Nonclinical Development of Novel Biologics, Biosimilars and Specialty Biologics

412 Pages·2013·7.987 MB·412\412

by  Lisa M. Plitnick and Danuta J. Herzyk (Eds.)

NONCLINICAL DEVELOPMENT
OF NOVEL BIOLOGICS,
BIOSIMILARS, VACCINES AND
SPECIALTY BIOLOGICS
Edited by
L M. P , Ms, P D
isa Litnick h
and
D J. h , P D
anuta erzyk h
Merck Research Laboratories, Merck & Co., Inc. West Point, PA, USA
AMSTERDAM • BOSTON • HEIDELBERG • LONDON
NEW YORK • OXFORD • PARIS • SAN DIEGO
SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
Academic Press is an imprint of Elsevier
Academic Press is an imprint of Elsevier
32 Jamestown Road, London NW1 7BY, UK
225 Wyman Street, Waltham, MA 02451, USA
525 B Street, Suite 1800, San Diego, CA 92101-4495, USA
Copyright © 2013 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced, stored in a retrieval system or transmitted in any
form or by any means electronic, mechanical, photocopying, recording or otherwise without the
prior written permission of the publisher Permissions may be sought directly from Elsevier’s
Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0)
1865 853333; email: [email protected]. Alternatively, visit the Science and Technology Books
website at www.elsevierdirect.com/rights for further information
Notice
No responsibility is assumed by the publisher for any injury and/or damage to persons or property
as a matter of products liability, negligence or otherwise, or from any use or operation of any
methods, products, instructions or ideas contained in the material herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should
be made
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-394810-6
For information on all Academic Press publications
visit our website at elsevierdirect.com
Typeset by TNQ Books and Journals Pvt Ltd.
www.tnq.co.in
Printed and bound in United States of America
13 14 15 16 17 10 9 8 7 6 5 4 3 2 1
Dedication
The Editors would like to dedicate this Peter’s contributions to the field, especially
book to Peter J. Bugelski who passed away in the form of his numerous important
in 2011. Peter was not only a leader in the publications, will be recognized and remem-
field of immunotoxicology and biologics bered long after his passing and he will
but a friend, a mentor, and an invaluable remain in our hearts and memories for
collaborator to many authors of this book. many years to come.
Preface
Biological medicines have been proven experts who contributed to this effort is
to be very effective both as prophylactic to educate and inform those interested
treatment in the form of vaccines and as in biopharmaceutical development, from
a desirable solution for complex unmet students and academicians to those cur-
medical needs in the form of biopharma- rently working in the biopharmaceuti-
ceuticals. Development of these medicines cal industry. This book complements and
has been highly successful. Nevertheless, it builds upon the solid foundation provided
remains very expensive, time-consuming, in the first comprehensive book dedicated
and requires many special considerations to nonclinical development of biophar-
in comparison with small-molecule drugs. maceuticals edited by Joy Cavagnaro. In
Although the nonclinical development of only a few short years the science has
biological and small molecule drugs dif- advanced sufficiently to warrant a second
fer in many ways, the approaches for non- book on nonclinical development of bio-
clinical evaluation have begun to converge. logics, which includes topics such as bio-
Development programs between biolog- similars and multispecific antibodies and
ics and small molecules are sometimes fragments that were only an idea a few
quite similar as the specificity of the latter years ago, but have since become a real-
increases and therapeutic targets for all ity. As those fields have progressed, so too
types of novel drugs begin to involve simi- have the regulatory guidelines such as the
lar molecular signaling pathways. ICH S6 addendum, and specific documents
Since the discovery of early biologics for biosimilars, vaccines, gene therapy,
such as vaccines and blood products, the and stem cells which aid researchers in the
field of biologics has evolved to include design of consistent and comprehensive
more advanced, target-specific modalities. nonclinical programs. The editors sincerely
Nonclinical Development of Novel Biologics, hope readers find the subject matter inter-
Biosimilars, Vaccines and Specialty Biologics is esting and educational, and that the knowl-
a testament to this evolution. The goal of this edge and enthusiasm of the authors will be
book and of all the many world-renowned appreciated.
xi
Contributors
Vikram Arora, PhD, DABT Toxicology, Grifols Timothy K. MacLachlan, PhD, DABT Novartis
Therapeutics, Inc., Research Triangle Park, NC, Institutes of Biomedical Research, Cambridge,
USA MA, USA
Eugene P. Brandon, PhD ViaCyte, Inc., San Diego, Melinda Marian, MS Biologics Discovery
CA, USA DMPK and Bioanalytics, Merck Research Labo-
ratories, Palo Alto, CA, USA
Joy A. Cavagnaro, PhD, DABT, RAC Access BIO,
L.C., Boyce, VA, USA Barbara Mounho-Zamora, PhD ToxStrategies,
Inc., Bend, OR, USA
Anu V. Connor, PhD, DABT Department of
Safety Assessment, Genentech Inc., South San Padma Kumar Narayanan, DVM PhD Compar-
Francisco, CA, USA ative Biology and Safety Sciences, Amgen Inc.,
Seattle, WA, USA
Justine J. Cunningham, PhD, DABT Allergan,
Inc., Irvine, CA, USA Rania Nasis, MD, MBA Regenerative Medicine
Strategy Group, LLC., Los Angeles, CA, USA
Maggie Dempster, PhD, DABT Nonclinical
Safety Projects, Safety Assessment, GlaxoSmith- Deborah L. Novicki, PhD, DABT Novartis Vac-
Kline, LLC., Philadelphia, PA, USA cines and Diagnostics, Cambridge, MA, USA
Christina de Zafra, PhD, DABT Department of Lisa M. Plitnick, MS, PhD Merck Research Labo-
Safety Assessment, Genentech, Inc., South San ratories, Merck & Co., Inc., West Point, PA, USA
Francisco, CA, USA Rafael Ponce, PhD Comparative Biology and
Thomas R. Gelzleichter, PhD, DABT Depart- Safety Sciences, Amgen Inc., Seattle, WA, USA
ment of Safety Assessment, Genentech, Inc., Rodney A. Prell, PhD, DABT Department of
South San Francisco, CA, USA Safety Assessment, Genentech Inc., South San
Wendy G. Halpern, DVM, PhD, DACVP Depart- Francisco, CA, USA
ment of Safety Assessment, Genentech Inc., Karen D. Price Bristol-Myers Squibb Company
South San Francisco, CA, USA Department of Immunotoxicology, New Bruns-
Danuta J. Herzyk, PhD Merck Research Labo- wick, NJ, USA
ratories, Merck & Co., Inc., West Point, PA, Gautham K. Rao Bristol-Myers Squibb Company
USA Department of Immunotoxicology, New Bruns-
Beth Hinkle, PhD Comparative Biology and wick, NJ, USA
Safety Sciences, Amgen Inc., Thousand Oaks, Theresa Reynolds, BA, DABT Department of
CA, USA Safety Assessment, Genentech, Inc., South San
Inge A. Ivens, PhD, DABT Toxicology, US Inno- Francisco, CA, USA
vation Center Mission Bay, Bayer HealthCare, Wolfgang Seghezzi Bioanalytics, Biologics Dis-
San Francisco, CA, USA covery DMPK and Bioanalytics, Merck Research
Amy Kim, MSPH, PhD, DABT Department of Laboratories, Palo Alto, CA, USA
Safety Assessment, Genentech, Inc., South San Marque D. Todd, DVM, MS, DABT Regulatory
Francisco, CA, USA Strategy & Compliance, Drug Safety Research &
Donna W. Lee, PhD, DABT Department of Development, Pfizer, Inc., La Jolla, CA, USA
Safety Assessment, Genentech Inc., South San Jayanthi J. Wolf, PhD Merck Research Laborato-
Francisco, CA, USA ries, Merck & Co., Inc., West Point, PA, USA
xiii
Acknowledgments
The editors wish to thank all the authors In addition, we would like extend special
who donated their time to share their exper- appreciation to Rodney Prell and Jayanthi
tise and greatly contributed to this effort. Wolf for their inspiration for the cover art.
Without them, there would be no book.
xv
C H A P T E R
1
Overview of Biopharmaceuticals and
Comparison with Small-molecule
Drug Development
Theresa Reynolds, Christina de Zafra, Amy Kim,
Thomas R. Gelzleichter
Department of Safety Assessment, Genentech, Inc., South San Francisco, CA, USA
INTRODUCTION
Therapeutic proteins have been an important component of medical practice since the late
nineteenth century, when the protective properties of passive immunization were discov-
ered in blood transferred from pathogen-infected animals [1,2]. This important discovery was
quickly followed by early twentieth century success with pancreatic extracts in the treat-
ment of diabetes mellitus [3]. Recombinant DNA technology enabled the mass production
of proteins and antibodies using living cells (bacterial, yeast, plant, insect, or mammalian)
using well-defined bioprocess methods. The resulting products have a defined specificity and
uniformity, which is a vast improvement over previous methods of extraction and purification
of proteins from human or animal blood and tissues. Recombinant DNA-derived medicinal
products are often interchangeably referred to as “biopharmaceuticals,” “biotherapeutics,”
“biologicals,” or “biologics.”
This chapter introduces the various classes of therapeutics that are produced using recom-
binant DNA technology, and provides background on the history and evolution of therapeu-
tic hormones, enzymes, cytokines, and monoclonal antibodies from an early understanding
of their value in the treatment of disease to present day production of genetically engineered
human proteins and novel constructs designed to improve uniformity, safety, efficacy, or dura-
tion of effect. The introduction of these products to the medical armamentarium h eralded the
beginning of the biotechnology industry and revolutionized medicine.
In order to bring these new medicines to patients, some specific considerations and different
approaches compared to those previously established for small-molecule drugs were needed
Nonclinical Development of Novel Biologics,
Biosimilars, Vaccines and Specialty Biologics.
3
http://dx.doi.org/10.1016/B978-0-12-394810-6.00001-0 © 2013 Elsevier Inc. All rights reserved.
4 1. OVERVIEW OF BIOPHARMACEUTICALS AND COMPARISON WITH SMALL-MOLECULE DRUG DEVELOPMENT
to characterize the safety profile of biopharmaceuticals. A comparative review highlighting
similarities and differences in the development of biopharmaceuticals and small-molecule
drugs is included in this chapter.
HISTORY AND EVOLUTION OF BIOPHARMACEUTICALS
The First Protein Therapeutics
In the 1920s and 1930s, prior to the advent of prophylactic vaccines, “serum therapy,”
derived from pathogen-infected animals, was employed to treat a variety of infectious
diseases including diphtheria, scarlet fever, pneumococcal pneumonia, and meningococcal
meningitis [4,5]. Despite relative success in the management of bacterial infections, systemic
administration of a heterologous (non-human), mixture of immunoglobulins (Igs) resulted in
high risk to patients for immunological toxicities such as allergic or anaphylactoid reactions.
Improvements in sanitation and hygiene had a positive impact on both primary infection
and contagion, and the discovery and development of antibiotics in the 1930s and 1940s pro-
vided a highly effective treatment alternative, which quickly became the standard of care for
bacterial infections. As a consequence, the use of animal sera for passive immunization was
reserved for toxin-mediated afflictions due to diphtheria, tetanus, botulism, and venomous
bites [4–6].
Immunoglobulin preparations derived from human placenta and plasma have been in
clinical use since the early to mid-1940s when gamma globulin injections were used for pre-
vention or treatment of viral diseases. Intravenous immunoglobulin (IVIG) infusion contin-
ues to be a mainstay of treatment for antibody deficiency disorders and autoimmune and
inflammatory conditions such as idiopathic thrombocytopenic purpura and Kawasaki syn-
drome [7]. In addition, hyperimmune IgG preparations (HIG) purified from the plasma of
human donors that have been exposed to viruses such as respiratory syncytial virus (RSV),
cytomegalovirus (CMV), or human immunodeficiency virus (HIV) continue to provide thera-
peutic or prophylactic benefit to vulnerable populations [8–11].
Early therapeutic proteins in clinical use were likewise derived initially from animal, and
subsequently from human sources. The identification and purification of insulin from bovine
pancreas in 1922 provided glucose control for diabetes patients who had no real treatment
options [3]. Clotting factor VIII for hemophilia was initially derived from human plasma,
β-glucocerebrosidase for Gaucher’s disease was initially purified from human placenta [12],
and human growth hormone was derived from the pituitary of human cadavers [13]. Each
of these products would later be replaced by homogeneous and well-characterized protein
therapeutics produced through recombinant DNA technology.
Biopharmaceuticals Produced by Recombinant DNA Technology
In 1978, human insulin was produced through genetic engineering [14,15], and in 1982 it
became the first biotechnology product to receive US Food and Drug Administration (FDA)
approval [16]. The cloning and expression of human insulin ushered in the age of biotech-
nology and this achievement was rapidly followed by the cloning and expression of human
I. DEVELOPMENT OF BIOPHARMACEUTICALS DEFINED AS NOVEL BIOLOGICS
HISTORy AND EVOLUTION OF BIOPHARMACEUTICALS 5
growth hormone [17], leading to US FDA approval in 1985, followed by approval of inter-
feron alphas 2a and 2b in 1986 [16]. The production of large quantities of a single human
protein improved patient access to life-saving treatment and reduced the risk of pathogen
transmission, or an immune reaction to other animal or human proteins that were present
in the product. The tragic consequences of unwitting hepatitis C and HIV transmission to
hemophiliacs treated with plasma-derived clotting products in the 1980s lent urgency to the
development of a recombinant factor VIII [18,19], as well as the development of screening
tools for the blood supply [20].
Alongside gene identification, cloning, and protein expression, Köhler and Milstein’s
[21] development of the technology to produce antibodies against a defined target stands
as a watershed moment in biotechnology. The fusion of long-lived murine myeloma cells
to murine spleen cells from an immunized donor to form a hybridoma capable of secreting
antigen-specific antibodies enabled production of monoclonal antibodies as targeted thera-
peutics for a wide variety of diseases.
Technical developments in the production of antibody therapeutics are reflected in the
chronology of marketing approvals. In 1986, muromonab-CD3 (OKT3®) was approved for
use in acute transplant rejection. OKT3® is a wholly murine monoclonal antibody that was
purified from a hybridoma generated via the fusion of a murine myeloma cell and a B cell
from mice immunized with human CD3 [22,23]. To create the next generation of monoclonal
antibodies, genes encoding the variable region of antibodies produced by murine hybridoma
cell lines were ligated to the genes encoding the constant region of human IgG and trans-
fected into murine myeloma [24,25], and later into immortalized mammalian cells [26–28] to
produce chimeric antibodies with a defined specificity. Abciximab (Reopro®) is an antibody
fragment (Fab) composed of the binding region only, eliminating the Fc portion, and was the
first chimeric biotherapeutic to be approved for human use (1994), followed by the chimeric
anti-CD20 antibody rituximab (Rituxan®) in 1997 [16].
Humanized monoclonal antibodies (mAbs) are produced by transplanting only the rodent
residues required for antigen binding onto a human IgG framework. Daclilzumab (Zenapax®)
was the first humanized mAb to be approved for human use in 1997, followed by palivi-
zumab (Synagis®) and trastuzumab (Herceptin®) in 1998 [16]. Fully human antibodies can
be produced by phage display, where an antigen of interest is screened against a library of
diverse human immunoglobulin variable region segments [29,30]. This technology was used
to produce adalimumab (Humira®), the first fully human mAb granted marketing approval
by the US FDA [31].
Following on the success of recombinant protein replacement therapies, recombinant
proteins expanded into cancer with the 1986 marketing approval of recombinant inter-
feron alphas 2a and 2b (Roferon A®, Intron A®, respectively), for the treatment of hairy
cell leukemia, a subtype of chronic lymphoid leukemia that affected just 2% of all US
leukemia patients at that time [32]. Because of the higher costs of producing biopharma-
ceutical products relative to small-molecule pharmaceuticals and because proteins require
parenteral administration, biopharmaceuticals were niche products in the early years,
indicated as replacement therapy, acute treatment for life-threatening indications, or for
difficult-to-treat disease areas refractory to the standard of care such as cancer [16,30]. As
the underlying mechanisms of disease were elucidated and positive patient outcomes with
acceptable benefit/risk profiles emerged with biopharmaceuticals, their use was expanded
I. DEVELOPMENT OF BIOPHARMACEUTICALS DEFINED AS NOVEL BIOLOGICS
6 1. OVERVIEW OF BIOPHARMACEUTICALS AND COMPARISON WITH SMALL-MOLECULE DRUG DEVELOPMENT
into chronic diseases, including autoimmune disorders such as asthma, multiple sclerosis,
and rheumatoid arthritis [16,31,33].
Recombinant DNA technology made it possible to produce therapeutic human proteins
at a large scale with greater purity, homogeneity, stability, and predictable potency than
had been available from protein products extracted from animal and human blood and
tissues. The state of the art has evolved from one of reduction—purifying a single protein
from large quantities of complex, heterogeneous human or animal protein mixture—to a
model of controlled expansion: cloning a gene encoding a protein of interest into a pro-
karyotic or eukaryotic cell and selectively expressing large quantities of a single human
protein. This has the advantage of eliminating the need for sources of human plasma (with
attendant concerns over pathogenic agents), while improving protein yields and product
uniformity.
The Emergence of Novel Constructs
Technological advances in protein and antibody engineering have provided the tools to
design biopharmaceuticals with attributes to improve systemic exposure, efficacy, product
stability, and safety. For example, site-directed mutagenesis was used to engineer recombi-
nant hemoglobin with the oxygen affinity and stable tetrameric structure necessary for effi-
cient oxygen dissociation to tissues without the renal damage caused by smaller constructs
[34,35]. Human insulin has been similarly engineered to improve half-life [36,37] and to
reduce aggregation for improved onset of activity [38]. Conjugation of therapeutic proteins
to inert polymers such as polyethylene glycol (PEG) to prolong plasma half-life, reduce fre-
quency of administration, and enhance efficacy has provided PEGylated treatment options
such as interferon alpha-2a (Pegasys®), interferon alpha-2b (PegIntron A®, ViraferonPeg®),
and GM-CSF (Neulasta®). More recent forms of protein engineering include the creation
of fusion proteins such as Ontak® (denileukin diftitox; recombinant IL-2 + diphtheria
toxin), Enbrel® (etanercept; recombinant TNF receptor + IgG Fc), and Amevive® (alefacept;
LFA-3 + IgG Fc) [31].
Modification of the glycosylation sites of proteins produced in mammalian cells can confer
distinct properties. Hyperglycosylation of erythropoietin to produce Aranesp® (darbepoetin
alfa) improved pharmacokinetic properties [39], while afucosylation of mAbs has been
shown to enhance binding to FcγRIII and improve effector functions such as antibody-
dependent cellular cytotoxicity (ADCC) [40,41]. Other structural alterations to IgGs include
amino acid substitutions to the complement component C1q-binding sites to increase com-
plement-dependent cytotoxicity (CDC) activity [42], FcRn mutations to improve plasma
half-life through antibody recycling and prevention of lysosomal degradation [43], and
modification of hinge regions to positively or negatively modulate both ADCC and CDC
effector functions [44].
As of 2010, over 200 biopharmaceuticals have been approved for human use, with clinical
indications spanning cancer, autoimmune disorders, metabolic imbalances, and infectious
disease [31,45,46]. In the 30 years since recombinant human insulin was first expressed in the
laboratory, recombinant DNA technology has made important contributions to medical sci-
ence and forged new directions in regulatory decision making, with a new approach to char-
acterizing the toxicity of new molecular entities (NMEs). Advances in genetic engineering
I. DEVELOPMENT OF BIOPHARMACEUTICALS DEFINED AS NOVEL BIOLOGICS