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Today’s protein scientists need to be creative and think outside the box. As standard monoclonal antibodies give way to new and diverse therapeutic modalities, protein scientists have to develop strategies that can better engineer these complex molecules, and improve their targeting, specificity, binding, intracellular penetration and bioactivity.

PEGS Europe’s 3rd Annual Engineering Antibodies invites scientists to present their creativity in designing novel antibody formats or alternative platforms, and in leveraging strategies and technologies to overcome challenging intracellular and membrane targets.


Final Agenda

WEDNESDAY 14 NOVEMBER

07:45 Registration and Morning Coffee

ANTIBODIES AGAINST INTRACELLULAR AND CHALLENGING TARGETS

08:30 Chairperson’s Remarks

Ulrich Brinkmann, PhD, Expert Scientist, Molecular Engineering, Roche


08:35 KEYNOTE PRESENTATION: Grp 94, an Intracellular Target of Antibody-Based Immunotherapy of Malignant Diseases – Opportunities and Challenges

Ferrone_SoldanoSoldano Ferrone, MD, PhD, Professor, Surgery, Massachusetts General Hospital, Harvard Medical School

The scFv W9 has been isolated from a phage display human antibody library. This antibody has the unique specificity to recognize an extracellular epitope of the heat shock protein Grp94. The characteristics and functional properties of this antibody will be described. In addition, the obstacles to the clinical applications of this and the strategies to overcome them will be discussed.

09:05 Engineering Alphabodies to Target Intractable Intracellular Cancer Targets

McGrath_YvonneYvonne McGrath, PhD, CSO, Complix

Alphabodies comprise a triple helical protein scaffold that can be engineered to bind target proteins with high specificity and affinity. Further modifications allow these biologics to traverse the cell membrane and inhibit disease-associated intracellular targets. A panel of these Alphabodies has been engineered to bind and inhibit important oncology intracellular targets hitherto considered intractable with conventional small molecules. Functional assessment of a selection of these Alphabodies will be presented.

09:35 Generating Potent and Selective Inhibitors of Kv1.3 Ion Channel by Fusing Venom Derived Mini Proteins into Peripheral CDR Loops of Antibodies

Karatt-Vellatt_AneeshAneesh Karatt-Vellatt, PhD, Group Leader, Antibody and Protein Engineering, IONTAS Ltd.

Pathogenic TEM cells drive many autoimmune disorders and are uniquely dependent on the Kv1.3 channel. A number of venom derived cysteine-rich mini-protein inhibitors of Kv1.3 are being developed as potential drug candidates, but can suffer from manufacturing difficulties, short half-lives and a lack of specificity. Using proprietary KnotBody technology, IONTAS has developed a panel of potent and selective Kv1.3 inhibitors that can be further developed as long acting immunomodulators for the treatment of autoimmune disorders.

10:05 Presentation to be Announced

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

STRATEGIES TO IMPROVE TARGETING, BINDING AND BIOACTIVITY OF MOLECULES

11:15 Targeting the Matrix Metalloproteinase (MMP)-14/MMP-2/Integrin αvβ3 Axis with Multispecific N-TIMP2-Based Antagonists for Cancer Therapy

Papo_NivNiv Papo, PhD, Group Leader, Assistant Professor, Biotechnology Engineering, Ben-Gurion University

The MMP-14/MMP-2/integrin αvβ3 axis thus constitutes a putative target for therapeutic interventions, but inhibitors that target this axis remain to be developed. Based on screening of a N-TIMP2 mutant library, we generated efficient protein monomers and heterodimer antagonists that contain monovalent and bivalent binding epitopes to MMP-14 and integrin αvβ3. These results enabled us to investigate the individual roles of the three signaling molecules in various malignant processes.

11:45 Multiple Mechanism of Ligand Blocking by Antibodies

Garces_FernandoFernando Garces, PhD, Senior Scientist, Therapeutic Discovery, Amgen

Antibodies can be generated and selected to block the binding of a protein receptor to its protein ligand. In such cases, the set of molecules generated usually show low sequence diversity and a common inhibition mechanism. Here we present a case study, where we have structurally characterized multiple antibodies, with high sequence diversity that recognize a protein receptor and block protein/ligand binding via several inhibition mechanisms.

12:15 The Molecular Landscape of the Immune Response following Treatment with Biologics

Wine_YarivYariv Wine, PhD, Assistant Professor, School of Molecular Cell Biology and Biotechnology, Tel Aviv University

The mechanisms that lead to the generation of ADAs and their molecular composition are unknown. We developed a new immunoassay to determine ADA level and their neutralizing capacity. We found that therapeutic mAb infusion mounts a vaccine boost like response reflected in a rapid rise of lymphocytes post-infusion. B Cells were isolated and their repertoire features were determined by NGS. Collectively we found: i) an increase in lambda/kappa antibody light chain ratio in the neutralizing ADA compartment; ii) an increase in ADA clonal polarization post-infusion.

12:45 An Integrated Approach to Managing Immunogenicity Risk And Optimum Protein Design

Jeremy Fry, DPhil, Director, Sales, ProImmune

Integrated platforms can be used to mitigate immunogenicity risk and characterize immune responses during the drug design and development stages. ProImmune offers mutational activity mapping for optimal protein design, DC-T/T cell proliferation assays for biologic lead selection/optimization, a Mass Spectrometry assay for characterization of antigen presentation; HLA-peptide binding assays to characterize individual epitopes & undiluted whole blood cytokine storm assays.

13:15 Luncheon Presentation I: Build Better Biologics with Machine Learning and Synbio

Claes Gustafsson, Co-Founder and CCO, ATUM (formerly DNA2.0)

This presentation will showcase how ATUM combines recent developments in genome engineering, automation, big data and product analytics to increase efficiency of engineering and developability of biologics and cell lines. Cell lines generated using the LeapIn® transposase combined with optimized vector constructs, proprietary codon optimization and QSAR-based protein engineering allow for an information rich and efficient optimization of mAbs, bispecifics, CAR-T molecules, and the increasingly complex biologics approaching the market place.

13:45 Luncheon Presentation II (Sponsorship Opportunity Available)

14:15 Session Break

NOVEL FORMATS AND ALTERNATIVE PLATFORMS

14:30 Chairperson’s Remarks

Philip M. Kim, PhD, Associate Professor, Donnelly Centre, University of Toronto

14:35 Use of Small and Stable Antibody Scaffold Fv-clasp to Facilitate Structural Studies of Drug-Target Molecules

Takagi_JunichiJunichi Takagi, PhD, Professor, Laboratory, Protein Synthesis and Expression, Institute for Protein Research, Osaka University

“Fv-clasp’’ is an artificially designed, small (˜37 kDa) two-chain antibody fragment format compatible with bacterial expression and is applicable to any IgG antibodies. The conformational rigidity and high heat stability of Fv-clasp contributed to its superior “chaperoning” activity over conventional Fab fragment, and facilitated the structure determination of many drug target proteins with high conformational flexibility.

15:05 Multi-Specific, Multi-Valent and Bi-Paratopic Nanobodies: Progress toward the Clinic

Boutton_CarloCarlo Boutton, PhD, Director, Technology & Information Management, Ablynx NV

Small Nanobodies with their modular design are a perfect starting point for generating multivalent and multispecific therapeutics in a wide range of human diseases. The formatting flexibility of the platform allows the development of the most optimal drug formats. The development of Nanobodies® and their progress towards the clinic will be shown by a number of examples.

15:35 Refreshment Break in the Exhibit Hall with Poster Viewing

16:15 V565 Is an Orally-Administered, Protease-Resistant, Anti-TNF Domain Antibody for the Treatment of Inflammatory Bowel Disease

Roberts_KevinKevin Roberts, PhD, Senior Scientist, VHsquared Ltd.

V565 is an anti-TNF domain antibody for oral administration in IBD patients, engineered to resist intestinal proteases. Oral dosing of V565, formulated in enteric-coated minitablets, resulted in micromolar levels of active V565 in the ileal fluid of volunteers fitted with ileostomy bags and in the faeces of Crohn’s disease patients. Oral administration to five ulcerative colitis patients for 6 to 7 days resulted in V565 localisation to the lamina propria and inhibition of mucosal inflammatory processes.

16:45 Development of mRNA-Encoded Bispecific Antibodies Targeting Solid Tumors

Hayat Bähr-Mahmud, PhD, Deputy Head, Bispecific Antibodies, BioNTech

Successful application of many T cell-engaging bispecific antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed (IVT) pharmacologically optimized and nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Due to the fast manufacturing process of pharmaceutical mRNA, the RiboMAB approach could accelerate the clinical development of novel bispecific antibodies.

17:15 Development of Highly Potent T Cell Receptor Bispecifics Targeting Tumor-Specific HLA Ligands

Bunk_SebastianSebastian Bunk, PhD, Director, Immunology, Immatics Biotechnologies GmbH

T cell receptor (TCR)-based immunotherapy has emerged as a promising treatment modality for malignant diseases. Immatic’s bispecific TCR molecules utilize affinity maturated and selective TCRs for targeting of tumor-specific, human leucocyte antigen (HLA)-bound peptides as identified by the target discovery engine XPRESIDENT®. The TCRs are engineered into our highly active bispecific TCR scaffold comprising a T cell-engaging antibody for potent redirection and activation of T cells and resulting in stable molecules with extended serum half-life.

17:45 Networking Reception in the Exhibit Hall with Poster Viewing

18:45 Problem-Solving Breakout Discussions

19:45 End of Day

THURSDAY 15 NOVEMBER

08:00 Registration and Morning Coffee

EMERGING TECHNOLOGIES IN ANTIBODY DISCOVERY AND ENGINEERING

08:30 Chairperson’s Remarks

Niv Papo, PhD, Group Leader, Assistant Professor, Biotechnology Engineering, Ben-

Gurion University

08:35 From Antibody-Targeted Toxins to Gene Editing: Disruption of Diphthamide Synthesis Genes and Resulting Toxin Resistance as a Robust Technology for Quantifying and Optimizing CRISPR/Cas9 Approaches

Brinkmann_UlrichUlrich Brinkmann, PhD, Expert Scientist, Molecular Engineering, Roche

Activity of antibody fusions harboring Pseudomomas Exotoxin derivatives requires diphthamide on eEF2. Diphthamide therefore serves as biomarker for immunotoxin efficacy; cells without diphthamide are toxin resistant. This phenotype can also be applied to identify and quantify events that result from CRISPR/Cas9 editing. DPH gene editing followed by toxin selection provides a simple robust method to differentiate and quantify homozygous/ heterozygous inactivation and integration events, and to optimize specificity and efficacy of editing procedures.

09:05 High-Throughput Antibody Engineering in Mammalian Cells by CRISPR/Cas9-Mediated Homology-Directed Mutagenesis

Sai Reddy, PhD, Assistant Professor, Biosystems Science and Engineering, ETH Zurich

Homology-directed mutagenesis (HDM) extends the concept of CRISPR/Cas9-mediated homology-directed repair to generate site-directed mutagenesis libraries in mammalian cells. Following cleavage by the Cas9 protein, single-stranded oligonucleotides containing degenerate codons serve as the repair template, providing integration of sequence diversity into the genome. We used HDM to generate libraries in the antibody CDRH3, and combined this with a mammalian surface display platform for high-throughput screening.

09:35 A Case Study in Adaptability: Exemplification of the Power of UCB’s Core Discovery Platform through the Discovery of a Potent Anti-Tau Antibody

Starkie_DaleDale Starkie, MSc, Senior Scientist, UCB Celltech

Here we describe the use of a number of cutting-edge antibody discovery technologies to efficiently interrogate the B cell repertoire of immunised animals and humans to identify rare antibodies with desirable characteristics. We employ a high-throughput automated B cell culture screening platform to mine out the memory B cell repertoire and a novel fluorescence-based proximity secretion assay to sample the plasma cell repertoire. We will discuss the use of multiple immunisation strategies utilising several forms of antigen and the discovery of an anti-tau lead antibody candidate capable of blocking uptake and aggregation of tau from three distinct human tauopathies in a novel robust and quantitative Tau seed uptake cellular assay.

10:05 Antibody Protein Sequencing with Mass Spectrometry

Mingjie Xie, CEO, Rapid Novor, Inc.

Many applications in antibody engineering require the direct sequencing of antibody proteins. At Rapid Novor (rapidnovor.com), we have developed a robust workflow and routinely sequenced antibody proteins. Here we share the success experiences, examine common mistakes novices make, and present our practices to ensure the correctness of every amino acid.

10:20 Sponsored Presentation (Opportunity Available)

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:15 Integrated Computational Design and Experimental Selection Leads to Custom Targeted Biologics

Kim_PhilipPhilip M. Kim, PhD, Associate Professor, Donnelly Centre, University of Toronto

I will present our technology platform on integrating a number of different computational protein strategies (including classic protein design, thermodynamic integration and machine learning) with high-throughput selection strategies (including phage display, yeast-2-hybrid and phenotypic selections in mammalian cell culture) to obtain custom targeted biologics.

11:45 Collecting Structural Data to Improve Predictions of Protein-Protein Interface Mutagenesis

Flores_SamuelSamuel Coulbourn Flores, Docent, Dean, Swedish National Graduate School in Medical Bioinformatics, Biochemistry and Biophysics, Stockholm University

Predicting the effect of mutations on protein-protein binding affinity is important for biotechnology and could open the door to in silico affinity maturation. Perturbative, empirically trained potentials such as FoldX are currently superior to physics-based and bioinformatical methods, but improvements in precision have slowed. In the meantime, structural data has continued to accrue, leading to growing redundancy in the Protein Data Bank. I will show how homologyScanner harnesses redundant structures to diversify the conformational input to perturbative potentials, leading to substantial increases in precision.

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

13:15 Dessert Break in the Exhibit Hall with Poster Viewing

14:00 End of Engineering Antibodies

17:00 Dinner Short Course Registration*

17:3020:30 Dinner Short Courses


* 活动内容有可能不事先告知作更动及调整。

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