antigen receptor (CAR)-T cell therapy. Here, we report a bispecific, OR-gate CAR that can trigger robust T cell activation in response to target cells that present either CD19 or CD20, thus preventing malignant B cells from escaping T- cell therapy by simply losing CD19 expression.

2:20 Bispecific CARs Targeting Discreet Conserved Sites on the HIV Env Glycoptoein: Toward a Functional Cure

Edward A. Berger, PhD, Chief, Molecular Structure Section, Laboratory of Viral Diseases, NIAID, National Institutes of Health

To achieve long-term (lifelong?) HIV suppression, CARs must be engineered not only to be highly potent, but also to approach the ideal properties of inescapability and non-immunogenicity. We have designed all-human bispecific CARs targeting containing CD4 linked to a second moiety that targets a highly conserved (essential) site on HIV-gp120. The second moiety enhances potency, and prevents the CD4 from acting as an HIV entry receptor on CD8+ T cells.


2:50 KEYNOTE PRESENTATION: Harnessing T Cells as Cancer Therapeutics: Bispecifics vs. CARs

Stephen Gottschalk, MD, Chair, Bone Marrow Transplantation & Cellular Therapy, St. Jude Children's Research Hospital

Redirecting T cells with bispecifics or CARs has shown impressive clinical results for CD19+ hematological malignancies resulting in their FDA approval. However, for other malignancies, including solid tumors and brain tumors, this therapeutic approach has been less effective. In my talk, I will review pros and cons of bispecifics and CARs, current obstacles, and preclinical efforts to improve their efficacy.

3:20 Industrializing IO Therapeutic Discovery Platforms: Multispecifics, Engineered TCRs and CARs

Maria Wendt, PhD, Head, Science, Biologics, Genedata

Novel classes of bio-molecules are currently evaluated for their use in cancer immunotherapy. Bi- and multi-specific antibodies, Ab-cytokine fusion proteins, non-Ig scaffolds, chimeric antigen receptors (CARs), engineered TCRs and TCR-based bispecific constructs promise significant advantages.However, these highly engineered molecules pose new challenges in design, engineering, cloning, expression, purification, and analytics. We present an infrastructure that addresses these challenges and enables the industrialization of these various novel therapeutic platforms.

3:50 Networking Refreshment Break

二重特異性抗体の改善に向けたエンジニアリング

4:15 Chairperson's Remarks

Robert Mabry, PhD, VP, Protein Science. Cogen Therapeutics, Inc.

4:20 Immunoglobulin Domain Interface Exchange as a Platform Technology to Engineer Bispecific Antibodies

Stanislas Blein, PhD, Senior Director, Head Antibody Engineering, Biologics Research, Glenmark Pharmaceuticals S.A.

Glenmark Pharmaceuticals' BEAT® platform is a robust and versatile bispecific antibody platform based on heavy chain heterodimerization. The technology relies on biomimicry wherein the protein-protein interfaces of two different immunoglobulin constant domain pairs are exchanged in part or fully to design new heterodimeric domains. Using our platform, we have engineered and in-house manufactured two clinical stage bispecific antibodies for cancer therapy. Engineering and Phase I manufacturing data will be presented.

4:50 "In Format" Display, Selection and Screening of Bispecific Antibodies

Nicolas Fischer, PhD, Head of Research, Novimmune

The unique mode of action of bispecific antibodies often requires binding sites in a defined geometry. Rather than randomly combining antibodies into one or multiple bispecific formats and testing of purified bispecific candidates, it would be preferable to screen and even co-select binders that support the desired mode of action. We have developed a dual-display technology allowing 'in format' enrichment of antibody fragments based on target co-engagement. In addition, different modalities to maximize throughput of functional screening for BiAb have been implemented.

5:20 End of Day

5:20 Registration for Dinner Short Courses*

*Separate registration required.

5月4日 (金)

8:00 am Morning Coffee

二重特異性抗体作製の新たな方法

8:30 Chairperson's Remarks

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

8:35 Redirecting T-Cell for Cancer Therapy Using Antibody Circuits

Mark Cobbold, MD, PhD, Cellular Immunotherapy Program, Center for Cancer Immunology, Massachusetts General Hospital; Member of the Faculty of Medicine, Harvard Medical School

Cytotoxic T-cells are amongst the most potent arms of the immune response, and immunotherapies harnessing these exhibit powerful effects against cancer. Separating toxicity from efficacy remains an ongoing challenge for both CAR T and bispecific T-cell engaging biologics. Here we describe a new antibody-based approach to selectively engage T-cells at tumor sites using Boolean operator logic based upon antigen and protease target site expression. By applying logic gating, we obviate many of the current challenges with T-cell engaging antibodies.

9:05 Productive Common Light Chain Libraries Yield Diverse Panels of High Affinity Bispecific Antibodies

Thomas J. Van Blarcom, PhD, Associate Research Fellow, Oncology Research and Development, Pfizer, Inc., Rinat Laboratories

Here we describe the design of a synthetic human antibody library based on common light chains to generate antibodies with biochemical and biophysical properties that are indistinguishable to traditional therapeutic monoclonal antibodies. We used this library to generate diverse panels of well-behaved, high affinity antibodies toward a variety of epitopes across multiple antigens including mouse 4-1BB, a therapeutically important T cell costimulatory receptor. This approach allowed us to identify antibodies with a wide range of agonistic activity which are being used to further investigate the therapeutic potential of antibodies targeting one or more epitopes of 4-1BB.

9:35 Sponsored Presentation (Opportunity Available)

10:05 Networking Coffee Break

治療指数の向上:二重特異性抗体の安全性と効能の強化

10:35 Chairperson's Remarks

Mahiuddin Ahmed, PhD, Assistant Member, Pediatrics, Memorial Sloan Kettering Cancer Center


10:35 KEYNOTE PRESENTATION: Engineered Antibody Derivatives for Modulation of Pharmacokinetic Properties of Small Molecules and Targeted Payload Delivery

Ulrich Brinkmann, PhD, Roche Pharma Research & Early Development, Large Molecule Research, Roche Innovation Center Munich (RICM), Penzberg, Germany

The presentation covers recent applications of hapten-binding antibodies and engineered derivatives, including modulation of the pharmacokinetic properties of small compounds or peptides. Hapten-binding antibodies can also serve as payload-capture modules of bispecific and/or multifunctional antibody formats. Here they serve as non-covalent or covalent coupling modules to haptenylated compounds, to enable specific delivery to tissues or cells.

11:05 IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, in vivo Expansion, and Enhanced Function

Jeffrey S. Miller, MD, Professor of Medicine, Deputy Director, Masonic Cancer Center, Hematology, Oncology and Transplantation, University of Minnesota

The effectiveness of NK cell infusions to induce leukemic remission is limited by lack of both antigen specificity and in vivo expansion. To address the first issue, we previously generated a bispecific killer engager (BiKE) containing single-chain scFv against CD16 and CD33 to create an immunologic synapse between NK cells and CD33(+) myeloid targets. We have now incorporated a novel modified human IL15 crosslinker, producing a 161533 trispecific killer engager (TriKE) to induce expansion, priming, and survival, which we hypothesize will enhance clinical efficacy.

11:35 Anti-Tumor x Anti-DOTA Bispecific Antibodies for Pre-Targeted Radioimmunotherapy

Steven M. Larson, MD, FACNM, FACR, Donna and Benjamin M. Rosen Chair, Attending Molecular Imaging and Therapy Service, Radiology; Member and Lab Head, Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute; Professor, Radiology, Weill Cornell University Medical Center, Radioimmunotherapy and Theranostics, Ludwig Center

We recently developed a promising theranostic; treatment of human solid tumors using a pretargeted radioimmunotherapy strategy (DOTAPRIT) based on a tumor antigen-targeting bispecific antibody (bsAb) and a small-molecule radioactive hapten, a complex of lutetium-177 (177Lu) and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177Lu-DOTA-Bn) that leads to high therapeutic index (Tis) for radiosensitive tissues such as blood and kidney. Studies targeting 3 solid tumor human xenografts in mouse models have shown proof of principle.

12:05 pm Trispecific Broadly Neutralizing HIV Antibodies for Prevention and Treatment of HIV-1 Infection

Amarendra Pegu, PhD, Staff Scientist, Laboratory of Virology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH

We have 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.

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善に向けたエンジニアリング

1:35 Chairperson's Remarks

Robert Mabry, PhD, VP, Protein Science. Cogen Therapeutics, Inc.

1:40 A Semi High-Throughput Method for Screening Small Bispecific Antibodies with High Cytotoxicity

Mitsuo Umetsu, PhD, Professor, Biomolecular Engineering, Graduate School of Engineering, Tohoku University

A number of studies on small bispecific T-cell-recruiting antibodies have showed that their cytotoxicity is critically dependent on their structural and functional properties. In this study, we constructed an optimized procedure for identifying highly cytotoxic antibodies from a variety of the T-cell-recruiting antibodies engineered from a series of antibodies against EGFR family and T-cell receptors, demonstrating the synergistic effects between target, epitope, binding affinity, and antibody structure.

2:10 A New Approach for Generating Bispecific Antibodies Based on a Common Light Chain Format and the Stable Architecture of Human Immunoglobulin G1

John de Kruif, PhD, CTO, Merus NV

We describe an approach for generating bispecific antibodies using common light chains and the stable architecture of human immunoglobulin G1. We used iterative experimental validation and computational modeling to identify an Fc variant pair that drives efficient heterodimerization of the antibody heavy chains. Long-term accelerated stability assays confirmed that this molecule is highly stable and has excellent biophysical characteristics. We show how this molecule is integrated in our discovery platform.

2:40 FIT-Ig: A Novel Tetravalent Bispecific Antibody Design without Peptide Linkers and Fc Mutations

Chengbin Wu, PhD, CEO, EpimAb Biotherapeutics

We describe here a new bispecific design, named Fabs-in-tandem immunoglobulin (FIT-Ig), in which two Fabs are fused directly in a crisscross orientation without any mutations or use of peptide linkers. This unique design provides a symmetrical IgG-like bispecific molecule with correct association of 2 sets of VH/VL pairs. In this paper, we show that FIT-Ig molecules exhibit excellent drug-like properties, in vitro and in vivo functions, as well as manufacturing efficiency for commercial development.

3:10 Chemically-Generated Immunomodulatory Bispecific Antibodies

Yanwen Fu, PhD, Director, Antibody Technology and Chemical Biology, Sorrento Therapeutics

Bispecific antibodies (BsAbs) capable of engaging cytotoxic T lymphocytes for tumor cell lysis are emerging as a new option for cancer treatment. Sorrento has developed a robust platform to generate BsAbs through hetero-dimerization of two chemically-modified antibodies or antibody fragments. Using this approach, we synthesized a variety of immunomodulatory bispecific antibodies. Results from BsAb assembly, biophysical characterization and effector-cell mediated cytotoxicity assays will be presented.

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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