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Cambridge Healthtech Institute’s Inaugural

Computational and Analytical Tools for Protein Engineering

Next-Generation Modeling and Informatics Tools for Biotherapeutic Engineering and Development

January 15-16, 2019

 

Improvements in computing power, instruments, modeling software and imaging technology are driving a new wave of interest in the application of these tools in antibody discovery and protein engineering. Structural biology and computational modeling are now routinely applied in identifying unique epitopes and binding activity, and it is becoming standard practice to run a suite of assays and structural studies to evaluate the developability and manufacturability before advancing leads into development. PepTalk’s new Computational and Analytical Tools for Protein Engineering gives researchers a comprehensive exchange in which to consider best practices and new technologies used to support the work of protein engineers on new constructs and the discovery of unique new biotherapeutics.

Final Agenda

TUESDAY, JANUARY 15

1:00 pm Registration

1:30 Refreshment Break in the Exhibit Hall with Poster Viewing

2:00 Chairperson’s Opening Remarks

Johan Fransson, PhD, Director, Antibody Discovery and Development, Northern Biologics


KEYNOTE PRESENTATION

2:05 A New Source of Tumor Neoantigens and Platform for Their Identification

Stephen Albert Johnston, PhD, CEO, Calviri, Inc.; Director and Professor, Biodesign Center for Innovations in Medicine, Arizona State University

We have discovered that frameshift neoantigens from RNA mis-processing are a rich source of components for cancer vaccines. All tumors produce many of these neoantigens. We have developed a peptide array that allows simple identification of the neoantigens in each tumor from a drop of blood.

Predicting Protein Behavior

2:45 Improved Computational Modeling of Antibody-Antigen Complexes by Integration of Deep Mutational Scanning Data

Andrew Wollacott, PhD, Principal Scientist, Visterra, Inc.

Accurate computational prediction of the structure of antibody-antigen complexes remains challenging due, in part, to the difficulty in identifying near-native models from incorrect poses. We have developed a workflow which integrates experimental deep mutational scanning data with antibody-antigen docking for robust model generation. The presentation will describe an application of this workflow to a panel of antibodies, which enabled rational selection and engineering of one antibody for cross-species antigen binding.

3:15 Advanced Analytics and Visualization for Biologics Drug Discovery

LeBeau_AndrewAndrew LeBeau, PhD, Senior Manager, Biologics Marketing, Dotmatics, Inc.

Biologics drug discovery places significant demands on software to handle the volumes of data and advanced computational routines necessary to uncover promising candidates. The software should also be accessible to the wide range of scientists involved in the process. This presentation will highlight such capabilities within Dotmatics Vortex.

3:30 Antibody Protein Sequencing with Mass Spectrometry

Zie_MingjieMingjie Xie, CEO, Co-Founder, 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.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Overcoming Challenges of High-Resolution Epitope Mapping by Use of NMR Spectroscopy: Case Studies and Practical Solutions

Feng Ni, PhD, Project Lead and Laboratory Supervisor, Human Health Therapeutics, National Research Council Canada

Practical epitope mapping is still limited by: (1) the ability to prepare soluble antigen-antibody complexes with lasting stability; (2) efficient collection of multi-dimensional NMR data; (3) the intrinsic dynamics of the binding interactions. We will present three case studies of (i) an intrinsically-unfolded domain of carbonic anhydrase IX; (ii) the well-folded Ig1 domain of human Axl with high affinity binding and (iii) the Ig2 domain of Axl with dynamic interactions.

5:00 Cellular and Analytical Assays for PK Engineering

Runyi Adeline Lam, PhD, Researcher, Chugai Pharmabody Research, Japan

During antibody optimization, antibodies with different properties are generated and these are evaluated using various cell-based or analytical assays. This presentation focuses on development of novel cell-based assays to aid in the screening process. Examples from different projects would be shown to illustrate how this can improve the screening workflow.

5:30 Close of Day

5:30 - 5:45 Short Course Registration


5:45 - 8:45 Recommended Dinner Short Courses*

SC1: Introduction to CAR-T Engineering for Protein Scientists

SC2: Structure-Based Optimization of Antibodies

Click here for more details.

*Separate registration required

WEDNESDAY, JANUARY 16

7:45 am Registration and Morning Coffee

Experimental Validation of Computational Results

8:15 Chairperson’s Remarks

Marissa Mock, PhD, Principal Scientist, Therapeutic Discovery, Biologics, Amgen

8:20 Using Interface Expansion to Manipulate the Affinity and Specificity of Protein-Protein Interactions

Brian Kuhlman, PhD, Professor, Biochemistry and Biophysics, University of North Carolina at Chapel Hill

Protein binding affinity and specificity can be manipulated by redesigning contacts that already exist at an interface or by expanding the interface to allow interactions with residues adjacent to the original binding site. Two alternative methods for interface expansion with the Rosetta molecular modeling program will be discussed. These approaches have been used to engineer tight binders for MAP kinases and the ubiquitin ligase KEAP1.

8:50 Computational Design of Protein Libraries

Chris Bailey-Kellogg, PhD, Professor, Computer Science, Dartmouth College

To increase the hit rate of discovering diverse, high-performance protein variants via library screening, we have developed computational library design methods that bias entire populations towards simultaneous improvements in multiple properties of interest. In application to biotherapeutic deimmunization, we have subjected optimized libraries to a single round of activity screening and successfully isolated highly mutated variants that are functionally equivalent to wild-type while also evading T cell recognition.

Methods and Models for Developability Assessment

9:20 A Platform Approach to Manage Developability and Manufacturability Risks of Biologics Molecules

Wendt_MariaMaria Wendt, Head, Science, Biologics, Genedata

We present a workflow system that enables very systematic developability and manufacturability assessments from the very early stage to the later stages of the biologics R&D process, using both in silico methods and high throughput analytical confirmatory methods. We show use cases not only for mAbs but also for complex multi/bispecific formats, as well as engineered therapeutic cell lines (e.g., CAR T cells). We also discuss building predictive models for developability utilizing such a system.

9:50 Coffee Break in the Exhibit Hall with Poster Viewing

10:35 How Large is the Sequence Space for Aggregation-Resistant Antibodies?

Christopher J. Roberts, PhD, Professor, Chemical & Biomolecular Engineering, University of Delaware

This presentation will focus on a multi-scale molecular modeling approach to providing design “rules” for down-selecting antibodies from a large number of sequence variants, without the need for expensive calculations or extensive expression screens, with a view towards creating antibodies that are aggregation resistant. The test systems are primarily monoclonal antibodies, but the approach can be extended to additional constructs.

11:05 Building Methods to Predict Large Molecule Developability for the Early Research Pipeline

Marissa Mock, PhD, Principal Scientist, Therapeutic Discovery, Biologics, Amgen

During the preclinical development of large molecule therapeutics, panels of engineered variants are designed, generated, and screened to optimize the developability of lead candidates. Since many standard assays for developability require large quantities of protein and are resource-intensive, we have developed and will present strategies and methods to predict complex biophysical behaviors from a combination of primary sequence and high throughput screening data.

11:35 In silico and Empirical Developability Assessment of Therapeutic Antibodies

Johan Fransson, PhD, Director, Antibody Discovery and Development, Northern Biologics

Antibody developability assessments are a key part of every discovery campaign. Typically, both in silico and empirical methods are used to rank candidates and assess risks impacting manufacturing, release and stability studies. An overview of current in silico and empirical methods employed in our lab will be provided. Case studies will also be presented, highlighting how molecular modeling can guide rational design and selection of better behaved lead candidate mAbs.

12:05 pm Session Break

12:15 Computational Design Coupled with Massively-Parallel Synthesis and Screens to Discover Interface Representative Peptides

Greving_MatthewMatthew Greving, PhD, Co-Founder, Vice President, Technology, RubrYc Therapeutics


12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:15 Session Break


2:00 PLENARY KEYNOTE PANEL

Click here for more details.

PepTalk Perspectives: Point-Counterpoint Discussions

Moderator:
Howard Levine, PhD, President and CEO, BioProcess Technology Consultants






Panelists:
Zhimei Du, PhD, Director, Bioprocess & Clinical Manufacturing, Merck






Lorenz Mayr, PhD, CTO, GE Healthcare Life Sciences




3:05 Refreshment Break in the Exhibit Hall with Poster Viewing

Computational Antibody Design

4:00 Chairperson’s Remarks

Philip M. Hemken, PhD, Principal Research Scientist, R&D, Abbott Laboratories

4:05 Structural Bioinformatics of Antibodies and Antibody Computational Design

Roland L. Dunbrack, Jr., PhD, Professor, Institute for Cancer Research, Fox Chase Cancer Center

We have performed extensive structural bioinformatics studies of the CDRs of antibodies as well as the ‘de’ loop or CDR4. We have developed a computational antibody design algorithm in Rosetta that utilizes our CDR clusters to graft new CDRs and to perform sequence optimization according to sequence variation observed in clusters of similar CDR conformations. We have benchmarked this method with a novel metric and validated it experimentally.

4:35 Exploration of Small Protein Folds and Their Defining Features

Eva-Maria Strauch, PhD, Assistant Professor, Pharmaceutical and Biomedical Sciences, University of Georgia

Nature only samples a small fraction in sequence space, yet many more amino acid combinations can fold into stable proteins. We developed a computational platform that enables us to efficiently sample and design any given topologies with high structural diversity to serve as new scaffolding proteins, guide future design efforts and help our general understanding of stability. Using a high-throughput stability screen, we evaluated 45,000 of 9 topologies designed with our new pipeline and derived stability prediction models using machine learning algorithm.

Applications in Biopharmaceutical Development

5:05 Development of Automated Companion Diagnostic Immunoassays in Collaboration with Therapeutic Partners

Philip M. Hemken, PhD, Principal Research Scientist, R&D, Abbott Laboratories

Abbott partnered to develop two automated diagnostic immunoassays as potential future companion diagnostic tests to identify patients with severe asthma who would most likely benefit from an investigational anti-IL-13 immunotherapy. Abbott developed tests to measure the serum levels of the proteins periostin and DPP4 (dipeptidyl peptidase-4), which have potential to be predictive biomarkers for up-regulated IL-13 in patients with severe asthma.

5:35 Assessment of Orthogonal Techniques for Epitope Mapping of Therapeutic Antibodies

Sam Wu, PhD, Principal Scientist, Janssen BioTherapeutics

Epitope mapping provides crucial information for selecting therapeutic antibodies. A progressive approach to mapping is applied to help identify new function, support antibody engineering, define a mechanism of action, and enable intellectual property. Specifically, DEPC-labelling and hydroxyl radical footprinting (HRF) results with epitopes of therapeutic antibodies identified by solution HDX-MS will be presented. Examples of the impact of binding site mapping on progression of antibody discovery will be described.

6:05 - 7:00 Networking Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Computational and Analytical Tools for Protein Engineering Conference

* The program is subject to change without notice, due to unforeseen reason.

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