Cambridge Healthtech Institute’s Fifth Annual

Enhancing Antibody Binding and Specificity

Scientific Strategies for Engineering Biotherapeutic Binding and Specificity for Next-Generation Antibody Therapeutics

January 9-10, 2018

 

As the industry expands its repertoire of antibody drug products into new therapeutic areas, product formats and protein constructs, the control of antibody/antigen targeting, binding and specificity will take on a new level of importance for researchers in this field. The second meeting in the Peptalk Protein Engineering & Development pipeline, Cambridge Healthtech Institute’s Fifth Annual Enhancing Antibody Binding and Specificity, presents innovative approaches to the modulation of binding activity for traditional antibodies, new product formats and difficult targets such as transmembrane proteins.

Final Agenda

TUESDAY, JANUARY 9

1:00 pm Registration

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

Advances in Targeting and Signaling

2:00 Chairperson’s Opening Remarks

Madhu Natarajan, Ph.D., Preclinical Therapeutic Area Head, Ophthalmology & Complement Biology, Shire

KEYNOTE PRESENTATION

2:05 Integrated Computational Design and Experimental Selection Leads to Custom Targeted Biologics

Philip_KimPhilip M. Kim, Ph.D., Associate Professor, Computational and Integrative Biology, University of Toronto, Canada

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.

2:45 Affinity-Tuned CARs Can Reduce On-Target Off-Tumor CAR T Cell Cytotoxicity

Mauro_CastellarinMauro Castellarin, Ph.D., Postdoctoral Researcher, Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine

CAR T cells can effectively kill malignant cells but autoimmune toxicity can occur when normal cells express the same targets. This type of on-target off-tumor toxicity can be lessened using affinity-tuned CARs. We developed an in vivo mouse model that expresses human tumor antigens in normal mouse tissue and showed that a low affinity Her2 CAR had a higher therapeutic index compared to its high affinity counterpart.

3:15 Featured Poster Presentation: An Integrated Nanofluidic and Optoelectronic Platform to Screen Engineered Antibody Panels

Fen-Fen Lin, Senior Scientist, Amgen

We explored an innovative nanofluidic cell culture platform from Berkeley Lights, the BeaconTM, to screen engineered antibody panels for the early stages of therapeutic antibody selection. We developed on-chip assays for both IgG secretion from mammalian cells and antigen binding and demonstrated correlation with standard assays. The Beacon™ platform could potentially compress timelines, increase capacity, and reduce resources required for our workflow. 

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

4:30 Engineering a Therapeutic Antibody for Long-Acting Delivery to the Eye

Devin_TesarDevin Tesar, Ph.D., Scientist, Drug Delivery, Genentech

Ocular delivery of protein therapeutics often requires favorable viscosity properties to support high-concentration formulations. Using structure-based design we generated high-affinity mutants of a backup Fab which exhibited superior viscosity properties but inferior target binding and inhibition as compared to the lead candidate. Two of these mutants, FM1 and FM2, exhibit binding and target inhibition equal or superior to that of the lead molecule, while retaining the superior viscosity profile.

5:00 Cytosol-Penetrating Antibody Technology for Targeting Oncogenic Ras Mutants

Yong-Sung_KimYong-Sung Kim, Ph.D., Professor, Molecular Science and Technology, Ajou University, Korea

Oncogenic Ras mutants are high-priority anticancer drug targets. However, direct inhibition of Ras mutants with small molecules has been extremely challenging. In this talk, I will introduce the development of cytosol-penetrating antibody that internalizes into the cytosol of living cells and selectively binds to the activated form of oncogenic Ras mutants to block the interactions with effector proteins, thereby exerting in vivo anti-tumor activity in mouse models after systemic administration.

5:30 Close of Day

5:30 - 5:45 Short Course Registration

5:45 - 8:45 Dinner Short Courses*

* Separate registration required

WEDNESDAY, JANUARY 10

8:00 am Registration and Morning Coffee

Analytical Methods

8:30 Chairperson’s Remarks

Tilman Schlothauer, Ph.D., Principal Scientist, Biochemical and Analytical Research, Large Molecule Research, Roche Innovation Center Munich

8:35 Germline Reversion of Broadly Neutralizing Antibodies for Vaccine Development

Fernando AlemanFernando Aleman, PhD, Research Associate, The Scripps Research Institute

A leading strategy for vaccine development aims at triggering broadly neutralizing antibodies, but how to achieve this goal is not yet clear. I will present an immunogenetic analysis of a panel of mouse monoclonal antibodies against Hepatitis C virus and highlight the two germline precursors that should be triggered for cross neutralization. The structure of the mature antibodies along with the germline precursors provide key templates for the needed antigen redesign.

9:05 Modeling Protein-Protein Complexes. The Good, the Bad and the Ugly

Enrico_PurisimaEnrico Purisima, Ph.D., Team Leader, Molecular Modeling, National Research Council Canada

The talk will examine the challenges of protein-protein docking with a particular emphasis on antibody-antigen complexes. A major complication is accounting for the conformational changes that can occur between the bound and free states of the docking partners. We will highlight recent progress in the field and describe specific efforts in our own lab. An assessment of what we can realistically expect from current methods will be given.

9:35 Featured Poster Presentation: Discovering Antibody Binding Signatures in Age-Related Macular Degeneration for Diagnostic Development

Joel Bozekowski, Ph.D. Candidate, Chemical Engineering, University of California, Santa Barbara

Signatures in the antibody repertoire can indicate the onset and presence of various diseases. Here, we utilized random peptide library screening to analyze the collection of peptides that bind serum antibodies from subjects at various stages of age-related macular degeneration (AMD). Bioinformatics analysis of the peptide sequences enabled the characterization of binding specificities present in AMD samples and absent from controls which could be utilized for early diagnostic development.

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

Engineering Binding Affinity

10:50 Conditional Fc Receptor Interactions – What Effector Cells Are Interested In

Tilman_SchlothauerTilman Schlothauer, Ph.D., Principal Scientist, Biochemical and Analytical Research, Large Molecule Research, Roche Innovation Center Munich

An assay platform has been established to assess antibody-Fc-receptor interaction. This platform, comprised of a broad panel of reagent tools and assay formats, is utilized for mechanistic studies towards the deeper understanding of Fc functionality. Besides the comparison of wildtype IgG1 antibodies, antibody variants with reduced or enhanced Fc-functionality can also be investigated by this comprehensive set of cell-free and cell-based in vitro functional assays.

11:20 Utilities of Biosensor Platforms in Antibody Discovery

Danlin_YangDanlin Yang, Ph.D., Scientist, Biophysics, Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals

Label-free optical biosensors are powerful tools in drug discovery for the characterization of biomolecular interactions. Here, we compare the strengths and weaknesses of four routinely used biosensor platforms by assessing their ability to provide quality kinetic data on high affinity antibody-antigen interactions. Applications including the classification of antibody binding epitopes via epitope binning studies and the profiling of the quality of antigen-induced polyclonal immune responses in immune sera are demonstrated.
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11:50 Human IgG Subtype Cross-Species Reactivity to Mouse and Cynomolgus Monkey FcƔReceptors

Mehebaw_DerebeMehabaw G. Derebe, Ph.D., Scientist, Biologics Engineering, Janssen BioTherapeutics

Animal models are routinely used to assess pharmacodynamics, toxicity, efficacy and other properties of candidate therapeutic antibodies. The interaction of human IgG molecules to endogenous FcƔ receptors of animal models can be different from their interaction to human FcƔ receptors. This study confirms the binding characteristics of human IgG subtypes IgG1, IgG2 & IgG4 as well as their silent versions to human, mouse and cynomolgus monkey FcƔ receptors. To control interactions between Fab and Fc domains, the test articles all have the same variable regions.

12:20 pm Enjoy Lunch on Your Own

Optimizing Antigen Specificity

2:00 Chairperson’s Remarks

Robert Pejchal, Ph.D., Scientist, Antibody Engineering, Adimab LLC

2:05 Engineering Antibodies to Modulate Their Spatiotemporal Behavior

Sally_WardE. Sally Ward, Ph.D., Professor, Molecular and Cellular Medicine, Texas A&M Health Science Center

The role of FcRn as a global regulator of antibody and albumin levels and transport in the body is well established. Recent studies using a combination of antibody engineering, microscopy and in vivo studies have led to strategies to modulate antibody levels for use in diagnostic imaging and therapy. Developments in these and other FcRn-related areas will be presented.

2:35 Altering Antibody Specificities for Better Clearance

Madhu Natarajan, Ph.D., Preclinical Therapeutic Area Head, Ophthalmology & Complement Biology, Shire

In recent years, the clearance of antibodies through antigen-mediated processes has re-emerged as a topic of interest, with the implication that engineering the affinities of therapeutic antibodies for antigens in a context-dependent manner can yield dramatic improvements in both pharmacokinetic and pharmacodynamic effects. We have systematically explored the biology and interdependencies of these mechanisms to understand and inform the rational engineering of novel therapeutic antibodies for improved pharmacodynamic and pharmacokinetic properties.

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

4:00 Highly Efficient Recovery of GPCR-Specific Antibodies Coupling Yeast Library Selection and Next-Generation Sequencing

Robert_PejchalRobert Pejchal, Ph.D., Scientist, Antibody Engineering, Adimab LLC

Discovery of antibodies specific to GPCRs, and other challenging multi-spanning membrane protein targets, has been a long-standing challenge for drug development. Adimab’s platform utilizes whole mammalian cells over-expressing the target membrane protein for selection and couples next generation sequencing (NGS) to identify antibodies with desired specificities. Methodologies and outcomes for discovery and optimization efforts on GPCR and tetra-spanning targets will be reviewed.

4:30 ProTIA – Bispecific T Cell Engagers Designed for Local Activation in the Tumor Environment

Ulrich Ernst, PhD, COO/SVP Technical Operations, Amunix Inc.

Amunix is developing ProTIA (Protease Triggered Immune Activator) therapeutics based on our proprietary XTEN™ protein polymer platform. ProTIAs are administered as inactive prodrugs that are activated in the tumor environment by release of their blocking XTEN polymer. AMX-168 is a ProTIA molecule targeting EpCAM, which is overexpressed in the majority of solid malignancies. AMX-168 has shown excellent efficacy and selectivity in a range of in vivo models.

5:00 Presentation to be Announced

 

5:30 - 6:45 Networking Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Enhancing Antibody Binding and Specificity Conference


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