Antibody-Drug Conjugates: An Emerging Modality for the Treatment of Cancer

Antibody-Drug Conjugates: An Emerging Modality for the Treatment of Cancer

Tuesday, January 28, 2014

The New York Academy of Sciences

Presented By

 

Conventional anticancer therapeutics often suffer from lack of specificity, resulting in toxicities to normal healthy tissues and poor therapeutic index. Antibody-drug conjugates (ADCs) constitute a therapeutic modality in which a cytotoxic agent is chemically linked to an antibody (Ab) that recognizes a tumor-associated antigen. The basic strategy underlying ADC technology is to combine the target selectivity of mAbs with the potency of cytotoxic agents, such as certain natural products and synthetic molecules, with the goal of generating therapeutic drugs that are highly efficacious but also safe. The ADC platform currently includes a growing repertoire of cytotoxic payloads, linker technologies and conjugation methods. Two ADCs have recently received FDA approval and more than 30 are in clinical development. This symposium aims to highlight advances in ADC research, clinical development and regulatory perspectives. Topics will range from early phase research focused on development of novel linker-payload and conjugation chemistries to clinical concepts and development of biomarkers and patient selection strategies.

*Reception to follow.

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The Biochemical Pharmacology Discussion Group is proudly supported by



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  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


Tuesday, January 28, 2014

8:30 AM

Registration and continental breakfast

9:00 AM

Welcome and Introduction:
Jennifer Henry, PhD, The New York Academy of Sciences
Mauricio Leal, PhD, Pfizer

9:10 AM

Antibody-drug conjugates: Achievements, Challenges and Future
Puja Sapra, PhD, Pfizer

9:50 AM

Clinical Development of Antibody-Drug Conjugates with a Focus on TDM1 in Breast Cancer
Sara Hurvitz, MD, UCLA Medical Center

10:30 AM

Networking coffee break

11:00 AM

Potent Immunoconjugates for Cancer Therapy
Peter D. Senter, PhD, Seattle Genetics, Inc.

11:40 AM

Improved Efficacy of Antibody Drug Conjugates via Site-Specific Incorporation of Linkable Amino Acids
Alan Wahl, PhD, Ambrx, Inc.

12:20 PM

Networking lunch break

1:20 PM

Nonclinical Safety Assessment of ADCS: Challenges of the Next Generation
Melissa M. Schutten, DVM, PhD, DACVP, Genentech Inc.

2:00 PM

Bench to Bedside Translation of ADC Efficacy
Dhaval K. Shah, PhD, The State University of New York at Buffalo and Nahor Haddish-Berhane, PhD, Pfizer

2:40 PM

Networking coffee break

3:10 PM

Regulatory Considerations for Antibody-Drug Conjugates: A Clinical Pharmacology Perspective
Stacey S. Shord, PharmD, BCOP, FCCP, Food and Drug Administration

3:50 PM

Diagnostic Approaches In Antibody-Drug Conjugate Development
Omar Kabbarah, PhD, Genentech Inc.

4:30 PM

Closing remarks
Hans-Peter Gerber, PhD, Pfizer

Networking reception

5:30 PM

Close

Speakers

Organizers

Mercedes Beyna, MS

Pfizer

Mercedes Beyna is a scientist in the Neuroscience Research Unit at Pfizer. Her research focuses on target identification and assay development in the areas of psychiatric as well as neurodegenerative disorders. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Jennifer Henry, PhD

The New York Academy of Sciences

Puja Sapra, PhD

Pfizer

Nahor Haddish-Berhane, PhD

Pfizer

Dr. Nahor Haddish-Berhane is a Senior Principal Scientist working at Pfizer. He works in the area of oncology specifically ADC efficacy and toxicology translational research. Dr. Haddish-Berhane has over 8 years of research experience in PK/PD and systems pharmacology modeling and simulation of biological systems in disease areas such as cardiovascular and metabolic, antibacterial and intestinal inflammation. Dr. Haddish-Berhane received his PhD in Bioscience Engineering from Catholic University of Leuven, Belgium.

Mauricio Leal, PhD

Pfizer

Dr. Leal is currently an Associate Research Fellow in the Pharmacokinetics, Dynamics & Metabolism (PDM) department within the Biotherapeutics R&D at Pfizer. He is responsible for providing PDM support for the Oncology Research Unit at the Pearl River, NY site with primary focus on supporting the Antibody Drug Conjugate (ADC) research programs. Prior to that, he was a Senior Director, Pharmacokinetics, at Wyeth and he started his career at Lederle laboratories. He is a member of the AAPS, ISSX, AACR and the New York Academy of Sciences. Dr. Leal received his BS in toxicology and PhD in toxicology / pharmacology from St. Johns University, NY.

Dhaval K. Shah, PhD

The State University of New York at Buffalo

Dr. Dhaval Shah is an Assistant Professor in the Department of Pharmaceutical Sciences at the State University of New York at Buffalo. After his graduation from the same department, he joined Pfizer, and after 3 years he left Pfizer to pursue his academic career. Dr. Shah's research interests include discovery and development of novel biological drugs like ADCs for the treatment of cancer, obesity. His work integrates the principles of PK/PD and mathematical modeling to quantify the efficacy and toxicity of drugs, which in turn provides a predictive systems framework for successful preclinical-to-clinical translation of drugs.

Speakers

Alan Wahl, PhD

Ambrx, Inc.

Dr. Alan Wahl is Vice President, at Ambrx, Inc. in La Jolla, CA, and is responsible for discovery and pre-clinical development of their protein and drug-conjugate therapeutics. Dr. Wahl received his MS and PhD in Biochemistry / Biophysics from the University of Rochester, and completed post-doctoral work in Experimental Oncology at Stanford University. Over the past 25 years he has held senior drug discovery positions at Bristol-Myers Squibb, Seattle Genetics, Biogen Idec and Abbott Labs, and during this time has led the discovery and pre-clinical development of numerous antibody drug conjugates.

Nahor Haddish-Berhane, PhD

Pfizer

Sara Hurvitz, MD

UCLA Medical Center

Sara Hurvitz, MD, is an Assistant Professor of Medicine at the University of California, Los Angeles (UCLA); Co-Director of the Santa Monica-UCLA Outpatient Oncology Practice; Medical Director of the Clinical Research Unit of the Jonsson Comprehensive Cancer Center of UCLA; and Director of the Breast Oncology Program, Division of Hematology-Oncology, at UCLA. Dr. Hurvitz received her medical degree from the University of Southern California School of Medicine. She served her internship and residency at UCLA, and was selected Chief Resident of Internal Medicine for 2002-2003. She then completed a Hematology-Oncology Fellowship at UCLA in 2006. Dr. Hurvitz is board-certified in Internal Medicine, Hematology, and Medical Oncology. Dr. Hurvitz is a member of numerous professional organizations including the American Society of Clinical Oncology and the American Association of Cancer Research and is a Fellow of the American College of Physicians. Her research interests include the preclinical and clinical evaluation of cutting-edge targeted therapies for breast cancer including novel therapeutic combinations. She has served as Principal Investigator for over 25 phase I, II and III international breast cancer clinical trials including studies evaluating T-DM1 and has presented the results of her breast cancer research at multiple national and international symposiums. She has also been active in community service, breast cancer advocacy, and patient education. Dr. Hurvitz has received numerous honors, including in 2007 a Young Investigator Award from the American Society of Clinical Oncology as well as the Marni Levine Breast Cancer Research Award in 2008-2011, the Andrea Dembrowsky Breast Cancer Research Award in 2009-2010 and the Diana Gordon Jonsson Award for Clinical Excellence in 2011.

Omar Kabbarah, PhD

Genentech Inc.

At Genentech, Dr. Kabbarah leads three clinical-stage Oncology programs, including two Antibody-Drug Conjugates (ADCs), and is driving a Biomarker Disease Strategy focused on Colorectal Cancer. Prior to joining Genentech, he was Principal Scientist at AstraZeneca in Boston, where he established an Oncology Target Discovery group and actively contributed to a Breast Cancer Strategy as a member of a Global Disease Area Team. He also headed an Oncology Target Identification and Validation group at AVEO Pharmaceuticals that delivered tens of well-validated oncology targets.

His educational background encompasses a variety of areas, including CNS development for an MS degree at the NIH, establishment and characterization of mouse models of cancer as part of a PhD from Washington University School of Medicine, and melanoma genomics and disease biomarker discovery as a post-doc at the Dana-Farber/Harvard Cancer Institute, where he discovered the first-in-class Golgi oncoprotein GOLPH3.

Puja Sapra, PhD

Pfizer

Puja Sapra is Senior Director at the Oncology Research Unit, Pfizer where she oversees all antibody drug conjugate therapeutic programs. Prior to joining Pfizer, she led Pharmacology groups at Enzon Pharmaceuticals and Immunomedics Inc. and developed oncology-based drugs that are undergoing clinical evaluation. She received a Bachelor's degree from All India Institute of Medical Sciences, MS from UK and a PhD in Pharmacology from University of Alberta, Canada. Since PhD she has developed various therapeutic modalities including antibodies, antibody-drug conjugates, pegylated drugs, nanoparticles and antisense oligonucleotides. She is an author of >50 scientific publications, book chapters and co-inventor on several issued patents. She has received numerous honors and grants some of which include British Chevening scholarship, Alberta Heritage foundation fellowship, NIH SBIR grant and EHA young investigator award.

Peter D. Senter, PhD

Seattle Genetics, Inc.

Peter Senter joined Seattle Genetics in August 1998 and has served as Vice President, Chemistry since September 2002. In February 2009, Dr. Senter was recognized as the company's first Distinguished Fellow. He leads Seattle Genetics' chemistry department, which carries out research in antibody-drug conjugate technologies, including the development of potent drug payloads, novel linker systems, conjugation methodology and mechanism of action studies. The work from his group at Seattle Genetics provided the basis for Adcetris, an approved antibody drug conjugate for the treatment of relapsed Hodgkin lymphoma and anaplastic large cell lymphoma. Prior to joining the company, Dr. Senter was with Cytokine Networks, Inc., the Bristol-Myers Squibb Pharmaceutical Research Institute and the Dana-Farber Cancer Institute, Harvard Medical School. While at Bristol Myers Squibb, Dr. Senter and his colleagues developed Etopofos, a water soluble anticancer prodrug approved for solid tumor therapy. Dr. Senter received an AB in Biochemistry from the University of California, Berkeley, a PhD in Chemistry from the University of Illinois, and did postdoctoral research at the Max Planck Institute of Experimental Medicine in Göttingen, Germany. He is the Senior Editor of Bioconjugate Chemistry and serves as an Affiliate Professor of Bioengineering at the University of Washington. His research interests include targeted drug delivery, protein chemistry and biochemistry, and anti-cancer drug design. Dr. Senter has authored more than 130 scientific publications and holds more than 40 patents.

Melissa M. Schutten, DVM, PhD, DACVP

Genentech Inc.

Dhaval K. Shah , PhD

The State University of New York at Buffalo

Dr. Dhaval Shah is an Assistant Professor in the Department of Pharmaceutical Sciences at the State University of New York at Buffalo. After his graduation from the same department, he joined Pfizer, and after 3 years he left Pfizer to pursue his academic career. Dr. Shah's research interests include discovery and development of novel biological drugs like ADCs for the treatment of cancer, obesity. His work integrates the principles of PK/PD and mathematical modeling to quantify the efficacy and toxicity of drugs, which in turn provides a predictive systems framework for successful preclinical-to-clinical translation of drugs.

Stacey S. Shord, PharmD, BCOP, FCCP

Food and Drug Administration: Silver Spring, MD

Dr. Shord is a reviewer for the Office of Clinical Pharmacology in the US Food and Drug Administration. She received her Doctorate in Pharmacy from the University of Maryland at Baltimore in 1997. Dr. Shord then completed a Pharmacy Practice residency at the University of Pittsburgh Medical Center and an Oncology Pharmacy Practice residency at the UNC Hospitals. She next completed a fellowship in Oncology Pharmacotherapy at the School of Pharmacy, University of North Carolina in 2001. Dr. Shord joined the faculty at the College of Pharmacy, University of Illinois at Chicago in 2001 as assistant professor where her research focused on drug metabolism in patients with cancer and hematological diseases. She joined the Food and Drug Administration in 2009 as a reviewer of oncology drug products. Special interests include the clinical development of antibody-drug conjugates and epigenome targeted drugs. Dr. Shord earned her Board Certification in Oncology Pharmacy in 2000. She has authored 44 peer reviewed papers and 9 book chapters. She is an active member of the American Society for Clinical Pharmacology and Therapeutics and the American College of Clinical Pharmacy.

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Abstracts

ADCs: Achievements, Challenges and Future
Puja Sapra, PhD, Pfizer

Antibody drug conjugates (ADCs) represent a promising therapeutic modality for clinical management of cancer. The ADC platform currently includes a growing repertoire of cytotoxic payloads, linker technologies and conjugation methods. Key considerations in generating an optimal ADC include target biology, antibody properties, linker chemistry and payload characteristics. This presentation will discuss the advancements made by the field in all aspects of ADC design. In addition, the presentation will discuss current limitations in ADC development and strategies for next generation ADC. Further, key concepts emerging from clinical trials of calicheamicin-based ADCs including dose fractionation studies will be discussed.
 

Clinical development of Antibody-drug conjugates with a focus on TDM1 in breast cancer
Sara Hurvitz, MD, UCLA Medical Center

Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate targeting HER2+ breast cancer consisting of trastuzumab, stably linked to a derivative of maytansine, a highly potent cytotoxic chemotherapy. Although other antibody drug conjugates have been developed, T-DM1 is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I and II clinical trials have now been completed showing that T-DM1 is safe, tolerable and has significant activity in the front-line or in the trastuzumab- and lapatinib-pretreated settings. Recently 2 large phase III studies have also been reported, leading to the FDA approval of T-DM1 in the second line setting. This presentation aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy, and safety of T-DM1 for the treatment of HER2-positive breast cancer.
 

Potent Immunoconjugates for Cancer Therapy
Peter D. Senter, PhD, Seattle Genetics, Inc.

Monoclonal antibodies (mAbs) have played a major role in cancer medicine, with active drugs such as trastuzumab (Herceptin), cetuximab (Erbitux), bevacizumab (Avastin) and rituximab (Rituxan) in a wide range of therapeutic applications. The mechanism of activity of these agents involves cell signaling, effector functions through interactions with Fcγ receptor positive cells, and complement fixation. In order to improve activity, attention has turned towards enhancing mAb ADCC activity by selecting stronger Fcγ receptor binders. This has been accomplished using engineered cell lines that generate mAbs with optimized Fc regions designed for enhanced receptor binding (Xencor technology), or by changing the carbohydrate structures on the heavy chains of mAbs (Glycart and Biowa technologies). We have discovered an alternative approach involving the identification of biochemical inhibitors of the enzymes fucosyl transferase and GDP-d-mannose dehydratase (GMD). The inhibitors are fucose analogues, and can be added to cells that not only produce mAbs, but other proteins in which fucosylation is important for activity. Several applications of this technology will be discussed, both in vitro and in vivo. mAb activity can also be enhanced by appending highly potent cytotoxic drugs to them. While this area has been investigated for many years, it has only been recently that mAb-drug conjugates have demonstrated the potential for playing a convincing role in cancer chemotherapy. The field has advanced significantly, with new insights gained into the roles that antigen target, normal tissue expression, drug potency, drug mechanism, linker stability, and mechanism of drug release play in generating active antibody drug conjugates (ADC) with acceptable safety profiles. ADCETRIS (Brentuximab vedotin, SGN-35) is an example an ADC that has been designed with these parameters in mind. In August 2011, ADCETRIS was approved by the US Food and Drug Administration for use in relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, two diseases with significant unmet medical needs. An overview of how this drug was developed and how we are extending the technology will be provided.
 

Improved Efficacy of Antibody Drug Conjugates via Site-Specific Incorporation of Linkable Amino Acids
Dr. Alan Wahl, Vice President of Discovery & Pre-Clinical Development, Ambrx, Inc. La Jolla, CA

The recent approvals of CD30 (Adcetris) and Her2 (Kadcyla) antibody-drug conjugates signal significant milestones in targeted drug technology. The efficacy of ADCs has dramatically improved over the past 3 decades with better understanding of antibody engineering, linker technology and appropriately potent warheads, yet what appears as significant therapeutic window in rodent models remains nominal in man. Typical drug-linkage methods provide a limited choice of mAb attachment sites and produce a heterogeneous mixture of conjugates, some contributing to poor pharmacokinetics and dose-limiting toxicities. These are now being eclipsed by new chemistries allowing both a defined number of drugs and their selective positioning on the antibody surface. This presentation will describe production cell lines engineered to incorporate reactive, non-natural amino acids into selected sites in the antibody structure. Using a medicinal chemistry approach varying the reacting amino acid and its position, linkage chemistry and warhead, an ADC of superior stability, potency and tolerability can be produced.
 

Nonclinical Safety Assessment of ADCS: Challenges of the Next Generation
Melissa M. Schutten, DVM, PhD, DACVP, Genentech, Inc., Safety Assessment

Antibody-drug conjugates (ADCs) represent a class of targeted therapies that hold great promise for oncology patients as they are purposefully designed to minimize systemic toxicity while delivering a highly potent, cytotoxic payload to a target cell population. Recent research advances in ADCs have expanded the variety of ADC targets, linkers, cytotoxins, and site-specific conjugation methods.  However, successful preclinical development of these complex molecules is subject to particular challenges and there are ongoing efforts to improve ADC technology to mitigate potential ADC-related toxicities.  This presentation will highlight the general determinants of ADC toxicity and offer specific case examples in which these challenges were identified and addressed in preclinical animal studies.  In particular, considerations regarding target molecule biology and deciphering antigen-dependent and -independent toxicities, linker stability, and species differences in candidate safety profiles will be discussed.
 

Bench to Bedside Translation of ADC Efficacy
Dhaval K. Shah, PhD, The State University of New York at Buffalo
Nahor Haddish-Berhane, PhD, Pfizer

In this presentation step-by-step development of a multi-scale mechanistic model will be discussed, using brentuximab vedotin as a case study. The ability of the model to predict tumor concentrations of ADC, and clinical outcomes such as progression free survival and complete response rates, will be presented. Finally, the utility of the model in design of novel ADCs, development of precision medicine efforts, and understanding different pathways of ADC disposition will be showcased.
 

Regulatory Considerations for Antibody-drug Conjugates: A Clinical Pharmacology Perspective
Stacey S. Shord, PharmD, BCOP, FCCP, Food and Drug Administration

Antibody-drug conjugates are an emerging therapy for patients with cancer. These conjugates contain a small molecule payload attached to a monoclonal antibody via a linker. The resulting drug product is a heterogeneous mixture that contains multiple conjugates with different amounts of the small molecule payload attached to each monoclonal antibody. Multiple species can be identified in the systemic circulation following administration of these conjugates, including the antibody conjugated drug, the total antibody and the unconjugated small molecule, leading to challenges in drug development. Three antibody-drug conjugates have been approved by the U.S. Food and Drug Administration. These approved products will be discussed to highlight key considerations for characterizing the clinical pharmacology of new antibody-drug conjugates under development. The discussion will focus on describing the pharmacokinetics and exposure-response relationships, the potential risk of drug interactions, and the impact of organ impairment on exposure. The potential for the development of immunogenicity and the prolongation of the QT/QTc interval will also be discussed along with considerations for the bioanalytical methods. The discussion will demonstrate that aspects of the typical development for both small molecule drugs and therapeutic proteins should be considered when developing new antibody-drug conjugates.
 

Diagnostic Approaches in Antibody-Drug Conjugate Development
Omar Kabbarah, PhD, Genentech Inc.

Antibody-drug conjugates hold tremendous promise in Oncology. Through selectively targeting tumor cells with lethal payloads while largely sparing normal cells from unwanted toxicities, this class of "smart drug" could offer meaningful clinical relief to patients suffering from cancer. For the therapeutic potential of ADCs to be fully realized, however, it is vital that the development of these compounds be coupled with a diagnostic can be used to identify patients who are likely to experience clinical benefit, as well as those who are not likely to respond to the ADC and would be better served to pursue other treatment options. Diagnostic approaches from Genentech's ADC pipeline will be presented.
 

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