Antibody-Drug Conjugates E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 988

Veröffentlichungsjahr: 2016

Beschreibung

Providing practical and proven solutions for antibody-drug conjugate (ADC) drug discovery success in oncology, this book helps readers improve the drug safety and therapeutic efficacy of ADCs to kill targeted tumor cells. * Discusses the basics, drug delivery strategies, pharmacology and toxicology, and regulatory approval strategies * Covers the conduct and design of oncology clinical trials and the use of ADCs for tumor imaging * Includes case studies of ADCs in oncology drug development * Features contributions from highly-regarded experts on the frontlines of ADC research and development

Leseprobe

Table of Contents

Cover

Title Page

Copyright

List of Contributors

Preface

Historical Perspective: What Makes Antibody–Drug Conjugates Revolutionary?

Introduction

Early Work in Monoclonal Antibody Development: Ehrlich’s Magic Bullets

Use of Monoclonal Antibodies to Identify and Treat Cancer

Linking Monoclonal Antibodies with Cytotoxic Agents

Antibody–Drug Conjugates in the Clinic

Why ADCs Are Revolutionary?

References

Part I: What is an Antibody–Drug Conjugate

Chapter 1: Typical Antibody–Drug Conjugates

1.1 Introduction

1.2 The Building Blocks of a Typical ADC

1.3 Building an ADC Molecule

1.4 Attributes of a Typical ADC

1.5 Summary

Acknowledgment

References

Part II: Engineering, Manufacturing, and Optimizing Antibody–Drug Conjugates

Chapter 2: Selecting Optimal Antibody–Drug Conjugate Targets Using Indication-Dependent or Indication-Independent Approaches

2.1 Characteristics of an Optimal ADC Target

2.2 Indication-Dependent ADC Target Selection

2.3 Indication-Independent ADC Target Selection

2.4 Concluding Remarks and Future Directions

Acknowledgments

References

Chapter 3: Antibody–Drug Conjugates: An Overview of the CMC and Characterization Process

3.1 Introduction

3.2 ADC Manufacturing Process

3.3 Characterization

3.4 Comparability

3.5 Concluding Remarks

References

Chapter 4: Linker and Conjugation Technology; and Improvements

4.1 Overview

4.2 Noncleavable

4.3 Cleavable Linkers and Self-Immolative Groups

4.4 Differences in Therapeutic Window of Cleavable and Noncleavable Linkers

4.5 Improving Therapeutic Window with Next-Generation Linker Technologies

4.6 Site-Specific Conjugation, Homogeneous Drug Species, and Therapeutic Window

4.7 Influence of Linkers on Pharmacokinetics and ADME

4.8 PEG Linkers to Optimize Clearance, Solubility, and Potency

4.9 Linkers to Optimize for Drug Resistance

4.10 Improving Solid Tumor Penetration with Linkers

4.11 Analytical Methods for Characterizing Linker Pharmacodynamics

4.12 Conclusion

References

Chapter 5: Formulation and Stability

5.1 Introduction

5.2 Stability Considerations for ADCs

5.3 Formulation Approaches

5.4 Logistical Considerations

5.5 Summary and Close

References

Chapter 6: QC Assay Development

6.1 Introduction

6.2 Drug-to-Antibody Ratio

6.3 Drug Loading Distribution

6.4 Positional Isomers

6.5 ADC Concentration

6.6 Drug-Related Substances

6.7 Antigen Binding Assays and Potential Impact of Drug Conjugation

6.8 Cell-Based Cytotoxicity Assays

6.9 Assays to Monitor Fc-Dependent Effector Functions to Characterize Additional Possible Mechanisms of Action

6.10 Immunogenicity Assays to Monitor the Immune Response to ADC

6.11 Conclusions

6.12 Key Guidance Documents

Acknowledgments

References

Chapter 7: Occupational Health and Safety Aspects of ADCs and Their Toxic Payloads

7.1 Introduction

7.2 Background on ADCs

7.3 Occupational Hazard Assessment of ADCs and Their Components

7.4 Occupational Implications and Uncertainties

7.5 General Guidance for Material Handling

7.6 Facility Features and Engineering Controls

7.7 Specific Operational Guidance

7.8 Personal Protective Equipment

7.9 Training

7.10 Industrial Hygiene Monitoring

7.11 Medical Surveillance Program

7.12 Summary and Future Direction

References

Part III: Nonclinical Approaches

Chapter 8: Bioanalytical Strategies Enabling Successful ADC Translation

8.1 Introduction

8.2 ADC LC/MS Bioanalytical Strategies

8.3 Non-Regulated ADC Pharmacokinetic and Immunogenicity Support Using Ligand Binding Assays

8.4 Biodistribution Assessment

8.5 Regulated ADC Pharmacokinetics and Immunogenicity Evaluation

8.6 ADC Biomeasures and Biomarkers

8.7 Summary

References

Chapter 9: Nonclinical Pharmacology and Mechanistic Modeling of Antibody–Drug Conjugates in Support of Human Clinical Trials

9.1 Introduction

9.2 Cell Line Testing

9.3 Xenograft Models

9.4 Nonclinical Testing to Support Investigational New Drug Applications

9.5 Mechanistic Modeling of Antibody–Drug Conjugates

9.6 Target-Mediated Toxicity of Antibody–Drug Conjugates

9.7 Considerations for Nonclinical Testing Beyond Antibody–Drug Conjugate Monotherapies

9.8 Summary

Acknowledgments

References

Chapter 10: Pharmacokinetics of Antibody–Drug Conjugates

10.1 Introduction

10.2 Pharmacokinetic Characteristics of an ADC

10.3 Unique Considerations for ADC Pharmacokinetics

10.4 Tools to Characterize ADC PK/ADME

10.5 Utilization of ADC Pharmacokinetics to Optimize Design

10.6 Pharmacokinetics of Selected ADCs

10.7 Summary

References

Chapter 11: Path to Market Approval: Regulatory Perspective of ADC Nonclinical Safety Assessments

11.1 Introduction

11.2 FDA Experience with ADCs

11.3 Regulatory Perspective of the Nonclinical Safety Assessment of ADCs

11.4 Concluding Remarks

References

Part IV: Clinical Development and Current Status of Antibody–Drug Conjugates

Chapter 12: Antibody–Drug Conjugates: Clinical Strategies and Applications

12.1 Antibody–Drug Conjugates in Clinical Development

12.2 Therapeutic Indications

12.3 Transitioning from Discovery to Early Clinical Development

12.4 Challenges and Considerations in the Design of Phase 1 Studies

12.5 First-in-Human Starting Dose Estimation

12.6 Dosing Strategy Considerations

12.7 Dosing Regimen Optimization

12.8 Phase 1 Study Design

12.9 Supportive Strategies for Phase 1 and Beyond

12.10 Clinical Pharmacology Considerations

12.11 Organ Impairment Assessments

12.12 Drug–Drug Interaction Assessments

12.13 Immunogenicity

12.14 QT/QTc Assessments

12.15 Pharmacometric Strategies

12.16 Using Physiologically Based Pharmacokinetic and Quantitative Systems Pharmacology Models with Clinical Data

12.17 Summary and Conclusions

Acknowledgments

References

Chapter 13: Antibody–Drug Conjugates (ADCs) in Clinical Development

13.1 Introduction and Rationale

13.2 Components of ADCs in Development

13.3 Landscape of ADCs

13.4 Clinical Use of ADCs

13.5 Future of ADCs

13.6 ADCs in Development

13.7 Future Directions

References

Chapter 14: ADCs Approved for Use: Trastuzumab Emtansine (Kadcyla®, T-DM1) in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer

14.1 Introduction

14.2 Preclinical Development of T-DM1

14.3 Early Clinical Studies of T-DM1

14.4 Clinical Pharmacology and Pharmacokinetics

14.5 Phase III Studies of T-DM1 in Patients with HER2-Positive MBC

14.6 Future Directions

14.7 Summary

References

Chapter 15: ADCs Approved for Use: Brentuximab Vedotin

15.1 Introduction

15.2 Early Efforts to Target CD30 with Monoclonal Antibodies

15.3 BV: Preclinical Data

15.4 Clinical Context

15.5 Mechanisms of Resistance

15.6 Current Research

15.7 Discussion

References

Chapter 16: Radioimmunotherapy

16.1 History of Radioimmunotherapy

16.2 Radioisotopes

16.3 Chemistry of RIT

16.4 Radioimmunotherapy Antibody Targets in Use Today (Table 16.2)

16.5 Other Hematologic Targets

16.6 Solid Tumors

16.7 Combination Therapy with RIT: Chemotherapy and/or Radiation

16.8 RIT and External Beam Radiation Treatment (EBRT)

16.9 RIT and EBRT and Chemotherapy

16.10 RIT Administration

16.11 Future of RIT

References

Part V : Future Perspectives in Antibody–Drug Conjugate Development

Chapter 17: Radiolabeled Antibody-Based Imaging in Clinical Oncology

17.1 Introduction

17.2 Applications for Clinical Antibody Imaging

17.3 Antibodies as Imaging Agents

17.4 Nuclear Imaging – Gamma Camera (Planar) Scintigraphy and SPECT

17.5 Nuclear Imaging - PET

17.6 Commercialization Considerations

17.7 Summary

References

Chapter 18: Next-Generation Antibody–Drug Conjugate Technologies

18.1 Introduction

18.2 Novel Cytotoxic Payloads and Linkers

18.3 Tailoring Antibodies for Use as ADCs

18.4 Conclusions

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Begin Reading

Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer

Edited by Kenneth J. Olivier Jr. and Sara A. Hurvitz

Copyright © 2017 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

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Library of Congress Cataloging-in-Publication Data:

Names: Olivier, Kenneth J., Jr., 1968- editor. | Hurvitz, Sara A., 1970-editor.

Title: Antibody-drug conjugates : fundamentals, drug development, and clinical outcomes to target cancer / edited by Kenneth J. Olivier Jr., Sara A. Hurvitz.

Other titles: Antibody-drug conjugates (Olivier)

Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2017] | Includes bibliographical references and index.

Identifiers: LCCN 2016032954 (print) | LCCN 2016034128 (ebook) | ISBN 9781119060680 (cloth) | ISBN 9781119060840 (pdf) | ISBN 9781119060802 (epub)

Subjects: | MESH: Immunoconjugates | Antibodies, Monoclonal | Antineoplastic Agents | Neoplasms–drug therapy

Classification: LCC RS431.A64 (print) | LCC RS431.A64 (ebook) | NLM QW 575.5.A6 | DDC 615.7/98–dc23

LC record available at https://lccn.loc.gov/2016032954

Cover image courtesy: Sylverarts/Getty images

List of Contributors

Kimberly L. Blackwell

Division of Medical Oncology

Duke Cancer Institute

Durham, NC

USA

Xiao Hong. Chen

Office of New Drug Products, Center for Drug Evaluation and Research

US Food and Drug Administration

Silver Spring, MD

USA

Savita V. Dandapani

Department of Radiation Oncology

City of Hope

Duarte, CA

USA

R. Angelo De Claro

Division of Hematology Products, Office of Hematology and Oncology Products (OHOP), OND, CDER

U S FDA

Silver Spring, MD

USA

Sanne de Haas

F. Hoffmann-La Roche, Ltd.

Basel

Switzerland

Sven de Vos

University of California

Department of Hematology/Oncology

Los Angeles, CA

USA

Riley Ennis

Oncolinx LLC

Boston, MA,

USA

and

Dartmouth College

Hanover, NH

USA

John Farris

SafeBridge Consultants, Inc.

New York, NY

USA

Daniel F. Gaddy

Merrimack Pharmaceuticals, Inc.

Cambridge, MA

USA

Sandhya Girish

Molecular Oncology (GDLP); Oncology Biomarker Development (SDH); Oncology Clinical Pharmacology (SG); Product Development Oncology (EG)

Genentech, Inc.

South San Francisco, CA

USA

Ellie Guardino

Molecular Oncology (GDLP); Oncology Biomarker Development (SDH); Oncology Clinical Pharmacology (SG); Product Development Oncology (EG)

Genentech, Inc.

South San Francisco, CA

USA

Manish Gupta

Clinical Pharmacology & Pharmacometrics

Bristol-Myers Squibb

Princeton, NJ

USA

Amy Q. Han

Regeneron Pharmaceuticals, Inc.

Tarrytown, NY

USA

Xiaogang Han

Pharmacokinetics, Dynamics and Metabolism - Biotherapeutics

Pfizer Inc.

Groton, CT

USA

Steven Hansel

Pharmacokinetics, Dynamics and Metabolism - Biotherapeutics

Pfizer Inc.

Groton. CT

USA

Jay Harper

Oncology Research

MedImmune

Gaithersburg, MD

USA

Bart S. Hendriks

Merrimack Pharmaceuticals, Inc.

Cambridge, MA

USA

Robert Hollingsworth

Oncology Research

MedImmune

Gaithersburg, MD

USA

Lynn J. Howie

Division of Medical Oncology

Duke Cancer Institute

Durham, NC

USA

Sara A. Hurvitz

UCLA Medical Center

Los Angeles, CA

USA

Amrita V. Kamath

Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics

Genentech Inc.

South San Francisco, CA

USA

Lindsay King

Pharmacokinetics, Dynamics and Metabolism - Biotherapeutics

Pfizer Inc.

Groton, CT

USA

John M. Lambert

ImmunoGen, Inc.

Waltham, MA

USA

Lucy Lee

Early Clinical Development & Clinical Pharmacology

Immunomedics

Morris Plains, NJ

USA

Douglas D. Leipold

Department of Preclinical Translational Pharmacokinetics and Pharmacodynamics

Genentech Inc.

South San Francisco, CA

USA

Gail D. Lewis Phillips

Molecular Oncology (GDLP); Oncology Biomarker Development (SDH); Oncology Clinical Pharmacology (SG); Product Development Oncology (EG)

Genentech, Inc.

South San Francisco, CA

USA

Patricia LoRusso

Yale Cancer Center

New Haven, CT

USA

Joseph McLaughlin

Yale Cancer Center

New Haven, CT

USA

Monica Mead

University of California

Department of Hematology/Oncology

Los Angeles, CA

USA

Satoshi Ohtake

BioTherapeutics Pharmaceutical Sciences

Pfizer Inc.

Chesterfield, MO

USA

William C. Olson

Regeneron Pharmaceuticals, Inc.

Tarrytown, NY

USA

Kenneth J. Olivier Jr.

Merrimack Pharmaceuticals, Inc.

Cambridge, MS

USA

Chin Pan

Biologics Discovery California

Bristol-Myers Squibb

Redwood City, CA

USA

Philip L. Ross

Wolfe Laboratories

Woburn, MA

USA

Brian J. Schmidt

Clinical Pharmacology & Pharmacometrics

Bristol-Myers Squibb

Princeton, NJ

USA

Natalie E. Simpson

Division of Hematology and Oncology Toxicology, OHOP, OND, CDER

U S FDA

Silver Spring, MD

USA

Sourav Sinha

Oncolinx LLC

Boston, MA

USA

and

Dartmouth College

Hanover, NH

USA

M. Stacey Ricci

Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER)

U S FDA

Silver Spring, MD

USA

Huadong Sun

Pharmaceutical Candidate Optimization

Bristol-Myers Squibb

Princeton, NJ

USA

Robert Sussman

SafeBridge Consultants, Inc.

New York, NY

USA

Mate Tolnay

Office of Biotechnology Products, Center for Drug Evaluation and Research

US Food and Drug Administration

Silver Spring, MD

USA

Kouhei Tsumoto

Medical Proteomics Laboratory, Institute of Medical Science

The University of Tokyo

Minato-ku, Tokyo

Japan

Heather E. Vezina

Clinical Pharmacology & Pharmacometrics

Bristol-Myers Squibb

Princeton, NJ

USA

Janet Wolfe

Wolfe Laboratories

Woburn, MA

USA

Jeffrey Wong

Department of Radiation Oncology

City of Hope

Duarte, CA

USA

Anthony Young

BioTherapeutics Pharmaceutical Sciences

Pfizer Inc.

Chesterfield, MO

USA

Preface

We are honored and privileged to have been part of assembling and editing Antibody–Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer. This is a critical field of drug discovery, development, and commercialization focused on improving a patient’s quality of life by specifically targeting the disease with a highly effective therapy, while simultaneously sparing normal tissue. We worked closely with distinguished, knowledgeable, and well-known industry, academic, and government researchers, drug developers, and clinicians to present a comprehensive story with concrete examples of novel therapies across various indications in oncology. We intentionally have overlap in various chapters to ensure full coverage of essential topics, which allows for a variety of opinions and strategies to be thoroughly explored.

As the reader may be aware, in order to effectively treat cancer and improve the quality of life for patients, therapeutic oncology molecules must kill all cancer cells without adversely affecting normal cells. Combinations of cytotoxic chemotherapeutic drugs have been the traditional means to this end, but often have off-target dose-limiting toxicities in normal cells and tissues that prevent sufficient exposure to kill all tumor cells. While the advent of engineered targeted monoclonal antibodies (mAbs) significantly improved the clinical outcomes for patients with several types of cancer, optimal efficacy requires they be given in combination with cytotoxic chemotherapy. Antibody–drug conjugates (ADCs) have the advantage of specifically targeting cancer cells to deliver cytotoxic drugs. This combination has created widespread enthusiasm in the oncology drug development community as well as in patient advocacy networks and can be largely explained by the properties of these molecules in their exquisite binding specificity and their substantially decreased toxicity profile. Several approaches are being evaluated including linkage of mAbs to highly cytotoxic drugs and targeted delivery of cytotoxic drug payloads in liposomes. This book will provide academic oncologists, drug researchers, and clinical developers and practitioners with a depth of knowledge regarding the following topics: (i) ADC fundamentals, (ii) molecules, structures, and compounds included in this class, (iii) chemistry manufacturing and controls associated with ADC development, (iv) nonclinical approaches in developing various ADCs, (v) clinical outcomes and successful regulatory approval strategies associated with the use of ADCs, and (vi) case studies/examples (included throughout) from oncology drug discovery. Readers will be educated about ADCs so that they can affect important improvements in this novel developing field. They will have practical, proven solutions that they can apply to improve their ADC drug discovery success.

We feel this book will be a valuable reference to significantly augment the scope of currently available published information on ADCs. Considering how expansive this field is and the potential benefit to researchers, clinicians, and ultimately our patients, we felt a more comprehensive book covering the newest cutting-edge information was essential to the field of oncology drug development.

Kennath J. Olivier Jr. andSara A. Hurvitz

Cambridge, MA and Los Angeles, CA,30 June 2016

Historical Perspective: What Makes Antibody–Drug Conjugates Revolutionary?

Lynn J. Howie and Kimberly L. Blackwell

Division of Medical Oncology, Duke Cancer Institute, Durham, NC, USA

Introduction

Developing drugs that are able to target disease and spare healthy tissue has been a long-time goal of both oncologic and non-oncologic drug development. Since the late nineteenth century, it has been recognized that effective treatment of disease by therapeutic agents is improved when therapeutics demonstrate selectiveness for foreign bodies (bacteria) or diseased cells and spare healthy cells. The development of novel and highly selective antibody–drug conjugates (ADCs) has moved us closer to this goal in cancer therapy (Figure 1). Agents such as trastuzumab emtansine (T-DM1) and brentuximab vedotin have shown promising results, particularly in patients with advanced disease who have progressed on other treatments. Combining cancer-specific antibody targets with potent cytotoxic therapies makes these agents revolutionary in their efforts to deliver potent treatments while minimizing adverse effects, coming closer to the “magic bullet” concept of Ehrlich and other early twentieth-century pharmacologists [1].

Figure 1 Timeline of events in development of ADCs.

Early Work in Monoclonal Antibody Development: Ehrlich’s Magic Bullets

Ehrlich and colleagues hypothesized that there may be antigens specific to tumors and bacteria that could be targeted with drugs for the treatment of cancer and infectious disease. Throughout the 1960s and 1970s, there was much work to develop specific antibodies that could be easily generated in large quantity and used for therapeutics. In a 1975 letter to the journal Nature, Georges Kohler and César Milstein described the development of a mechanism to generate large quantities of antibodies with a defined specificity by fusing myeloma cells that reproduce easily in cell culture with mouse spleen cells that are antibody-producing cells [2]. By combining these two types of cells, a continuous supply of specific antibody was produced in quantities sufficient for use as therapeutic agents. As with the production of other human proteins, the use of microbial agents for antibody production further advanced the field, as these methods were able to generate antibody and antibody fragments in the quantities needed for drug development [3–5].

Subsequent work demonstrated that monoclonal antibodies could be used to identify and characterize the multiple different types of surface receptors found on cells [6, 7]. These receptors could then be used as targets for cancer therapeutics with better tumor specificity and potentially less toxicity.

Use of Monoclonal Antibodies to Identify and Treat Cancer

Early on, the potential for monoclonal antibodies in the detection and treatment of cancer was recognized as promising [8, 9]. The use of antibodies to improve tumor localization was of great interest in the 1970s and 1980s and was a first step in transitioning the use of these antibodies from tumor identification to tumor treatment [10]. Radioactive iodine was conjugated to a tumor-associated monoclonal antibody to effectively deliver cytotoxic doses of radiation to tumor sites in women with metastatic ovarian cancer with lower doses of radiation to surrounding tissues and the remainder of the body [11].

During the 1980s and 1990s, the development of monoclonal antibodies for therapeutic treatment of cancers delivered promising results. In 1997, rituximab, an anti-CD20 monoclonal antibody that targets malignant B cells, was initially approved for use in relapsed follicular lymphoma [12]. Trials demonstrated that in low-grade lymphomas, this agent had a response rate of 48%. Importantly, this therapy was relatively well tolerated with only 12% grade 3 and 3% grade 4 toxicity [13]. Subsequent trials established the role of rituximab in aggressive B-cell lymphomas as it significantly improved survival when added to standard chemotherapy [14–16].

Following the initial approval of rituximab, trastuzumab was approved in 1998 for the treatment of human epidermal growth factor receptor-2 (HER2) overexpressing metastatic breast cancer (MBC). Based on significant survival benefits in phase III clinical trials, this agent was approved in combination with paclitaxel for the first-line treatment of HER2 overexpressing MBC and as a single agent for those who had progressed on one or more previous chemotherapy regimens [17]. Similar to rituximab, trastuzumab was well tolerated with few side effects. The main safety signal reported was cardiomyopathy that was primarily seen when used in combination with anthracycline-containing regimens [18, 19]. Subsequently, a number of other agents were approved for use in solid tumor malignancies including those that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Table 1 is a comprehensive listing of monoclonal antibody that have been approved along with their approval dates and indications.

Table 1 Monoclonal antibodies directed at malignant cell surface receptors.

Drug name

Target

Year approved

Initial indication

Rituximab

CD20

1997

Follicular lymphoma

Trastuzumab

HER2

1998

Metastatic HER2 overexpressing breast cancer

Alemtuzumab [20]

CD52

2001

CLL refractory to fludarabine

Cetuximab [21]

EGFR

2004

Metastatic colorectal cancer

Bevacizumab

VEGF-A

2004

Metastatic colorectal cancer

Panitumumab [22]

EGFR

2004

Metastatic colorectal cancer that is KRAS wild type and has progressed on a regimen containing a fluoropyrimidine and oxaliplatin or irinotecan

Ofatumumab [23]

CD20

2009

Refractory CLL

Obinutuzumab

CD20

2014

Combined with chlorambucil for the treatment of previously untreated patients with CLL

Ramucirumab

VEGF-2

2014

Patients with metastatic gastric or GE junction cancer that progressed on fluoropyrimidine- or platinum-containing regimen

Abbreviations: CLL, chronic lymphocytic leukemia; GE, gastroesophageal.

Although these agents have provided therapeutic benefits, there have been multiple efforts to enhance the efficacy of monoclonal antibodies. This has been done in a variety of ways including the development of monoclonal antibodies that target immune cells [24, 25], the development of bispecific monoclonal antibodies that target multiple cell surface receptors and link malignant cells with host immune cells [26], and the development of monoclonal antibodies through the conjugation of radioisotopes for the targeted delivery of cytotoxic radiation [27, 28]. Examples of these agents are found in Table 2.

Table 2 Additional monoclonal antibodies approved for use.

Type of modification

Drug name

Target

Year approved

Immune cell surface receptors targeted to enhance immune response

Ipilimumab

CTLA-4

2011

Nivolumab

PD-1

2014

Pembrolizumab

PD-1

2015

Bispecific monoclonal antibody to link immune cell and malignant cell

Blinatumomab

CD3 and CD19

2014

Conjugate with radioisotope

Ibritumomab tiuxetan

CD20; linked to yttrium-90 for treatment

2002

Iodine tositumomab

CD20

2003; as of February 2014, this drug has been discontinued by manufacturer and is no longer available

Linking Monoclonal Antibodies with Cytotoxic Agents

The linkage of monoclonal antibodies to potent cytotoxic drugs is a further step toward enhancing the efficacy of these agents in cancer treatment. Although specific cell surface receptors on malignant cells may not be directly involved in tumor proliferation, receptors that are identified as unique to tumor cells can allow for targeted delivery of cytotoxic agents. An effective ADC consists of three primary components: a monoclonal antibody that recognizes a cell surface receptor that is expressed primarily on malignant cells, a linking agent, and a potent cytotoxic agent that is known as the “payload” [29].

Much work has been devoted to improving the linking molecule between the monoclonal antibody and the cytotoxic agent as this is a crucial component of drug stability and potency. Effective linkers are able to maintain the cytotoxic agent on the monoclonal antibody such that it is trafficked to the targeted cancer cell and then transported into the cell where the link is then cleaved within the lysosome. This linkage allows potent cytotoxic whose dosing is limited by its toxicity to be delivered directly to malignant cells and improves the therapeutic index of these agents. Improvements in the identification and development of monoclonal antibodies to specific tumor cell targets, along with the type of cytotoxic agent and the linker used to conjugate the agents, have been critical in the development and improvement of ADC agents for use in oncology [30].

Antibody–Drug Conjugates in the Clinic

The first ADC approved for use in oncology was gemtuzumab ozogamicin (GO), a CD33 monoclonal antibody linked to a calicheamicin, a potent cytotoxic derived from bacteria. This agent was given accelerated approval based on phase II data and was approved from 2000 to 2010 for use in patients aged 60 and older with acute myeloid leukemia who were otherwise unable to be treated with standard induction chemotherapy. Food and Drug Administration (FDA) approval was withdrawn in 2010 as results from the SWOG S0106 study evaluating the use of GO combined with standard induction chemotherapy in patients younger than 60 years demonstrated no improvement in efficacy and no difference in overall survival (OS), with a 5-year OS rate in the arm containing GO being 46–50% in the standard therapy arm [31]. This lack of survival benefit combined with toxicities observed post-approval including hepatotoxicity with severe veno-occlusive disease, infusion reactions including anaphylaxis, and pulmonary toxicity leading to Pfizer’s voluntary withdrawal of the product in 2010. However, there are additional data demonstrating the benefit of this agent in acute promyelocytic leukemia and in those patients without adverse cytogenetic features [32]. Although this agent is no longer approved for routine clinical use, there may be a role for this drug in the treatment of specific subtypes and in specific populations of patients with acute myeloid leukemia [33].

Brentuximab vedotin, an ADC that links anti-CD30 activity with the antimitotic agent monomethyl auristatin E (MMAE), was the second agent approved in this class of drugs and was initially approved in 2011 for the use in refractory Hodgkin’s disease (HD) and in anaplastic large-cell lymphoma (ALCL) [34, 35]. While early work on monoclonal antibodies targeting CD30 had demonstrated little therapeutic efficacy, the linkage of this antibody to the potent cytotoxic agent MMAE [36, 37] resulted in potent drug delivery to the target and enhanced treatment effect. Trials of this agent in patients who had relapsed after autologous stem cell transplant (ASCT) demonstrated an overall response rate of 75% with a complete remission in 34% of patients [38]. Subsequent trials have demonstrated the efficacy of this agent as consolidation therapy after ASCTs in patients with Hodgkin’s disease who are at high risk of relapse [39]. This agent has shown significant efficacy in those patients with high-risk Hodgkin’s disease as well as those with ALCLs where initial trials of naked monoclonal antibodies to CD30 demonstrated little to no efficacy [40].

Shortly after the approval of brentuximab vedotin, trastuzumab emtansine was approved in February 2013 for the treatment of HER2-positive MBC that had progressed on trastuzumab-based therapy [41]. This agent used the already effective monoclonal antibody to HER2, trastuzumab, and linked the antibody to the potent cytotoxic DM1, a maytansinoid, which is a microtubule depolymerizing agent [42]. OS with this agent in patients who had progressed on prior therapy with trastuzumab and taxane was improved by 5.8 months when compared to capecitabine and lapatinib. This agent is a significant advance for patients who have MBC that has progressed on standard anti-HER2 regimens and is well tolerated without significant alopecia or neuropathy.

Table 3 demonstrates the clinical trials and settings where each of these agents has been or is currently being evaluated. As of 1 June 2015, over 200 clinical trials evaluating ADCs across a variety of hematological and solid tumor malignancies were listed on clinical trials.gov. For both brentuximab vedotin and trastuzumab emtansine, successful use of these therapies in patients with recurrent or refractory disease has prompted evaluation of the use of these agents earlier in disease course. Data from these pivotal trials will help us to better understand the role of these agents at various stages of the treatment trajectory.

Table 3 Clinical trials evaluating brentuximab vedotin and trastuzumab emtansine.

Trial

Study design

Results

Brentuximab vedotin

Phase II evaluation of brentuximab vedotin in patients with relapsed or refractory Hodgkin’s disease after ASCT

Single-arm study evaluating safety and efficacy

CR 34%ORR 75%Median PFS 5.6 months

Phase II evaluation of brentuximab vedotin in patients with relapsed or refractory anaplastic large-cell lymphoma

Single-arm study evaluating safety and efficacy

CR 57%ORR 86%Median PFS 13.3 months

Phase III evaluation of brentuximab vedotin with doxorubicin, dacarbazine, and vinblastine vs. doxorubicin, bleomycin, dacarbazine, and vinblastine as frontline treatment for advanced Hodgkin’s disease

RCT evaluating upfront brentuximab in place of bleomycin in the standard regimen for Hodgkin’s disease

Study ongoing