Cambridge Healthtech Institute’s Inaugural

Bispecific Antibody Design and Applications
( 二重特異性抗体の設計と応用 )

新たなプラットフォームを用いた免疫療法の治療可能性の向上

2020年3月11日~12日

 

二重特異性抗体の設計と応用をテーマにしたこのカンファレンスプログラムでは、二重特異性抗体の開発とがん免疫療法への応用にまつわる課題が焦点となる予定であり、T細胞やNK細胞のエンゲージャーなどをリダイレクトする細胞傷害性エフェクター細胞、抗体薬物複合体 (ADC) の効能と内在化の強化などさまざまなトピックが取り上げられます。

Final Agenda

3月11日(水)

PLENARY KEYNOTE SESSION

11:15 Organizer’s Remarks

Ngoc ‘Emily’ Le, PhD, Conference Producer, Cambridge Healthtech Institute

11:20 Chairperson’s Remarks

Andrew Sewell, PhD, Distinguished Research Professor and Wellcome Trust Senior Investigator, Infection & Immunity, Cardiff University School of Medicine

11:30 Strategies to Improve Antitumor Efficacy of Genetically Engineered T Cells

Stanley Riddell, MD, Scientific Director, Clinical Research, Fred Hutchinson Cancer Research Center; Professor, University of Washington School of Medicine

Immune cells can be readily genetically modified to express natural tumor targeting antigen receptors or synthetic chimeric antigen receptors (CARs) that activate immune cell signaling pathways to result in destruction of tumor cells expressing the relevant target molecule. The presentation will discuss advances in our understanding of receptor signaling and the development of strategies that combine therapeutic agents to improve efficacy and safely extend the spectrum of cancers that can be treated with cell therapies.

12:00 PD-1 Antibodies Are Transforming Cancer Treatment

Roy D. Baynes, MD, PhD, Senior Vice President and Head, Global Clinical Development, CMO, Merck Sharpe & Dohme

PD-1 antibodies have shown significant activity as monotherapy across multiple cancer types and lines of therapy. Precision medicine tools have been used to identify subjects most likely to respond to PD-1 antibody monotherapy, to provide insight to potential resistance mechanisms, and to inform combination therapies. A number of these combinations have demonstrated significant activity in additional tumor types and lines of therapy.

12:30 Enjoy Lunch on Your Own

二重特異性抗体の創薬、設計、最適化

13:30 Chairperson’s Opening Remarks

Paul Widboom, PhD, Associate Director, Antibody Discovery, Adimab LLC


13:35 KEYNOTE PRESENTATION: Current Landscape and Outlook of Bispecific Antibody

Roland Kontermann, PhD, Professor, Biomedical Engineering, Institute of Cell Biology and Immunology, University of Stuttgart

Bispecific antibodies have experienced a dramatic interest and growth for therapeutic applications, with more than 80 molecules in clinical development; e.g., in oncology, immuno-oncology, but also for non-oncology applications. An overview will be given on the making of bispecific antibodies and the various therapeutic concepts and applications, e.g., for dual targeting strategies, retargeting of immune effector cells, and substitution therapy by mimicking the function of natural proteins.

14:05 Unbiased functional screening for the identification of effective and safe T cell engagers

Veninga_HenrikeHenrike Veninga, PhD, Senior Scientist, Research, Merus

Case studies of clinical assets will be discussed that highlight the role of empirical functional screening. Examples will include both I-O and targeted therapies demonstrating that diverse functional readouts can be incorporated into bispecific antibodies screens.

GemPharmatech 14:35 Development and Application of Innovative Immuno-Oncology Mouse Models

Guo_ShiyingShiying Guo, PhD, Study Director, Pharmacology & Phenotyping, GemPharmatech Co., Ltd.

Mouse is the most commonly used animal model in preclinical evaluation of new drugs. However, with lacking human drug targets and human immune cells, mouse cannot be directly used for preclinical study of macromolecular drugs such as antibodies. Genetic modified mouse model through human gene replacement and immune reconstituted NCG mouse developed by engraftment of human PBMC or CD34+ HSC can exactly solve this problem, which make them the powerful tools for pharmacological effect studies.

15:05 Refreshment Break in the Exhibit Hall with Poster Viewing

二重特異性抗体の創薬、設計、最適化 (続き)

15:45 Selection-Based Development of a Heavy Chain-Light Chain Pairing Technology

Widboom_PaulPaul Widboom, PhD, Associate Director, Antibody Discovery, Adimab LLC

A significant challenge in the development of multivalent bispecific antibodies involves solving the “heavy chain-light chain pairing problem.” While most heavy chain-light chain pairs possess a preference for their cognate partner, noncognate mispairing occurs. Avoiding these undesired mispairs is a relevant challenge in the field of bispecific antibody manufacturing. Here we present a solution to the heavy chain-light chain problem derived from a novel selection system. This system finds mutations that improve cognate heavy chain-light chain pairing while maintaining antigen binding affinity.

16:15 CrossMabs, Fusions and DutaFabs: An Update on Roche’s Bispecific Platforms

Hinner_MarlonMarlon J. Hinner, PhD, Principal Scientist, Group Leader Phage Display, Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich

Bi- and multispecific antibodies facilitate novel modes of action for the treatment of diseases including but not limited to immuno-oncology and autoimmunity. With multiple bispecifics programs in pre-clinical and clinical development, Roche is constantly increasing its experience and expertise in this area. In this presentation, an update on new and existing bispecific antibody formats and their applications will be provided. 

16:45 Selective Inhibition of the Ubiquitously Expressed Immune Checkpoint CD47 on Cancer Cells with Bispecific Antibodies

Majocchi_StefanoStefano Majocchi, PhD, Therapeutic Program Lead, Light Chain Bioscience

Up-regulation of CD47 is an immune evasion mechanism used by both solid and hematological cancers which is generally associated with poor clinical outcome. In the past years CD47 has become the focus of various therapeutic approaches, but because of the ubiquitous expression of CD47, molecules which cannot discriminate between on-tumor and off-tumor CD47 were shown to result in poor pharmacokinetic properties and/or hematological toxicities. By designing bispecific antibodies with unbalanced affinity for CD47 and for selected Tumor Associated Antigens (TAA), we can selectively target CD47 on TAA-expressing tumor cells, resulting in potent anti-cancer efficacy both in vitro and in vivo while retaining favorable pharmacological and toxicology profiles.

17:15 Problem Solving Breakout Discussions (See complete list of Problem-Solving Breakout Discussion)

Immunogenicity of Bispecific Antibodies

Moderator: Anne Mansson-Kvarnhammar, PhD, Senior Scientist, Alligator Bioscience AB

  • What challenges could one expect for novel bispecific scaffolds in terms of immunogenicity?
  • What can be done to test this early to avoid immunogenicity in the clinic?
  • What is the usefulness and “predictability” of in silico and in vitro assays to predict clinical immunogenicity of IO antibodies?

Going Beyond Bispecifics – Trispecific Antibodies and Other “Multispecific” Approaches

Moderator: Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.

  • What are the opportunities for using multispecifics
  • What challenges would one expect for multispecifics
  • Which benefits are expected when using multispecifics
  • Which approaches are enabled by multispecifics and which ones remain impossible?

18:15 Dinner Short Course Registration

18:45 Dinner Short Course


Recommended Short Course*

Dinner SC3: Engineering of Bispecific Antibodies and Multi-Specific Non-Antibody Scaffolds - LEARN MORE

Mathieu Cinier, PhD, Scientific Director, Affilogic

Mattias Levin, PhD, Senior Scientist, Antibody Engineering, Alligator Bioscience AB

*Separate registration required.

3月12日(木)

8:00 Registration and Morning Coffee

T細胞エンゲージャー

8:30 Chairperson’s Remarks

Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.

8:35 Advancing T Cell Engaging Bispecific Antibodies and Optimized Cytokines for Immuno-Oncology

Bernett_Matthew_1Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.

Xencor has applied its XmAb bispecific technology platform to create multiple novel modalities for modulating T cells. These include tumor-associated antigen x CD3 bispecifics for mediating cytotoxicity against tumor cells, dual checkpoint inhibitor bispecifics for T cell derepression, and a bispecific that combines checkpoint blockade and costimulation. Additionally, we have utilized our heterodimeric Fc domain to create novel long-acting cytokine Fc-fusions for expanding T cells.

9:05 Advances in Immunotherapy: Maximizing T Cell Responses with Tumor Antigen Directed Bispecific Antibodies and Co-Stimulation

Karasarides_MariaMaria Karasarides, PhD, Executive Director, ImmunoOncology, Regeneron Pharmaceuticals

Immunotherapy has advanced as an integral cancer treatment modality primarily from the survival outcomes observed from checkpoint inhibition (α-CTLA-4, α-PD-1, α-PD-L1). While the benefits from checkpoint inhibition are evident, long term survival is enjoyed by only a small proportion of cancer patients harboring immune-responsive tumors. In this talk we will (1) review the long term survival outcomes provided by checkpoint inhibition (2) discuss immunotherapy combination strategies and outcomes to date (3) explore potential of achieving maximal T cell responses through the use of tumor antigen directed bispecific antibodies and co-stimulation to address the unmet need remaining for cancer patients with immune-response and non-responsive tumors.

9:35 Pharmacokinetics And Immunogenicity Of Three Anti-HER2/CD3 T Cell Dependent Bispecific (TDB) with Varying Affinities to Their Targets in Cynomolgus Monkeys

Meric_Ovacik_AyseAyse Meric Ovacik, PhD, Scientist, Preclinical and Translational Pharmacokinetics in Development Sciences, Genentech

The clinical success of heme tumor-targeting TDBs is to be followed solid tumor targeting TDBs. More in-depth tools are needed to be developed for understanding solid tumor targeting TDBs as they required to be distributed to the tissues. We will present a systematic approach to develop a minimal PBPK model of HER 2/CD3 for projecting clinical exposures. 

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

10:15 Speed Networking in the Exhibit Hall

二重特異性抗体と抗体薬物複合体 (ADC)

10:45 Chairperson’s Remarks

Julian Andreev, PhD, Research Fellow, Oncology & Angiogensis, Regeneron Pharmaceuticals, Inc.

10:50 ZW49 – A Novel Bispecific Antibody-Drug Conjugate (ADC) Targeting HER2-Expressing Cancers

Babcook_JohnJohn 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.

11:20 Bispecific ADCs Targeting HER2: Intracellular Trafficking of the Antibody Dictates the Choice of Linker-Payload

Andreev_JulianJulian Andreev, PhD, Research Fellow, Oncology & Angiogensis, Regeneron Pharmaceuticals, Inc.

Bispecific ADCs bridging HER2 and high turnover proteins travel to lysosomes and improve efficacy of HER2 ADCs with stable linker-DM1. Biparatopic HER2 ADCs induce target recycling and require cleavable linker for greater efficacy. Combining various bispecific antibody approaches with correct linker-payload technology may allow to generate ADCs with better efficacy and safety profiles.

11:50 Site-Selective Antibody Conjugates by Disulfide Bridging and Cysteine-to-Lysine Transfer

Baker_jamieJamie Baker, PhD, Chemistry, University College London

The selective chemical modification of specific amino-acid residues in antibodies and antibody fragments is likely to form the basis of the next generation of ADCs, and also offer the prospect of chemical bispecifics and related conjugates. In this talk, two different strategies will be presented for the construction of highly homogenous conjugates from native antibodies, precluding the need for engineering. The first strategy involves targeting the interchain disulfide bonds with bridging reagents. This has been exploited to generate potent ADCs, bispecific conjugates and even trispecifics. The second strategy we have recently pioneered involves the use of cysteine residues as temporary hooks, delivering conjugation reagents to specific lysine residues. The resultant lysine conjugates are site-selective and offer the advantage of generating clinically validated, robustly stable, amide linkages.

MaxCyte12:20 Networking Lunch in the Exhibit Hall with Poster Viewing

二重特異性抗体とチェックポイント阻害剤

13:05 Chairperson’s Remarks

Dimitris Skokos, PhD, Director, Immunity & Inflammation, Regeneron Pharmaceuticals

13:10 A Novel Class of Fully Human Co-Stimulatory Bispecific Antibodies for Cancer Immunotherapy

Skokos_DimitrisDimitris Skokos, PhD, Associate Director, Immunology & Inflammation, Regeneron Pharmaceuticals

T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-MHC complexes (“signal 1”); activation is then enhanced by engagement of a second “co-stimulatory” receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell (“signal 2”). Recently described CD3-based “bispecific antibodies” act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific, and bridging to TCR/CD3 with the other.

13:40 Combination Immunotherapy: The New Paradigm for the Treatment of Metastatic Melanoma and Renal Cell Carcinomay

John WagstaffJohn Wagstaff, MD, MB ChB, Director, South West Wales Cancer Institute & Professor, Medical Oncology, Swansea University College of Medicine 

Both melanoma and renal cell carcinoma (RCC) has been increasing incidence over the past twenty years. When metastatic disease develops these cancers were notorious for their lack of response to conventional chemotherapy and the prognosis of these patients was poor. The median survivals were between 11 and 13 months. The discovery of anti-CTLA4 (ipilimumab (Ipi)) and anti-PD1 (nivolumab (Nivo)) inhibitory monoclonal antibodies has transformed the prognosis of these patients. The five-year survival of patients with metastatic melanoma is 53% and the survival curve is flat suggesting that these patients may be cured. In RCC the median survival with sunitinib was 26.1 months but the median OS for Ipi+Nivo has not been reached. These impressive results do however come at the cost of autoimmune-related adverse events but despite this quality of life improves with these new therapies. these therapies herald a new era in the treatment of metastatic cancers.

14:10 ATOR-1015 – From Discovery to the Clinic

Mansson-Kvarnhammar_AnneAnne Mansson-Kvarnhammar, PhD, Senior Scientist, Alligator Bioscience AB

ATOR-1015 is a tumor-directed CTLA-4 x OX40 bispecific antibody designed to improve the efficacy and safety of current CTLA-4 targeting therapies. This talk will cover preclinical in vitro and in vivo data and give an overview of the ongoing Phase 1 study and the clinical development path.

14:40 Managing T Cell Activation and Macrophage Differentiation with a Dual Player Nanofitin to Treat Cancer

Cinier_MathieuMathieu Cinier, PhD, Scientific Director, Affilogic

Success of immune check point inhibitors highly depends of the number of T cell infiltrates as well as other factors such as inflammatory markers (e.g.; macrophage differentiation). We demonstrated the efficacy of a combination targeting several immunology pathways to treat cancer.

15:10 Close of Summit

* 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。