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Perfect the Biochemistry Behind ADC Synthesis, Vaccine and Nanoparticle Conjugation

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Transitioning Innovation into Viable Therapeutic Candidates

June 13-15, 2016
Parc 55 Hilton
San Francisco, CA

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Agenda

Agenda

Monday, June 13, 2016

8:00
Opening Remarks

Keynote Presentation

8:15
Expressed Protein Ligation as Bioconjugation Platform
In this session Dr. Thiel will discuss how expressed protein ligation offers a practical solution to conjugate peptides on the C-terminus of proteins.
Oliver Thiel, Ph.D., Director Process Development, Amgen

Perfecting Chemistry to Overcome Challenges in ADC Synthesis

8:45
New Data
Cysteine Arylation for Site-Specific Antibody Conjugation
Here we report a robust bioconjugation method using cysteine arylation. This chemistry enables site-specific conjugation at cysteine residues within peptides, proteins, and antibodies. Our two developed approaches use either perfluoroaryl-cysteine SNAr chemistry or organometallic palladium reagents. Recently, we discovered a self-labeling four-residue sequence that enables regioselective conjugation at only one cysteine residue within an intact antibody containing natural amino acids.
Bradley L. Pentelute, Ph.D., Pfizer-Laubach Career Development Professor; Associate Member, Broad Institute of Harvard and MIT; Member, Center for Environmental Health Sciences MIT

9:15
Creating Next Generations ADCs with Unnatural Amino Acids (uAAs)
Amino acids with non-natural side chains can be genetically encoded into proteins and used for site specific modification. We have created next-generation antibody conjugates by directly coupling drugs, as well as nucleic acids to unnatural amino acids on antibodies. This basic technology lends itself to creation of not only drug conjugates, but also novel multimeric structures through nucleotide basepairing.
Vaughn Smider, Chief Scientific Officer, Sevion Therapeutics; Asst Professor, The Scripps Research Institute

9:45
Networking Refreshment Break in Poster & Exhibit Hall

Identifying ADC Targets & Site Specific Conjugation

10:15
New Data
Site Specific Conjugation through Antibody Glycans with PBD Dimers
Dimiter Dimitrov, Ph.D., Senior Investigator, Protein Interactions, National Cancer Institute, NIH

10:45
New Data
Metal-Mediated Site-Selective Labeling of Wild-Type Proteins
The focus of this session lies on the development of new methods for controlled labeling of proteins. This is most commonly obtained through techniques based on genetic modification of the protein of interest. Here we show a method for controlled protein labeling which is based exclusively on properly designed probes. This method has resulted in high yielding and site-selective labeling of IgG1-antibodies.
Michael Rosholm Mortensen, Ph.D. Student, Chemistry and iNANO, Aarhus University

11:15
Case Study
Selection of Cell Binding and Internalizing Phage Abs for Targeted Drug Delivery
Phage antibody technology has been typically applied to the generation of antibodies to purified proteins, it is also possible to directly select cell binding and internalizing antibodies on cells. This allows use of the antibody to deliver a range of payloads into the cell to achieve a therapeutic effect.
Yu Zhou, Associate Adjunct Professor, Department of Anesthesia, University of California, San Francisco

Technology Workshop

11:45
Enzymatic Ligation as a Tool for Assembling Bioconjugates
Peptiligases, genetically engineered ligases, are shown to be highly effective (conversion > 90%, low molar equivalents) at coupling peptides and peptide-linked molecules selectively to the N- and C-terminals of peptides and proteins, enabling the assembly of fusion proteins and protein conjugates. Fusion proteins > 800 amino acids (recombinant + peptide fragment) and synthetic proteins >200 amino acids (peptide + peptide fragments) have been assembled.
Rodney Lax, Ph.D., Scientific Advisor & Business Development Consultant, EnzyPep B.V.

12:15
Networking Luncheon in the Poster & Exhibit Hall

Clinical Updates for Bioconjugates

1:25
Staphylococcus Aureus Vaccine Development
Staphylococcus aureus is a Gram positive microorganism that causes a range of infections from mild skin conditions to severe and life threatening invasive disease. Infections can be complicated by antibiotic resistance and therefore an approach, such as a prophylactic vaccine, to prevent infections in at risk populations would be highly desirable. Many bacterial pathogens, including S. aureus, coat themselves with polysaccharide based capsules as a mechanism to evade host immune defenses. Conjugate polysaccharide vaccines that induce anti-capsular antibodies thwart this mechanism and have been highly successful at preventing disease caused by other prominent bacterial pathogens. Development efforts continue to use this approach against S. aureus despite observed clinical failures. Careful consideration is therefore required regarding the composition of S. aureus prophylactic vaccines. These and the approaches for demonstrating efficacy will be discussed.
Annaliesa S. Anderson, Ph.D., Chief Scientific Officer, Bacterial Vaccines, Vaccine Research and Development, Pfizer, Inc

1:55
New Data
Targeted Protein Therapeutics (TPTs) for the Systemic and Local-regional Treatment of Cancer
TPTs incorporate antibody fragments and protein toxin payloads into a single gene-fused molecule. Results will be presented from phase II clinical trials in non-muscle invasive bladder cancer and squamous cell carcinoma of the head and neck with TPTs targeting Ep-CAM. Clinical evidence of successful de-immunization of our deBouganin payload TPTs and their lack of sensitivity to multidrug resistance mechanisms will also be presented.
Greg Adams, Ph.D., Chief Development Officer, Viventia Biotechnologies Inc

Developments in Combination Therapies

Keynote Presentation

2:25
Immune Checkpoint Inhibitors - Combinatorial Approaches in Melanoma and Other Malignancies
While PD-1 pathway blockade has remarkable single agent activity in subsets of patients, the combination of PD-1 and CTLA-4 inhibition increases the efficacy (and toxicity) of PD-1 inhbition in melanoma, leading to FDA approval of the combination of nivolumab and ipilimumab. Building on the experience in melanoma, multiple variables contributing to successful immune checkpoint combination strategy, including dosing and scheduling will be presented. Key principles governing rational immunooncology combination strategies will be highlighted.
Patrick A. Ott, MD, Ph.D., Clinical Director, Melanoma Disease Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute; Assistant Professor of Medicine, Harvard Medical School

3:00
Networking Refreshment Break in Poster & Exhibit Hall

Developments in Combination Therapies (continued)

3:30
Adoptive T Cell Therapy and Immune Checkpoint Inhibitors: A Combination Strategy for Cancer Treatment
Adoptive cellular therapy can provide large numbers of tumor-reactive T cells especially in cases where the endogenous T cell response is inadequate. Combining the use of ACT with Immune Checkpoint Inhibitors can lead to a synergistic response in patients with solid tumor malignancies. Judicious use of combination approaches may be facilitated through the use of a well-defined population of adoptively transferred T cells as a transferrable cellular biomarker.
Cassian Yee, MD, Professor, Department of Immunology, MD Anderson Cancer Center

Progress in Conjugate Vaccines

4:00
Recent Trends in the Design of Carbohydrate-Based Conjugate Vaccines
Carbohydrate-based conjugate (glycoconjugate) vaccines represent one of the keys for success of vaccination in children. They are a potent tool for prevention of life-threatening bacterial infectious diseases like meningitis and pneumonia. The immunogenicity of these glycoconjugates is influenced by a series of interconnected parameters, some of which are related to the sugar carbohydrate antigen (length, non-end terminal residues, exposition of charged functional groups, number of sugar copies linked to the protein) and other to the conjugation chemistry to protein carrier (type of linker, length, etc.) The complexity of randomly prepared glycoconjugates has not made possible to decipher the contribution of all the single parameters that underlay the overall immunological activity of the biomolecules. Recently, different methods for chemical or enzymatic assembly of defined oligosaccharides have rendered feasible the synthesis of complex carbohydrates. The modern methods for site selective conjugation could contribute to the production of a new generation of glycoconjugate vaccines with defined sugar and attachment site and to establish robust structure-immunogenicity relationship.
Francesco Berti, Ph.D., Head of Antigen Design, Preclinical R&D, GSK Vaccines

4:30
New Data
Development of a Vaccine to Interrupt Malaria Transmission using a Chemically Conjugated Protein-protein nanoparticle platform
One approach to develop effective vaccines uses well-characterized recombinant proteins that are chemically conjugated to form nanoparticles. We have found that the conjugation of recombinant malarial proteins to potent carriers can significantly enhance immunogenicity in animals and humans. In phase 1 trials, conjugate vaccines that target the malaria parasite during transmission to the mosquito appear to be safe and induce functional antibodies whose activity is enhanced by human complement.
David L. Narum, Ph.D., Head, Process Development Unit, Laboratory of Malaria Immunology and Vaccinology, NIH

5:00
Networking Cocktail Reception in the Poster & Exhibit Hall

Tuesday, June 14, 2016

Analytical and Characterization Strategies

8:00
Opening Remarks

8:15
New Data
Combating Challenges in Analytical Methods and Characterization in ADCs
The combination of low molecular weight toxins with high molecular weight monoclonal antibodies (mAb) in antibody-drug conjugates (ADCs) adds significant complexity to the analytical method development for this promising class of drugs. This complexity makes it very challenging to develop analytical methods for monitoring potential critical quality attributes (pCQAs), such as aggregate, fragment, and charge variants. The dual nature of ADCs also imposes unique considerations related to ADC-specific CQAs, such as identity, drug-antibody ratio (DAR), multiple mechanisms of action (MOAs), impurity levels for small molecule toxins (free drug), and free antibody content. This presentation will discuss the development of ADCs at MedImmune and highlight the common and unique analytical challenges encountered with this class of drugs.
Jinhua Feng, Scientist, MedImmune

8:45
Case StudyNew Data
Characterization Roadmaps for Antibody Drug Conjugates: Integration of New Approaches for Improved Process and Product Understanding
Comprehensive, ADC-specific product characterization roadmaps have been developed to harmonize and strategically guide the projects at each stage of process and product development. As new modalities of ADCs are developed, it is important to infuse new approaches and methods into the characterization roadmaps to adequately evaluate the molecular complexity and critical quality attributes. MS-based characterization strategies for various ADCs will be discussed.
Olga V. Friese, Ph.D., Associate Research Fellow, Analytical Research and Development, Pfizer WRD

9:15
Case StudyNew Data
Non-Natural Amino Acid Based ADC Molecule
Non-natural amino acid (nnAA) based ADC molecules represent a new direction in Bioconjugates, and require new analytical strategies to characterize them, in particular for DAR and free drug linker related critical quality attributes. A case study with a combination of HPLC and Mass spec approaches will be presented for analytical development and characterization purpose.
Boxu Yan, Ph.D., Principal Scientist, Celgene

9:45
Networking Refreshment Break in Poster & Exhibit Hall

10:15
New Data
Strategies for Analytical Characterization of Antibody-Drug Conjugates (ADCs) Conjugated through Lysines
ADCs conjugated through lysines are heterogeneous molecules due to the nature of conjugation chemistries involved. Understanding this heterogeneity and its impact on intrinsic properties of an ADC is critical for successful development of these compounds. The presentation will discuss important strategies for analytical characterization to support CMC development.
Karan K. Shah, Senior Analytical Associate, ImmunoGen

Keynote Presentation

10:45
A Novel Site Specific Antibody-Drug Conjugate for Her2-Positive Solid Tumors
The preclinical data on the development of a next-generation Antibody-Drug Conjugate (ADC) targeting the HER2 receptor (NG-HER2-ADC). This ADC utilizes a novel proprietary site specific conjugation chemistry that uses engineered cysteines on the antibody molecule to conjugate the cytotoxic payload. When tested in preclinical models, the NG-HER2 ADC induced significantly lower levels of off-target toxicities such as neutropenia compared to ADCs that used conventional, random conjugation methodologies. The NG-HER2-ADC displayed superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory tumors. Our findings indicate that NG-HER2-ADC has promising potential as an effective therapy for HER2-positive tumors including metastatic breast cancer, gastric cancer, lung cancer and other solid tumors.
Puja Sapra, Senior Director, Oncology Research Unit, Pfizer

Breakthrough Discoveries and Advances in ADCs

11:15
Case StudyNew Data
Antibody Drug Conjugates Targeting Protein-Protein Complexes at the Cells Surface
The human Na+/K+-ATPase (NKA) is a plasma membrane ion pump that is essential for mammalian cell life. For Human cells, pump inhibition by a naturally occurring steroid leads to cell swelling followed by necrotic cell death. Using a new type of antibody drug conjugate that simultaneously targets two interacting proteins, we discovered that the NKA interacts with multiple seemingly unrelated proteins, a fact that can now be exploited for medicinal purposes. We call these new drug conjugates, extracellular drug conjugates (EDCs) due to their extracellular mechanism of action which does not require internalization. And because EDC activity is driven by proximity, breakdown products are essentially inactive. Specifically, this talk will discuss multiple EDCs with potencies and specificities matching todays ADCs. It will also discuss the similarities and differences between the two. The talk should also enhance an ongoing discussion around the drugability of protein-protein interactions and how EDC technology can be exploited to not only find such interactions, but also produce drugs that precisely target them.
James R. Prudent, Ph.D., President and Chief Executive Officer, Centrose

11:45
Case Study
Highly Potent HER-2 Targeting Bispecific ADC Development in ADC's and Technologies
In this case study Dr.Dixit will explore concepts in lysosomal trafficking and opportunities to enhance ADC internalization. He will also be discussing a biparatopic, bispecific HER-2 ADC that combines and improves MOAS of herceptin, pertuzumab, and kacyla. Efficacy and safety differentiation will also be taken into consideration.
Rakesh Dixit, Ph.D., Vice President, R & D, Global Safety Assessment, MedImmune

12:15
Roundtable Networking Luncheon in the Poster & Exhibit Hall

1:25
New Data
Factors Involved in ADC Antitumor Activity: Receptor, Payload and Beyond
This presentation will discuss the role of released payload in antigen-mediated cytoxicity, in vivo efficacy, and by stander killing. In addition, the impact of tumor microenvironment and pharmacokinetics on ADC activity will be discussed. Learn how:
  • Intramural drug release determines antitumor activity and bystander killing of ADC in vivo
  • Tumor associated macrophages can contribute to ADC activity in xenograft models
  • Host of xenograft models can impact ADC pharmacokinetics and activity
Fu Li, Ph.D., Senior Scientist, Preclinical Research, Seattle Genetics, Inc.

Keynote Presentation

2:00
Developing Site-Specifically Modified ADCs Using a Chemoenzymatic Approach
Antibody-drug conjugates (ADCs) have become de rigueur for pharmaceutical oncology drug development pipelines. There are more than 50 ADCs undergoing clinical trials and many more in preclinical development. The field has rushed to follow the initial successes of Kadcyla™ and Adcetris™. Within the research realm, innovations in conjugation chemistry and linker technologies have suggested that there is much room for improvement in the conventional methods. We have developed the SMARTagTM technology platform, which enables precise, programmable, site-selective chemical protein modification. Leveraging the target sequence of Formylglycine Generating Enzyme (FGE) we chemoenzymatically modify proteins to generate a precisely placed aldehyde functionality that can be chemically elaborated. Subsequently, novel ligation chemistry is employed that exploits this "aldehyde tag" site. We will present our novel protein modification platform and its application to generating ADCs, including our new conjugation chemistries and linkers. The application of these chemistries to the generate site-specifically modified bioconjugates with improved efficacy and safety profiles will be presented. Additionally, we will highlight progress in developing these SMARTagTM ADCs with a focus on preclinical studies as well as highlight our progress in cell line development and manufacturing of bioconjugates using this chemoenzymatic approach.
Romas Kudirka, Senior Research Scientist, Catalent Pharma Solutions

Rapid Fire Poster Presentations

Our scientific advisors will handpick the top poster submissions and provide them an opportunity to give a brief introduction to their work. Further discussions on posters will be fostered in the exhibiting hall during networking functions.

2:30
Poster Presenter #1

2:45
Poster Presenter #2

3:00
Networking Refreshment Break in Poster & Exhibit Hall

Advancements in Linker Payload Technology

3:30
New Data
A Novel Quaternary Ammonium Salt Linker for Antibody-Drug Conjugates
In this talk we describe a quaternary ammonium salt linker that can connect and tracelessly release a wide array of tertiary and heteroaryl amines. The concise, chemoselective synthesis allows the rescue of drugs previously unamenable to antibody conjugation. The resulting antibody conjugates have reduced aggregation, are stable, and possess increased therapeutic activity.
Thomas Pillow, Ph.D., Scientist, ADC Team Leader, Genentech

4:00
Design, Synthesis and Evaluation of a Novel Class of Potent DNA-Aikylating Agents for use in Antibody-Drug Conjugates (ADCs)
There are currently over 50 Antibody-Drug Conjugates (ADCs) in clinical development, reflecting the growing interest in ADCs for the treatment of cancer. In order to extend the application of ADCs to more cancer types we have designed a new class of potent DNA-alkylating agents, "indolino-benzodiazepine dimers" (IGNs). The chemical design, synthesis and preclinical data for representative IGNs and their ADCs will be discussed. Join us for a discussion that covers:
  • New Class of DNA-alkylating agents designed and synthesized
  • ADCs of these agents prepared and evaluated
  • Promising preclinical activity demonstrated
Michael L. Miller, Ph.D., Associate Director, Chemistry, ImmunoGen, Inc.

4:30
Case StudyNew Data
Topoisomerase I Inhibitor Exatecan-Derivative Based ADC Payloads and Preclinical Application
Antibody drug conjugates (ADCs) covalently connected with exatecan derivatives via a cleavable linker system showed low aggregation ratio, high drug-to-antibody ratio (DAR), and strong efficacy. DS-8201a is a novel anti-HER2 ADC with one of the exatecan derivatives and Phase I dose escalation part is ongoing. The preclinical data of this new class of topoisomerase I inhibitor-based ADC technology will be described.
Yuki Abe, Ph.D., Senior Director, Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd.

5:00
Happy Hour Offsite Reception / Close of Day 2

Wednesday, June 15, 2016

8:00
Opening Remarks

From Discovery to Commercialization: Readiness for Manufacturing & Commercialization

Opening Keynote Presentation

8:15
Case Study
Challenges in Purification of Antibody Drug Conjugates
This presentation would focus on a case study with Anti-EFNA4 ADC, a new calicheamicin conjugate, to illustrate Pfizer's development paradigm. In the process development arena the approach to maintain acceptable yields while maintaining quality attributes will be discussed. Our emphasis on thorough characterization of the final product will be discussed as well as consistency across multiple batches.
Vimal Patel, Senior Scientist, Conjugation and Polytides Process Development, Pfizer, Inc.

9:00
Panel Discussion: Assessing Late Stage Commercial Readiness
Panelists:
Boxu Yan, Ph.D., Principal Scientist, Celgene
Vimal Patel, Senior Scientist, Conjugation and Polytides Process Development, Pfizer, Inc.
Rakesh Dixit, Ph.D., Vice President, R & D, Global Safety Assessment, MedImmune

9:45
Networking Refreshment Break in Poster & Exhibit Hall

Novel Conjugation Techniques: ADC's and Nanoparticle Conjugation

10:15
New Data
Delivery of Immunotargeted Nanotherapeutics for the Treatment of Solid Tumors
  • Development of highly stabilized controlled released nanoformulations of small molecule drugs can result in a novel and highly flexible format of antibody drug conjugates
  • A second generation antibody directed nanotherapeutic (ADN) has been shown to have broad spectrum activity in a range of solid tumors and a substantially altered toxicity profile when compared to the unencapsulated or free drug
  • Clinical development of a first generation ADN targeted to ErbB2 and delivering doxorubicin has entered Phase II clinical trials for the treatment of third line ErbB2-overexpressing breast cancer
Daryl C. Drummond, Ph.D., Vice President, Discovery, Merrimack

10:45
New Data
Strategies for Analytical Characterization of Antibody-Drug Conjugates (ADCs) Conjugated through Lysines
ADCs conjugated through lysines are heterogeneous molecules due to the nature of conjugation chemistries involved. Understanding this heterogeneity and its impact on intrinsic properties of an ADC is critical for successful development of these compounds. The presentation will discuss important strategies for analytical characterization to support CMC development.
Pirouz Daftarian, Senior Scientist, Immuno-oncology, NGM Bio

11:15
New Data
Site Selective Enzymatic Polymer Conjugation to Proteins by Transglutaminase
Transglutaminases are a class of enzymes capable of catalyzing an acyl transfer between two proteins involving the glutamyl group of a glutamine (acyl donor) and a primary amine (acyl acceptor). Transglutaminase has been also investigated for bioactive drug applications such as site-specific polymer conjugation to pharmaceutical proteins by using amino-polymers as acyl acceptors. This enzyme offers new perspectives in the field of polymer conjugation.
Gianfranco Pasut, Ph.D., Pharmaceutical and Pharmacological Sciences, University of Padova, Italy

11:45
New Data
PNA-mediated Affibody-Based Pretargeting of Malignant Tumors
We have developed a pretargeting system based on PNA-based probes for tumor-targeting. The objective is to reduce the accumulation of radioactivity in off target organs, especially kidneys, associated with Affibody-mediated direct targeting. In a proof-of-principle study, the PNA-based probes were used to specifically label HER2-expressings xenografts in mice with 111In. In comparison with direct targeting, kidney accumulation was reduced ca. 30-fold.
Kristina Westerlund, Ph.D., School of Biotechnology, Division of Protein Technology, Royal Institute of Technology (KTH), Sweden

12:15
Closing Remarks / Conference Close

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