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Bioconjugates: From Targets to Therapeutics

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Increase Your Market Share with the Latest Conjugation Design and Manufacturing Science

June 04-06, 2014
Grand Hyatt Hotel
San Francisco, CA

Agenda

Agenda

Wednesday, June 4, 2014

7:00
Registration and Coffee

8:00
Chairman's Opening Remarks
Jonathan Davis, Ph.D., Principal Scientist, Protein Design, Bristol-Myers Squibb

Keynote Presentations

8:15
Unpublished Data
Carolyn R. Bertozzi, Ph.D. Bioorthogonal Chemistries for Biomolecular Engineering
Bioorthogonal chemical reactions have such exquisite selectivity that they can be employed to modify biomolecules even within the environs of live organisms. This presentation will focus on recent developments in bioorthogonal reaction methodology and applications to the production of chemically modified protein therapeutics such as antibody-drug conjugates. The use of bioorthogonal chemical reporters for in vivo imaging and disease biomarker discovery will also be discussed.
Carolyn R. Bertozzi, Ph.D., T.Z. and Irmgard Chu Distinguished Professor of Chemistry and Professor of Molecular and Cell Biology, UC Berkeley; Investigator, Howard Hughes Medical Institute; Senior Faculty Scientist, Lawrence Berkeley National Laboratory

8:45
Unpublished Data
Karl Dane Wittrup, Ph.D. Does Targeting Contribute to Immunocytokine Efficacy?
Immunocytokines are fusions of antibodies to immunostimulatory cytokines that can exhibit greater anti-tumor efficacy than the parent antibody. However, the cytokine component of an immunocytokine may systemically activate immune cells, leading both to potential systemic toxicity or contributions to efficacy. We have performed simple pharmacokinetic analyses that provide quantitative design objectives for immunocytokines.
K. Dane Wittrup, Ph.D., Professor, Chemical Engineering & Biological Engineering, MIT

9:15
The Evolution of ADCs: Lessons Learned from the Past. Where are We Going?
This talk will cover what has been learned in the two decades of ADC clinical development. It will highlight the problems encountered with current technologies and discuss where new technologies, such as site directed conjugation, alternate scaffolds, and new payloads may provide answers (or new problems!).
Robert Lutz, Ph.D., Vice President, Translational Research and Development, ImmunoGen, Inc.

9:45
Networking Refreshment Break in Poster & Exhibit Hall

ADC Development Challenges and Successes

Chairman: Alan C. Rigby, Ph.D., Vice President Research, Computational Discovery and Chemistry, ImClone Systems, A wholly-owned subsidiary of Eli Lilly and Company

Featured Presentation

10:30
Fred Jacobson, Ph.D. Reproducible Heterogeneity: CMC Challenges in the Manufacturing and Control of Kadcyla® (T-DM1)
Kadcyla® is a lysine-linked ADC recently approved for treatment of HER2-positive metastatic breast cancer. Because of the molecular complexity associated with this ADC architecture, specific analytical methods were needed to enable development of a robust commercial manufacturing process. This presentation will describe some of the assays we developed and how they were used in process development and in demonstrating that the resulting product has highly reproducible heterogeneity with respect to drug loaded forms.
Fred Jacobson, Ph.D., Principal Scientist, Genentech, Inc.

11:00
Unpublished DataCase Study
Defining the Higher Order Structure of ADCs by Hydrogen Exchange Mass Spectrometry
This talk will focus on our recent work to fully characterize the higher order structure of ADCs that are manufactured using Seattle Genetics platform technologies. We will specifically highlight the utility of implementing hydrogen exchange mass spectrometry to gain an understanding of how conjugation technology impacts the parent antibody conformation at the molecular level.
Lucy Y. Pan, Ph.D., Scientist, Process Science, Seattle Genetics, Inc.

11:30
Analytical Investigation into the Functional Relationship of Antibody Maytansinoid Conjugate Structural Variants
Abstract unavailable at press date.
Daniel Tavares, Ph.D., Head of Antibody Engineering, ImmunoGen, Inc.

12:00
Spotlight Presentation to be Announced
For more information on spotlight presentations, please contact Patty Rose at (508) 614-1406 or prose@ibcusa.com

12:30
Networking Luncheon and "Hot Topic" Roundtable Discussions in the Poster & Exhibit Hall

1:40
Chairman's Remarks
Philip S. Low, Ph.D., Director, Purdue Center for Drug Discovery; Ralph C. Corley Distinguished Professor of Chemistry, Purdue University

Frontiers in Imaging and Radiotherapy

1:45
Cancer Cell-Specific Fluorescence Imaging Using Target Vectors Conjugated to Activatable Fluorophores for Assisting Surgical and Endoscopic Procedures
Activatable fluorescent imaging probes yield signals only when bound to target molecules, therefore, specifically depict tiny cancer foci with super-high contrast to normal organs. Activatable fluorescent imaging probes can be designed based on several different photo-chemical strategies and synthesized using bio-conjugate chemistry. Toward further clinical translation, appropriate materials should be selected and chemical methods should be optimized for scale-up synthesis.
Hisataka Kobayashi, M.D., Ph.D., Molecular Imaging Program, NCI/NIH

2:15
Unpublished Data
Ligand-Targeted Imaging Conjugates for Cancer, Autoimmune and Infectious Diseases
I will discuss the development of high affinity, ligand-targeted optical, PET and radioimaging agents for the diagnosis, staging, and assessment of response to therapy of patients with cancer, autoimmune and infectious diseases. In all cases, the process involves: i) identification of a receptor that is over-expressed on the desired pathologic cell, ii) design of a targeting ligand that will bind selectively to that receptor, and iii) evaluation of the specificity and sensitivity of the ligand-targeted imaging agent in appropriate animal models. Both preclinical and clinical data will be presented to illustrate this process in malignant, autoimmune and infectious diseases.
Philip S. Low, Ph.D., Director, Purdue Center for Drug Discovery; Ralph C. Corley Distinguished Professor of Chemistry, Purdue University

2:45
Unpublished Data
Bioconjugation Approaches for Decreasing Kidney Localization of Radiolabeled Proteins
Kidney localization of radiolabeled proteins used in radioimaging and targeted radiotherapy applications can limit the amount of radioactivity administered, resulting in lengthy imaging times and/or degraded images, and it can severely limit the amount of radioactivity administered resulting in ineffective radiotherapy. This presentation will describe several bioconjugation approaches that we have evaluated for decreasing the kidney concentrations of radiolabeled proteins.
D. Scott Wilbur, Ph.D., Professor, Radiation Oncology, University of Washington

3:15
Networking Refreshment Break in Poster & Exhibit Hall

Conjugated Vaccines

Chairman: Mark J. Pozzo, Associate Research Fellow, Group Leader, Conjugation and Polytide Process Development, Biotherapeutics Pharmaceutical Sciences, Pfizer Inc

4:00
Development of a Malaria Transmission Blocking Vaccine as a Chemically Conjugated Nanoparticle
The current control strategy for elimination of malaria will benefit from the development of an effective malaria vaccine. Our approach is to develop a well-characterized recombinant protein based, chemically conjugated transmission blocking malaria vaccine. The chemical conjugates comprised of Pfs25 and/or Pfs230 with a carrier protein form nanoparticles that significantly enhance immunogenicity in mice and humans, and induce transmission blocking antibodies.
David L. Narum, Ph.D., Head of Process Development, Laboratory of Malaria Immunology and Vaccinology, NIH

4:30
Unpublished Data
The Genetic Engineering of E. coli for the Production of Bioconjugate Vaccines
The prokaryotic bacterium Escherichia coli is widely used to produce recombinant proteins. Genetic engineering opens up the possibility to produce bioconjugate vaccines in a robust and reproducible manner. These bioconjugates consist of polysaccharides covalently linked to specific residues of any protein and are able to elicit functional antibodies for the prevention of deadly infections.
Michael Wacker, Ph.D., Chief Scientific Officer, GlycoVaxyn AG, Switzerland

5:00
The Role of Conjugation Science in Designing the Next Generation of Vaccines
In addition to successful conjugated vaccines of the recent era and the forthcoming introduction of a conjugate vaccine against group B streptococcus, conjugation technology can also be used for a variety of novel purposes in vaccine research, including the conjugation of new generation adjuvants to antigens. However, it must be clear that adjuvant conjugation brings advantages over the more traditional formulation and co-delivery approaches, using Alum adsorbents, emulsions and liposomes etc.
Derek T. O'Hagan, Ph.D., Vice President, Global Head of Vaccine Chemistry and Formulation Research, Novartis Vaccines

5:30
Networking Cocktail Reception in Poster & Exhibit Hall

Thursday, June 5, 2014

7:30
Coffee

8:00
Chairman's Remarks
David Meininger, Ph.D., Executive Director, Molecular Discovery, Merck Research Labs

Featured Presentation

8:15
Geert-Jan Boons, Ph.D. Metal Free Click Reactions for Site-Specific Protein and Glycoprotein Modification
We have developed methods to install abiotic functional groups such as azides, nitrones and nitrile oxides in a site-specific manner into proteins and glycoproteins for chemical modification through metal-free strain-promoted cycloadditions. The technology has been applied for the generation of antibody-drug conjugates, pegylation of proteins and design and synthesis of well-defined vaccines. The new site-specific coupling methodologies make it possible to improve properties of protein conjugates by structure-function relationships in a medicinal-chemistry like fashion.
Geert-Jan Boons, Ph.D., Distinguished Professor, Biochemical Sciences, The Complex Carbohydrate Research Center, The University of Georgia

Site Specific Conjugation through Carbohydrates

8:45
Antibody Drug Conjugation through Carbohydrates: An Update
Conjugation of antibodies with small molecules through carbohydrates will be overviewed and latest results presented including generation of ADCs against cancer-related targets. Advantages of using the native antibody glycans for conjugation include: naturally occurring site for conjugation and no need for mutations, site-specific, no effect on antigen binding and thermal stability, and possibility for conjugation of multiple small molecules at one site. Other methods for site-specific conjugation will be also discussed and compared.
Dimiter Dimitrov, Ph.D., Senior Investigator, Protein Interactions, National Cancer Institute, NIH

Audience Interactive Panel Discussion

9:15
Site Specific Conjugation and Novel Linkers: Where are we now?
Moderator: David Meininger, Ph.D., Executive Director, Molecular Discovery, Merck Research Labs
Panelists: All morning presenters

9:45
Networking Refreshment Break in Poster & Exhibit Hall

Alternative Scaffolds and Delivery Strategies

10:30
Case Study
Development of an Intein Based Conjugation Platform for the Synthesis of Fc-fusion Proteins
Identification of an ideal platform technology for conjugation of small molecules and peptides to biomolecules for improved pharmacokinetics has been a recent focus within academic and industrial laboratories. This contribution will focus on the development of an intein based platform for conjugation of peptides at the C-terminus of the Fc domain of immunoglobulins. In the course of platform development, selection of intein, cleavage residue, and linker between Fc and intein were examined.
Oliver Thiel, Ph.D., Principal Scientist, Amgen Inc.

11:00
Unpublished Data
Extension of in vivo Half-Life of Biologically Active Molecules via Chemical Conjugation to XTEN Protein Polymer
XTEN (unstructured biodegradable polypeptides) have been used to extend the half-life of genetically fused therapeutic proteins and peptides. To expand the applications of XTEN technology to half-life extension of other classes of molecules, XTEN protein polymers and methods for chemical XTENylation were developed. Monovalent, multivalent and bispecific XTEN conjugates with various payloads have been synthesized and tested for their biological activities.
Vladimir N. Podust, Ph.D., Associate Director of Analytical Chemistry, Amunix Operating Inc.

11:30
Unpublished Data
A Chemical Approach to Half-Life Extension
We recently reported an approach to half-life extension using sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo β-elimination to release the native drug with half-lives ranging from a few hours to over one year. Here, we use β-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a wide range.
Gary Ashley, Ph.D., Co-Founder and Chief Scientific Officer, ProLynx LLC

12:00
Homogeneous and Stable ADCs by Chemoenzymatic Glycan Remodeling-Conjugation
SynAffix has developed a fully proprietary, site-specific, bioconjugation technology suitable for covalent modification of glycoproteins using posttranslational glycan remodeling and a subsequent metal-free click reaction. The corresponding GlycoConnect platform enables production of antibody-drug-conjugates with excellent homogeneity (DAR = 2) and stability, amenable to HTS, and applicable to all IgG subclasses.
Sander S. van Berkel, Ph.D., Chief Technology Officer, SynAffix B.V., The Netherlands

12:15
Spotlight Presentation to be Announced
For more information on spotlight presentations, please contact Patty Rose at (508) 614-1406 or prose@ibcusa.com

12:30
Networking Luncheon and "Hot Topic" Roundtable Discussions in the Poster & Exhibit Hall

1:40
Chairman's Remarks
Arne Skerra, Ph.D., Managing Director & Chief Scientific Officer, XL-protein GmbH, Germany

Next Generation ADCs - Novel Conjugation Technologies, Linkers and Payloads

1:45
Unpublished DataCase Study
Advances in Drug Conjugate Technology Using Centyrin Proteins
Centyrex has designed a novel FN3 domain alternative scaffold with superior stability properties and is exploring the robustness of the platform via novel therapeutic applications that may address outstanding challenges in antibody drug conjugate technology. We will describe how the excellent biophysical properties of Centyrins make them ideal conjugation partners for applications designed to combine small molecule and large molecule opportunities.
Robert J. Hayes, Ph.D., Venture Leader and Vice-President, Janssen R&D, a Johnson & Johnson company

2:15
Case Study
Novel Pyrrolobenzodiazepine Payloads for ADC Therapies
The pyrrolobenzodiazepines (PBDs) are a family of naturally occurring antitumour antibiotics found in various Streptomyces species. Completely synthetic, highly potent PBD dimers have been developed as antitumour agents and these molecules have been modified to allow conjugation to tumour targeting antibodies. The resulting PBD antibody conjugates have exhibited excellent in vivo antitumour activity across a range of xenograft models.
Philip Howard, Ph.D., Chief Scientific Officer, MedImmune Spirogen Business Unit, United Kingdom

2:45
Unpublished Data
Antibody Drug Conjugates with Novel DNA Alkylating Agents: Design and Preclinical Evaluation
The cytotoxic effector molecule is a key component of antibody-drug conjugates (ADCs). A new class of potent DNA-alkylating agents, (IGNs), have been designed and synthesized for use in ADCs. These compounds are cytotoxic in vitro towards cancer cell lines, with IC50 values in the picomolar range. Results from preclinical evaluation of ADCs of these novel DNA alkylators will be presented.
Ravi J. Chari, Ph.D., Executive Director, Chemistry and Biochemistry, ImmunoGen, Inc.

3:15
Networking Refreshment Break in Poster & Exhibit Hall

4:00
Unpublished Data
DeBouganin: De-Immunized Cytotoxic Payload for Targeted Cancer Therapy
Immunotoxin fusion proteins represent a highly potent alternative to conventional anti-cancer agents. We have developed a de-immunized variant of the plant-derived, type I ribosome-inactivating protein (RIP), bouganin. Various antibody drug formats linked to deBouganin were engineered and characterized for biologic activity. The biologic characterization of deBouganin-conjugates as well as the Phase I clinical data are presented.
Glen C. MacDonald, Ph.D., Chief Scientific Officer, Viventia Bio Inc.

Towards Homogeneous ADCs - The Promise of Better Clinical Impact and Product Safety

4:30
Addressing Tumor Heterogeneity and Resistance; Production of Homogeneous ADCs with Combination Warheads
Homogeneous single species ADCs hold the promise to enhance the efficiency of tumor killing while reducing systemic damage and increasing their tolerability. Using biochemical protein synthesis methods, parallel production of many positional variants can be expressed in hours and rapidly assessed for function. We will describe the power and utility of the platform to address efficient non-natural amino acid incorporation and optimized conjugation kinetics for manufacturing. Finally we will demonstrate the design and manufacture of new classes of homogeneous mono- or multi-specific antigen-targeted antibodies conjugated to combinations of different warheads promising even better clinical impact and safety.
Trevor Hallum, Ph.D., Chief Scientific Officer, Sutro Biopharma, Inc.

5:00
Unpublished DataCase Study
Site Specific Bioconjugates - A Pathway to Better Biologics
Biological therapeutics are effective interventions in many diseases. However it is apparent that the natural protein is often not optimum due to shortcomings such as in potency PK, delivery or specificity. To address this, modifications or conjugations to the proteins/peptides have been made, for example to extend half-life, to incorporate cytotoxic moieties or to impart additional pharmacology. To do this well requires an exquisite understanding of the effect of the site of conjugation on the function, stability, pharmacology and toxicology of the resulting bioconjugate. The specific incorporation of a non-natural amino acid subsequently allows a detailed determination of how to build the optimal bioconjugate. We will discuss Ambrx's approach.
Peter A. Kiener, Ph.D., Chief Scientific Officer, Ambrx, Inc.

5:30
Close of Day Two

5:30
Happy Hour @ Pier 39 Overlooking San Francisco Bay
This networking reception is at Players Sports Grill & Arcade, which has sweeping views of San Francisco Bay, and is just two blocks from the Hyatt. Enjoy buffet finger food and drinks (beer, wine, soft drinks) plus arcade games and pool tables. Advance RSVP is required when registering with an additional $125 fee.

Friday, June 6, 2014

7:30
Coffee

8:15
Chairman's Opening Remarks
Dimiter Dimitrov, Ph.D., Senior Investigator, Protein Interactions, National Cancer Institute, NIH

Site Specific Conjugation

Keynote Presentation

8:30
Jaume Pons, Ph.D. Site-Specific Approaches to Conjugation: Advantages beyond Homogeneity
ADCS are a new therapeutic class offering a great promise for cancer therapy. Today, most ADCs in the clinic use maleimide based conjugation on antibody hinge cysteines or lysine chemistry. Different site specific conjugation strategies are now being pursued by several companies, initially with the aim of improving the homogeneity of the final product. In this talk we show that, in addition to improved homogeneity of the final product, the site of attachment has an effect on stability, toxicity, and efficacy.
Jaume Pons, Ph.D., Senior Vice President, Pfizer; Chief Scientific Officer, Rinat

9:15
Site-Specific ADC Generation using SMARTag™ Technology Platform
Learn about the development of a novel technology platform that enables precise, programmable, site-specific chemical protein modification. Leveraging the target sequence of Formylglycine Generating Enzyme, via the SMARTag™ Technology, homogenous enhanced biotherapeutics can be engineered, including ADCs. Additionally, the presentation will discuss how the novel conjugation chemistry results in ADCS having enhanced stability while maintaining the potency of the cytotoxic payload.
David Rabuka, Ph.D., CSO and Founder, Redwood Bioscience

9:45
Networking Refreshment Break

10:15
Unpublished Data
Site-Specific Conjugation for Stable and Homogeneous ADCs
Significant effort has been devoted recently to developing site-specific conjugations for producing homogenous ADCs with well-defined drug antibody ratios. This presentation will discuss the engineering approaches to generate ADCs that allow precise control of conjugation site and stoichiometry. Upon conjugation to a drug, the site-specific ADCs showed enhanced stability and decreased off-target toxicity while maintaining highly potent in vitro and in vivo anti-cancer activities.
Changshou Gao, Ph.D., Fellow, R&D, Department of Antibody Discovery & Protein Engineering, MedImmune LLc

Novel Linkers and Payloads

10:45
Unpublished DataCase Study
Second Generation HER2-Targeted ADCs: New Linkers and Payloads
This presentation will focus on second generation HER2-targeted ADCs, and how new stable linkers as well as variations in the drug load result in site-specific ADCs with improved therapeutic activity. Additionally, the presentation will discuss the application of new payloads and how the resulting ADCs are highly efficacious, even against resistant tumor models.
Thomas Pillow, Ph.D., Scientist, ADC Team Leader, Discovery Chemistry, Genentech, Inc.

11:15
Unpublished DataCase Study
ADCs Based on RNA-Polymerase II Inhibiting Toxins
Toxic warheads of today's ADCs are exclusively based on compounds acting on microtubules or DNA replication and seem to suffer from limitations in certain cancer indications and tumor cells. Heidelberg Pharma is working on a new generation of ADCs based on the toxin amanitin, a highly effective inhibitor of the eukaryotic RNA Polymerase II. This presentation will summarize the current status of preclinical research.
Jan Anderl, Ph.D., Director, Biochemistry and Cell Biology, Heidelberg Pharma GmbH, Germany

11:45
Spotlight Presentation to be Announced
For more information on spotlight presentations, please contact Patty Rose at (508) 614-1406 or prose@ibcusa.com

12:15
Lunch on Your Own

1:25
Chairman's Remarks
Jagath Junutula, Ph.D., Vice President, Antibody Discovery & Development, Cellerant Therapeutics

Bioconjugate Development

1:30
Development Challenges of a FGF21 Protein-Antibody Conjugate
Significant improvements needed to be made to the drug development process of a FGF21 protein-antibody conjugate that reached Clinical Trials for metabolic disease indications, in order to make it commercially viable. This presentation will highlight the optimization of the conjugation process. Through thorough understanding of the key attributes, the stability and quality of intermediates were greatly improved. This allowed for a significant reduction in the cost of goods, such that the projections made for a commercial process were exceeded.
Anouk Dirksen, Ph.D., Principal Scientist, Conjugation and Polytide Process Development, Bioprocess R&D, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc

2:00
Controlling ADC Quality through Process Development
Manufacturing highly potent ADCs is a demanding task - combining conventional organic synthesis with biotechnological manufacturing. A series of challenges have to be addressed in order to develop a robust, reliable and safe process that allows delivery of this promising novel class of therapeutics at the desired quality.
Bernhard Stump, Ph.D., Process Development Team Leader, Bioconjugates, Lonza, Switzerland

2:30
Case Study
Off-Target Toxicities of Highly Targeted Antibody Drug Conjugates: Risk Mitigation Strategies
Technological advances in ADCs with innovative targets, payloads, linkers and warheads have revolutionized the opportunities to treat deadly cancers. Although the use of new linker technologies with innovative cancer antigen targets, the off-target toxicities of ADC continue to pose significant safety challenges limiting selectivity and therapeutic index. The presentation will two or three case studies will discuss both off-target and on-target toxicities of the next generation ADC molecules and opportunities for risk mitigation of these toxicities to improve therapeutic index.
Rakesh Dixit, Ph.D., DABT, Vice President, R&D; Head, Global Biologics Safety Assessment, MedImmune (AstraZeneca Biologics Company)

3:00
Networking Refreshment Break

Cysteine and Selenocysteine Conjugation Strategies for ADCs

3:30
Unpublished Data
Molecularly Defined Antibody-Drug Conjugates Built on a Selenocysteine Interface
We previously described site-specific conjugation strategies based on engineering antibodies with single or dual C-terminal selenocysteines. Here we utilize this concept for the conjugation of auristatin derivatives to antibodies in IgG and IgM format that target various hematologic and solid malignancies. The resulting antibody-drug conjugates demonstrate selective and potent killing of tumor cells in vitro, ex vivo, and in vivo.
Christoph Rader, Ph.D., Associate Professor, Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute

4:00
Unpublished Data
A Universal Chemically Driven Approach Toward the Synthesis of Homogeneous ADCs
Current ADCs in clinical development are heterogeneous mixtures that differ in both DAR (drugs/antibody) and their conjugation sites. Igenica has invented site-specific bifunctional ADC linkers to enable synthesis of homogeneous ADCs. The linkers are compatible with current ADC payloads and can be applied to any antibody without prior modification. Homogeneous ADCs were synthesized and compared with ADCs containing conventional linkers. Analytical data, functional activity, and efficacy of these ADCs in two different tumor models will be presented.
David Y. Jackson, Ph.D., Principal Scientist, Igenica, Inc.

4:30
Close of Bioconjugates Conference