Engineering Antibodies

- 抗体工程 -


The field of protein engineering is at an exciting point in its development, with new generations of therapeutic antibodies now progressing through development and into the market, great advances in protein science and discovery technology, and a body of clinical evidence that can be used to inform the development of safe, highly effective therapies for unmet medical needs. The PEGS Engineering Antibodies conference explores case examples of the most significant emerging discovery and informatics technologies used by protein engineers working at the discovery and design stages to quickly and efficiently craft biotherapeutics directed at the most elusive targets and biological functions.

Final Agenda

5月5日(二)

Recommended Short Course*

SC11: Developability of Bispecific Antibodies: Assays and Case Studies

*Separate registration required.

5月6日(三)

7:15 am Registration and Morning Coffee

7:25 Women in Science Panel Discussion with Continental Breakfast

Rochard_LucieModerator: Lucie Rochard, PhD, Liaison, Scientific & Entrepreneurial Initiatives; Director, Innovation Services, Massachusetts Biotechnology Council


Panelist: Nora Mineva, PhD, CSO, Adecto Pharmaceuticals

APPLICATIONS OF MACHINE LEARNING IN BIOTHERAPEUTIC R&D

8:40 Chairperson’s Opening Remarks

Shohei Koide, PhD, Professor, Biochemistry and Molecular Pharmacology, NYU School of Medicine; Perlmutter Cancer Center

8:50 Applying Machine Learning to Improve Protein Expression and Solubility

Erik Vernet, PhD, Director, Protein Engineering, Novo Nordisk Research Center Seattle

The elusive relationship between protein sequence, expression, and solubility necessitates costly and time-consuming analogue screening for protein therapeutics R&D. In this presentation, I will share our work on applying machine learning to predict protein expression and to accelerate protein solubility assessment, using internal and publicly available data sources.

9:20 Machine Learning Methods for De-novo Design of Proteins and Antibodies

Philip Kim, PhD, Associate Professor, Molecular Genetics, University of Toronto

I will present novel methodologies for the de-novo design of proteins and antibodies, including a protein design platform based on modern convolutional neural network architectures and methods for de-novo design of H3 loops.


9:50 KEYNOTE PRESENTATION: Machine Learning-Based Antibody Discovery

David Gifford, PhD, Professor, Computer Science and Biological Engineering, MIT

We present a machine learning method that optimizes complementarity-determining regions of antibodies drawn from phage display experiments. We discuss how machine learning can improve target specificity by the modular composition of models from different experimental campaigns, enabling a new integrative approach to improving target specificity. We demonstrate how predictive and differentiable models of antibody binding can be learned from high-throughput experimental data without the need for target structural data.

10:20 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Women in Science Speed Networking in the Exhibit Hall

IMPROVING TARGETING SPECIFICITY

11:05 Design of Exquisite Binding Specificity

Shohei Koide, PhD, Professor, Biochemistry and Molecular Pharmacology, NYU School of Medicine; Perlmutter Cancer Center

There is increasing demand for sophisticated specificity profiles for next-generation biotherapeutics. Gone are the days when we simply needed to generate high affinity to the target of interest. We often need to achieve extremely high specificity, as well as cross-reactivity among relevant targets and epitopes. I will illustrate critical roles that the design of library sorting schemes plays in achieving exquisite binding specificity using several case studies.

11:35 A Novel Mammalian Display Platform for the Engineering of Highly Specific T Cell Receptors

Rodrigo Vazquez-Lombardi, PhD, Postdoctoral Fellow, Biosystems Science and Engineering, ETH Zurich, Switzerland

Traditional approaches for engineering T cell receptors (TCR) with increased affinity can be largely unsuitable for T cell therapy applications, as they can yield TCR variants that promote T cell exhaustion, preclude serial TCR triggering and, in some instances, cause fatal cross-reactivity. Using multi-step CRISPR-Cas9 genome editing, we have developed a novel cellular TCR display platform supporting high-throughput selection of optimal TCRs by means of functional screening and deep sequencing.

12:05 pm Engineering Acidic pH-Selective mAbs Targeting VISTA

Julie Su, PhD, Senior Research Investigator, Molecular Discovery Technologies, Bristol-Myers Squibb

VISTA is a checkpoint inhibitor that preferentially engages T cells at low pH. We engineered potent, acidic pH-selective mAbs that bind to VISTA and block its interaction with the receptor PSGL-1. Further characterization using revertants, as well as a structure of VISTA:Fab complex revealed the mechanism for the acidic pH selectivity. The acidic pH-selective mAbs have improved PK and superior tumor targeting compared to a pH-independent mAb, while retaining in vivo efficacy.

12:35 Lessons in Generating Monoclonal Antibodies against Multipass Membrane Proteins

Ross Chambers, PhD, Vice President, Antibody Discovery, Integral Molecular

Integral Molecular has a 95% success rate of discovering high-affinity monoclonal antibodies against multipass membrane proteins despite the structural complexity and low immunogenicity of these targets. Here we present some of the lessons we have learned to enable discovery campaigns against these historically intractable targets, including GPCRs, ion channels, and transporters. Case studies for CB1, P2X7, SLC2A4, and Claudin18.2 will be discussed.

1:05 Session Break

1:10 LUNCHEON PRESENTATION I: Integrated mAb Pipeline from Virtual Machine Learning to Transposon-Mediated Cell Line Development

Claes Gustafsson, PhD, Co-Founder and CCO, ATUM

Monoclonal antibodies in their many divergent formats have revolutionized medicine and today represent >$100B/year in pharmaceutical sales. ATUM has built an integrated pipeline from generation of antigens via affinity maturation, developability, engineering, and humanization all the way through scale-up and stable cell line generation. The presentation will include case studies highlighting the process; each step using technological breakthroughs in synthetic biology, machine learning, LIMS data integration, robotics, and engineered transposases to ensure maximum efficiency.

1:40 LUNCHEON PRESENTATION II: Amplifying Antibody Diversity: Single-Cell Screening Combined with Repertoire Sequencing from Humanized Mice

Kevin Heyries, PhD, Co-Founder, Head of Business Development, AbCellera

We identified hundreds of target-specific antibodies using high-throughput single-cell screening from humanized mice. To reveal greater diversity, we sequenced the immunoglobulin repertoire of immunized animals and superimposed validated single-cell-derived sequences using bioinformatics to reconstruct clonal trees. This versatile approach dramatically expands the total available number of fully human, in vivo-generated antibodies against any therapeutic target.

2:10 Session Break

SUBCELLULAR AND INTRACELLULAR TARGETING

2:25 Chairperson’s Remarks

David Gifford, PhD, Professor, Computer Science and Biological Engineering, MIT

2:30 Subcellular Trafficking Pathways as Targets for the Design of Therapies for Autoimmunity and Cancer

Sally Ward, PhD, Professor, Molecular Immunology, University of Southampton, United Kingdom

The presentation will describe how analyses of the Fc receptor, FcRn, using a combination of protein engineering, cellular biological studies, and mouse disease models, have been used to design therapeutics to modulate the dynamic behavior of antibodies. The generation of engineered antibody-drug conjugates that are designed to deliver their cytotoxic payload more efficiently through altered subcellular trafficking behavior to tumor cells will also be discussed.

3:00 Developing Therapeutics for Intracellular Targets

Francois-Thomas Michaud, PhD, CEO, Feldan Therapeutics

To allow biologics to reach intracellular targets, Feldan Therapeutics generated peptides that can deliver proteins, peptides, and protein complexes in cells. Using intranasal instillations, Feldan and collaborators showed that these carrier peptides (“Feldan Shuttles”) efficiently deliver CRISPR complexes in lungs, leading to genetic modifications of epithelial cells in vivo. This example proves the therapeutic interest of the Shuttle platform for pulmonary diseases by showing that it can lead to functional changes in lungs.

3:30 Function vs. Force: Accelerated Identification of Relevant Antibody Candidates in the Modern Discovery Landscape

Colby Souders, PhD, CSO, Abveris

As the complexity of therapeutic targets continues to evolve, more efficient and predictive identification of pertinent antibody candidates becomes increasingly valuable. Incorporating state-of-the-art, high-resolution characterization tools and methods into discovery workflows enables rapid and reliable selection of lead candidates more effectively than traditional techniques. The presentation will focus on elucidating function early during screening and development to enhance candidate triage, as opposed to relying on brute-force methods to characterize large panels containing primarily non-functional clones.

4:00 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 Problem-Solving Breakout Discussions - View All Breakout Discussion Topics

TABLE: Mammalian Cell Display for High-Throughput Engineering of Immune Receptors

Moderator: Rodrigo Vazquez-Lombardi, PhD, Postdoctoral Fellow, Biosystems Science and Engineering, ETH Zurich, Switzerland

  • Advantages and limitations of mammalian cell display platforms relative to traditional display methods
    • Design and development of mammalian display platforms using CRISPR-Cas9 genome editing
    • Deep mutational scanning as a key method for the design of highly focused combinatorial libraries
  • Orthotopic introduction of immune receptor libraries into the genome of mammalian cells using CRISPR-Cas9
  • Selection of desired variants using flow cytometry coupled with deep sequencing and enrichment analysis

TABLE: Modulating the Dynamic and Subcellular Trafficking Behavior of Antibodies for Therapy

Moderator: Sally Ward, PhD, Professor, Molecular Immunology, University of Southampton, United Kingdom

  • How can microscopy inform the design of therapeutics?
  • Targeting FcRn to clear pathogenic antibodies
  • Half-life extension technology
  • Modulating endosomal trafficking of ADCs to enhance drug delivery to lysosomes

TABLE: Big Data Challenges in Protein Engineering

Moderator: David Gifford, PhD, Professor, Computer Science and Biological Engineering, MIT

  • The role of machine learning in the discovery and optimization of biologics
  • What quantity of data is required to build effective machine learning models
  • What experimental designs are necessary to get optimum machine learning performance
  • Error correction and processing of data for machine learning

6:00 Taste of New England Networking Reception in the Exhibit Hall with Poster Viewing

7:15 End of Day

5月7日(四)

8:00 am Registration and Morning Coffee

OVERCOMING LIABILITIES

8:30 Chairperson’s Remarks

Nicoletta Bivi, PhD, Director, Assay Development, Immunogenicity and Immunoassays, Laboratory for Experimental Medicine (LEM), Eli Lilly and Company

8:35 Presentation of Non-germline Residues and Clinical Consequences: A Case Study

Nicoletta Bivi, PhD, Director, Assay Development, Immunogenicity and Immunoassays, Laboratory for Experimental Medicine (LEM), Eli Lilly and Company

The anti-PCSK9 antibody, Bococizumab, was terminated after Phase 3 due to high immunogenicity. We assessed its intrinsic immunogenicity risk using our current tools, consisting of in silico analyses, MAPPS, and T cell activation. We observed significant presentation of non-germline residues and Bococizumab-driven T cell activation in 90% and 56% of donors respectively. In contrast, anti-PCSK9 antibodies with low immunogenicity (Evolocumab and Alirocumab) demonstrated low-to-moderate presentation of non-germline residues and no T cell activation.

9:05 Molecular Design Intent in Early Drug Discovery

Carlos Reis, PhD, Team Leader Molecular Design and Engineering, GlaxoSmithKline, United Kingdom

The early selection of biotherapeutics requires the meticulous assessment of a variety of molecule properties to ensure their desired quality, safety, and efficacy. The increased complexity of non-standard formats requires further molecular design and engineering strategies to optimize their properties, as well as new screening approaches to select the best candidate molecules. In this presentation, I will discuss applications and current engineering challenges to optimize the developability profile of molecules during early discovery and accelerate their development.

9:35 Finding the Gold Antibody: Not Only about Having a Comprehensive Toolbox

María González Pajuelo, PhD, CSO, FairJourney Biologics

To maximize the possibility to select “the” antibody, the highly experienced team at FJB has taken antibody discovery to an unprecedented level by creating and using wisely a versatile toolbox that allows selection of antibody fragments of different species from large naïve and immune repertoires by phage display. These fragments are engineered, converted to mono- and bi-specific formats, produced in CHO cells, and fully characterized for functionality and biophysical characteristics. Case studies will be presented.

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

CHALLENGES AND SOLUTIONS

11:05 Next-Generation Technologies for Antibody Library Design and Screening

Brandon DeKosky, PhD, Assistant Professor, Chemical Engineering, University of Kansas

Recent advances in paired heavy-light sequencing, native antibody display, and computational analysis of NGS datasets have opened up new possibilities for mining antibody responses. We have also developed new strategies in library design and screening to enable comprehensive antibody developmental pathway assessment and to survey the entire landscape of possible single mutations. We will discuss applications of these technologies to better understand antibody development and to identify improved antibody variants.

11:35 Antibody Engineering and Vaccine Design Based on Proteomic Profiling of Antibody Repertoire

Jiwon Lee, PhD, Assistant Professor, Engineering, Dartmouth College

Antibody molecules circulating in blood and neutralizing different pathogens is a key element of the immune system. Combining high-resolution proteomics with Next-Gen sequencing of B cell receptor transcripts, we have developed a quantitative approach for delineating and characterizing the antigen-specific antibody repertoire. Here I will present insights gained from characterizing serological repertoires and highlight recent work demonstrating how this knowledge can guide the engineering efforts for next-generation therapeutics and vaccines.

12:05 pm A High-Throughput Production Workflow for Complex Format Therapeutic Molecules

Avinash Gill, PhD, Senior Scientific Manager, Genentech

A high-throughput, automated platform for production of large molecules makes it feasible to generate purified, high-quality material for screening potential therapeutic candidates in assays. We have developed a highly productive, preparative HPLC workflow to rapidly purify complex engineered antibody-like molecules for use in assays designed to evaluate novel large-molecule formats for desired functionality, thereby overcoming some of the limitations of traditional purification techniques.

12:35 End of Engineering Antibodies


Recommended Short Course*

SC13: Design Strategies and Development of ADCs

*Separate registration required.

* 活动内容有可能不事先告知作更动及调整。

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