Engineering Bispecifics Track Banner


二重特異性抗体のエンジニアリング
標的化と機能性の分野における進歩

このカンファレンスプログラムでは、さまざまな治療領域に対応する新たな構造や併用療法など、二重特異性抗体設計の最新の成果が披露されます。主なトピックは、プラットフォームの長所と課題、特殊な作用機序、多用途性、相乗効果のエビデンス、二重特異性抗体のリード化合物や併用療法の選択とスクリーニングのための基準などであり、2つの結合部位の最適な配置や空間分布の決定に関する研究の成果、生成物の機能性を強化するためこの分野の指導的な研究者が行っている工学的な調整の取り組みなども紹介されます。

Final Agenda

11月16日 (木)

12:30 Registration

13:00 Dessert Break in the Exhibit Hall with Poster Viewing

二重特異性抗体のための新たなツールボックスとプラットフォーム

13:30 Chairperson's Opening Remarks

Frank S. Walsh, Ph.D., CEO, Ossianix

13:35 Spy and Snoop Superglues to Engineer Diverse Protein and Peptide Architectures

Mark_HowarthMark Howarth, DPhil, Associate Professor, Protein Nanotechnology, Biochemistry, University of Oxford

There is need for efficient approaches for new bispecific and polyspecific architectures. We created a peptide (SpyTag) spontaneously reacting with its protein partner (SpyCatcher). Reaction is high-yielding, genetically encodable and specific. SpyTag generated affibody polymers for cancer cell capture from blood and cyclized enzymes resilient to boiling. I will describe the use of different peptide superglues for programmable synthesis of multi-functional nanobody/affibody teams, to modulate precisely signaling in cancer cell death.

14:05 TRACS (Trivalent Ab Conjugates): A Plug and Play Multivalent Ab Format

Diego_EllermanDiego Ellerman, Ph.D., Scientist, Protein Chemistry, Genentech

We describe a novel multivalent format based on protein conjugation (TRACS). The building blocks are mAbs and Fabs with good expression yields and stability. A conjugation site that supports high conjugation rates and an efficient process was identified. The spatial arrangement of all the Fabs allows their simultaneous binding with reduced steric hindrance. We provide examples of different TRACS that require concurrent binding of all Fabs for their biological activity.

14:35 Computational Advances in Antibody Discovery: Toward Earlier and Better Assessment, Triage and Optimization

David Pearlman, Ph.D., Senior Principal Scientist, Business Development, Schrodinger, Inc.

In the field of antibody drug discovery, there is growing realization that methods to assess, triage, and avoid liabilities in potential candidates must come early in the discovery process. Recent advances in computational approaches for antibody structure prediction, identification of protein liabilities (such as aggregation propensity), and in methods for protein engineering hold substantial promise in moving us closer to reaching this goal in an effective and efficient manner.

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

二重特異性抗体のための新たなツールボックスとプラットフォーム

15:50 Developing Next Generation Biologics Therapies Using a Novel Bispecific Technology FIT-Ig

Chengbin Wu, Ph.D., CEO, EpimAb Biotherapeutics

We have developed a new generation of bispecific antibody technology termed FIT-Ig, which maintains the structural integrity and biological properties of the 2 parental mAbs, and also shows drug-like properties and high productivity in CHO cells. This unique design of bispecifics does not require any mutations or use of linkers, and is potentially a plug-and-play platform approach for efficient bispecific generation and development.

16:20 Next-Generation Bispecific Antibody Platform Enabling a Turnkey Formatting from Pairs of Monospecific Antibodies as Building Blocks

Eugene Zhukovsky, Ph.D., CSO, Research, Biomunex Pharmaceuticals

The BiXAb platform has a tetra-Fab IgG1 antibody structure and enables plug-and-play bispecific antibody formatting from any pair of mAbs. Point mutations at the CH1/CL interface were introduced to prevent light chain mispairing. BiXAbs possess excellent CHO cells manufacturability and superior drug-like properties (stability, no aggregation, predictable PK). We will present a case study of EGFR/HER2 BiXAb, which exhibits synergistic in vivo activity of both Fabs on their antigen targets.

16:50 End of Day

17:00 Dinner Short Course Registration

17:30 - 20:30 Recommended Dinner Short Course*

SC6: Engineering of Bispecific Antibodies

*Separate registration required

11月17日 (金)

08:00 Registration and Morning Coffee

特異性強化のための改変

08:30 Chairperson's Remarks

Nicolas Fischer, Ph.D., Head, Research, Novimmune

08:35 Structure Guided Specificity Engineering in a MAGE A3 Specific TCR

Stephen_HarperStephen Harper, Ph.D., Group Leader, Protein Engineering Research, Protein Science, Immunocore Ltd.

ImmTAC molecules are bispecific therapeutics that use a TCR targeting domain and anti-CD3 specific scFv effector function to re-direct a potent T cell response to kill cancer cells. Here we present an example of structure guided engineering in a TCR targeting the HLA-A*01 -restricted epitope of MAGE-A3. Mutants were designed to reduce off-target cross-reactivity to a structurally related peptide derived from titin, a protein expressed in cardiac tissue.

09:05 Balancing Selectivity and Efficacy of Bispecific EGFR x c-MET Antibodies and Antibody-Drug Conjugates

Lars Toleikis, Ph.D., Director, Protein Engineering & Antibody Technologies, Merck KGaA

Therapies targeting the tumor-associated antigen epidermal growth factor receptor (EGFR) often suffer from toxicities due to basal EGFR expression in normal tissue. Furthermore, EGFR-directed inhibitors might struggle with limited efficacy because of c-MET mediated resistance mechanisms. Hence, we aim to construct bispecific EGFR x c-MET antibodies employing affinity-optimized binding moieties to balance selectivity and anti-tumor efficacy and to evaluate their potential for an innovative antibody-drug conjugate approach.

09:35 A Tale of Two Specificities: The Balancing Act of Tumor-Targeting Selectivity and Therapeutic Index in Bispecific Antibodies

Yariv_MazorYariv Mazor, Ph.D., Senior Scientist, Antibody Discovery & Protein Engineering, Medimmune, Inc.

Dual targeting of antigen double-positive cancer cells is believed to enhance therapeutic efficacy, restrict escape mechanisms and increase selectivity, leading to reduced systemic toxicity and improved therapeutic index. However, the interplay of factors regulating target selectivity is not well understood and often overlooked. We show in vivo that dual targeting alone is not sufficient to endow selective tumor-targeting, and report the pivotal roles played by the affinity of the individual arms, overall avidity and format valence.

10:05 Coffee Break with Poster Viewing

血液脳関門の透過/リンカーの構成

10:35 KEYNOTE PRESENTATION: Optimizing Delivery of Bispecific Antibodies to the Brain

Frank S. Walsh, Ph.D., CEO, Ossianix

Using in vitro and in vivo phage display technology, we isolated cross species binders to the transferrin receptor 1 (TfR1) from synthetic single domain VNAR libraries. At therapeutic (2 mg/kg) doses delivered by tail vein injection, high levels (>5% brain/plasma ratio) of the bispecific antibodies were found in the brain after 18 hours. We have now optimized the BBB transfer by mutagenesis of the VNAR CDR3 region and identified epitopes involved in transfer.

11:05 Engineering Proteins of Circular Architecture

Anke_SteinmetzAnke Steinmetz, Ph.D., Senior Scientist, Integrated Drug Discovery/Structure, Design & Infomatics, Sanofi R&D

Design of therapeutic proteins seldom aims at circular architecture. Protein engineers in applied pharmaceutical research avoid conceptually sophisticated structural design due to limitations in time, resources, and the lack of user-friendly, fast, easy to use, reliable molecular modeling tools for such purposes. We illustrate how we designed a bispecific antibody of circular self-supporting architecture and present implications of circular versus linear domain constellation on biological effects.

11:35 One Size Does Not Fit All; Opportunities and Challenges of Using Artificial Disulfide Bonds for the Production of Bispecific IgGs

Itai Benhar, Ph.D., Professor, Molecular Microbiology and Biotechnology, Tel-Aviv University

We present a solution for correct pairing of heavy and light chains of bispecific IgGs; an engineered disulfide bond between the antibodies' variable domains that asymmetrically replaces the natural interchain disulfide bond. A novel approach for precise evaluation of correct chain pairing by LC-MC-MS combined with chemical crosslinking is presented. Examples will be provided for some of these bsAbs and future directions of the study will be discussed.

12:05 Sponsored Presentation (Opportunity Available)

12:35 Problem-Solving Breakout Discussions with a Light Snack in the Foyer

13:35 Session Break

効能、安全性、純度、収率の改善に向けた早期段階の選択と改変

14:00 Chairperson's Remarks

Mark Howarth, D.Phil., Associate Professor, Protein Nanotechnology, Biochemistry, University of Oxford

14:05 Early Stage Developability Assessment to Enable Bispecific Design

Laura Lin, Ph.D., Senior Director, BioMedicine Design, Worldwide Research & Development, Pfizer, Inc.

The presentation will showcase our strategies of applying early stage developability assessment to enable the design and optimization of bispecific molecules. I will be sharing several case studies highlighting the impact of such assessment on lead selection and optimization, and predictability of early screens on efficacy, PK, and manufacturability.

14:35 Towards "in Format" Selection and Screening of Bispecific Antibodies

Nicolas Fischer, Ph.D., Head, Research, Novimmune

Optimal geometry of the two binding sites is often important for the function of Bispecific Antibodies. In addition to combinatorial assembly followed by extensive functional testing, we aimed at identifying appropriate binding pairs as early as possible, i.e. at selection and screening stages. We have developed a dual-display technology that allows the an 'in format' preferential enrichment and co-selection of antibody fragments based on target co-engagement. Different modalities to maximize the throughput of functional screening for BiAb have been implemented to optimize the discovery process.

15:05 Using a Design of Experiments Approach to Identify Critical Residues in FcR Engagement for Both IgG1 and IgG4 Fc-Hexamers

Shirley_PetersShirley Peters, Ph.D., Senior Scientist, Protein Sciences, UCB

We have used antibody engineering and recombinant expression to produce Fc with controlled hexa-valency, "Fc-multimer". Fc-hexamer engages with FcR's on multiple cell types and was engineered to maximize potency whilst minimizing potential safety concerns. Initial in vitro and in vivo experiments showed differential efficacy for IgG1 and IgG4-hexamers and we used a statistical design approach ('Design of Experiments') to explore the two extremes defined by these two isotypes.

15:35 Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency

Stylianos Bournazos, Ph.D., Research Assistant Professor, Molecular Genetics and Immunology, The Rockefeller University

A key immune evasion mechanism of HIV-1 is the low density of the envelope glycoprotein (Env) on the viral surface, which precludes high-avidity bivalent interactions of anti-Env antibodies. By engineering the hinge domain of IgG to favor heterobivalent interactions, we generated bispecific anti-Env antibodies with improved neutralization potency and therapeutic activity. These findings suggest innovative strategies for generating engineered bispecific antibodies with enhanced activity, representing ideal candidate molecules for HIV-1 and other viral infections.

16:05 Product Quality by Design: Cell Line Engineering to Enhance Specific FAP DR5 2+2 CrossMab Yields

Wolfgang_PaulWolfgang Paul, Ph.D., Senior Scientist & Group Leader, Cell Culture Research Pharma Research and Early Development, Large Molecule Research, Roche

The challenge for the production of new complex protein formats is the generation of cell lines producing high yields of functional proteins with low amounts of product related site products. The novel bispecific agonistic FAP-DR5 antibody contains tetravalent binding properties (2+2 format), secreted with several product-related side products. The presented approach shows successfully the improvement of specific properties by subsequent transfection of a production cell line to decrease the formation of these side products.

16:35 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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