Table Of ContentCancer Drug Discovery and Development
Marc Damelin Editor
Innovations for
Next-Generation
Antibody-Drug
Conjugates
Cancer Drug Discovery and Development
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Marc Damelin
Editor
Innovations
for Next-Generation
Antibody-Drug Conjugates
Editor
Marc Damelin
Mersana Therapeutics, Inc.
Cambridge, MA, USA
ISSN 2196-9906 ISSN 2196-9914 (electronic)
Cancer Drug Discovery and Development
ISBN 978-3-319-78153-2 ISBN 978-3-319-78154-9 (eBook)
https://doi.org/10.1007/978-3-319-78154-9
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Preface
Chemotherapy is good but not good enough: it is standard-of-care treatment for
many tumor types, yet its efficacy is matched by and limited by toxicity. The con-
cept of the antibody-drug conjugate (ADC) – to deliver chemotherapy preferentially
to tumor tissue by conjugation to an antitumor antibody – has enticed scientists,
clinicians, and drug developers to invest in ADCs for several decades. To date, the
overall clinical success of ADCs has been modest, for which various explanations
are offered throughout this volume. Nevertheless, there are many reasons to believe
that the next generation of ADCs will command impressive success.
This volume is about the promise and excitement of the innovations that are
enabling next-generation ADCs. The inherent complexities of ADCs were long
appreciated as a general principle, and now with the data from preclinical studies
and hundreds of clinical trials with ADCs, we can truly appreciate the challenges
that are intertwined with the complexities. That understanding has brought us to an
inflection point in the evolution of ADCs: new technologies have been developed to
address specific observations and are beginning to emerge in the clinical space. This
volume includes a critical assessment of the ADC field as a framework for contex-
tualizing the innovations. As I wrote the Introduction (Chap. 1) in this mindset, the
sequence of chapters came about rather organically, and the reader is encouraged to
read them in order! It also became clear to me that this volume is much greater than
the sum of its parts: each chapter is an independent, focused analysis, yet taken
together, the chapters will allow the reader to integrate the complexities with the
innovations, and ultimately to develop a holistic perspective on ADCs and devise
thoughtful actions for future research.
A word about the volume’s title: it includes two terms that suffer from overuse:
“innovation” and “next-generation.” In spite of their overuse, I chose these terms
because they are incredibly powerful when used in a meaningful way. What is inno-
vation? It is not just a new idea elevated by a trendy term – it is an idea that leads to
a substantial change or improvement. For an inspirational read on this topic, I
highly recommend “The Innovators” by Walter Isaacson (published by Simon and
Schuster). What is “next generation”? It is not just what happens to come next and
is elevated by a trendy term – it is a significant advance that reflects a new capability
v
vi Preface
or approach. This volume describes a series of true innovations both in technology
and thinking that, when considered critically, will enable true next-generation
ADCs that promise to greatly improve the lives of patients with cancer (and other
diseases – see Chap. 14).
I want to take this opportunity to thank many people who joined me in the jour-
ney of this project. The authors have shared my enthusiasm about the project since
its inception; I thank them for their significant efforts that resulted in meaningful,
consequential contributions. The anonymous peer reviewers are acknowledged for
their extremely beneficial insights and suggestions. I thank the team at Springer,
especially William Helms for guidance in the formative stages of the project, Maria
David for effectively managing the project, and S. Suresh and the team who pro-
duced the book from the set of files that the contributors provided. I am very grateful
to my many colleagues and collaborators over the past decade for all of the exciting
work that we have done and are doing together on ADCs – with much more to come,
of course. Finally, many thanks to my wife Sarah and our children Naomi, Leah, and
Max for being supportive and accommodating while I worked on this project.
Cambridge, MA, USA Marc Damelin
Contents
Introduction: Motivations for Next- Generation ADCs . . . . . . . . . . . . . . . . 1
Marc Damelin
Combining ADCs with Immuno-Oncology Agents . . . . . . . . . . . . . . . . . . . 11
Philipp Müller, Jonathan Rios-Doria, Jay Harper, and Anthony Cao
Improving the Safety Profile of ADCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Magali Guffroy, Hadi Falahatpisheh, and Martin Finkelstein
Utility of PK-PD Modeling and Simulation to Improve
Decision Making for Antibody- Drug Conjugate Development . . . . . . . . . 73
Aman P. Singh and Dhaval K. Shah
Regulatory Considerations and Companion Diagnostics . . . . . . . . . . . . . . 99
Elizabeth VanAlphen and Omar Perez
Outlook on Next Generation Technologies and Strategy
Considerations for ADC Process Development and Manufacturing . . . . . 113
Olivier Marcq
HER2-Targeted ADCs: At the Forefront of ADC
Technology Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Kevin J. Hamblett
Next Generation Payloads for ADCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
L. Nathan Tumey
Delivering More Payload (High DAR ADCs) . . . . . . . . . . . . . . . . . . . . . . . . 215
Natalya Bodyak and Alexander V. Yurkovetskiy
Site-Specific Antibody-Drug Conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Feng Tian, Dowdy Jackson, and Yun Bai
Bispecific and Biparatopic Antibody Drug Conjugates. . . . . . . . . . . . . . . . 267
Frank Comer, Changshou Gao, and Steve Coats
vii
viii Contents
Targeting Drug Conjugates to the Tumor Microenvironment:
Probody Drug Conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Jack Lin and Jason Sagert
Antibody-Drug Conjugates: Targeting the Tumor Microenvironment . . . 299
Alberto Dal Corso, Samuele Cazzamalli, and Dario Neri
Next Horizons: ADCs Beyond Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Shan Yu, Andrew Lim, and Matthew S. Tremblay
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Introduction: Motivations
for Next-Generation ADCs
Marc Damelin
Abstract The new and emerging ADC technologies together with the field’s cumu-
lative experience provide new opportunities for ADCs and make them a more prom-
ising therapeutic modality than ever before. Despite a rapidly evolving clinical
landscape in oncology, there is substantial unmet clinical need that could be
addressed by next-generation ADCs. ADCs are also being explored to combat other
diseases. This introductory chapter provides context for the key innovations of next-
generation ADCs described throughout the volume. A framework for designing and
interpreting preclinical pharmacology studies is proposed such that emerging tech-
nologies can be rigorously evaluated and molecules can be judiciously optimized.
Keywords Preclinical studies · In vivo · Pharmacology · Oncology · Challenge ·
Innovation · Tool · Technology · Patient-derived xenograft · PDX
The antibody-drug conjugate (ADC) is a therapeutic modality in which a small
molecule is directly linked to an antibody or related biologic – thus marrying the
potency of the small molecule (often called the “payload”) with the tumor specific-
ity of the antibody. The history of this modality and the current technologies,
approaches and clinical molecules have been described [4–6, 9]. Tolcher’s candid
history of ADCs cautions against self-deception yet conveys optimism about next-
generation ADCs [10]. This volume focuses on emerging ADC technologies, and in
this chapter, I would like to provide context for how the reader might evaluate,
integrate and ultimately act on the information. How will next-generation ADCs fit
into the clinical landscape? What are the most pressing challenges? How can the
emerging technologies be rigorously evaluated in the preclinical setting to maxi-
mize the chances of clinical success?
In the design of an ADC, not only are there seemingly endless possibilities for
the small molecule and the antibody, but there are seemingly endless ways in which
M. Damelin (*)
Mersana Therapeutics, Inc., Cambridge, MA, USA
© Springer International Publishing AG, part of Springer Nature 2018 1
M. Damelin (ed.), Innovations for Next-Generation Antibody-Drug Conjugates,
Cancer Drug Discovery and Development,
https://doi.org/10.1007/978-3-319-78154-9_1
Description:Antibody-drug conjugates (ADCs) stand at the verge of a transformation. Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges. This volume focuses on the next generation of ADCs and the i
