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The Lock and Key of MedicineMonoclonal Antibodies and the Transformation of Healthcare$

Lara V Marks

Print publication date: 2015

Print ISBN-13: 9780300167733

Published to Yale Scholarship Online: January 2016

DOI: 10.12987/yale/9780300167733.001.0001

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(p.xi) Preface

(p.xi) Preface

The Lock and Key of Medicine

Lara V. Marks

Yale University Press

We purchase them through catalogs and online suppliers; we mail them in polypropylene tubes; we pass them surreptitiously from hand to pocket at scientific meetings; we borrow (with or without permission) a drop from a labmate for a crucial assay; we add microliter amounts to cultures of cells to activate, isolate, kill, block, blot, immunoprecipitate, and stain; we inject them into experimental animals to inhibit or elicit responses or to track specific cell populations; and we introduce them into our patients in an effort to view or destroy their tumors. As scientists, we imagine the one that will define a new molecule, a new cell type, a new signaling pathway. As clinicians, we visualize a better therapy, a complete cure. We hope for the one that will answer the central question, make us famous, or make us rich. Each one is different, yet all are the same. No single class of reagents stirs our creativity, or propels our successes, even in our dreams, with as much excitement as do monoclonal antibodies, or Mabs.

D. Margulies, “Monoclonal Antibodies,” 2005

EVERYWHERE AROUND US today imperceptibly small “magic bullets” called Mabs are quietly affecting our lives. Six out of ten of the bestselling drugs in the world are Mabs. In 2013 the global sales of the ten blockbuster Mabs were estimated to be worth over $58.1 billion. The Mabs market was estimated to be approximately $78 billion for the year 2012, and it is predicted to grow around 15 percent between 2012 and 2018.

Mabs are not only successful drugs but also powerful tools for a wide range of medical applications. In industry, they are critical to the purification of drugs. Elsewhere they are essential research probes for determining the pathological pathway and cause of diseases such as cancer and autoimmune and neurological disorders. They are used on a routine basis in hospitals to type blood and tissue, a process vital to ensuring safe blood transfusion and organ transplantation. On the diagnostic front, (p.xii) Mabs are intrinsic components in home-testing kits for detecting ovulation, pregnancy, or menopause. They are used for the analysis of body fluids for medical diagnosis, and to determine whether a heart attack has occurred. They are at the forefront of public health efforts, helping, for example, to identify hospital infections such as methicillin-resistant Staphylococcus aureus (MRSA). At a global level, governments also depend on Mab-based tests to contain the spread of infectious diseases such as AIDS and pandemic flu, or to detect the potential release of anthrax or smallpox by bioterrorists.

Mabs are indispensable not only to health, but also to many other aspects of modern life: they help identify viruses in animal livestock or plants, prevent food poisoning, and are used to investigate environmental pollution. Yet, despite their ubiquity and significance, most people have never heard of Mabs or how they have both transformed healthcare and spawned an entire new industry.

Produced in the laboratory, Mabs are derived from the billions of tiny antibodies made every day by our immune systems to combat substances, known as antigens, that are regarded as foreign or potentially dangerous. Millions of different types of antibodies can be found in the blood of humans and other mammals. Made by white blood cells known as B lymphocytes, each antibody is highly specific, that is, it has the ability to bind to only one particular antigen, which may be derived from bacteria, viruses, fungi, parasites, pollen, or nonliving substances such as toxins, chemicals, drugs, or foreign particles considered alien to the body. Once antibodies have marked their particular antigen, they and other types of cells produced by the immune system can attack it.

The story of Mabs started when an Argentinian émigré, César Milstein, arrived at the Laboratory of Molecular Biology (LMB) in Cambridge, England. It was here—where Francis Crick and James Watson had unraveled the structure of DNA in 1953—that Milstein, together with Georges Köhler, a German biologist, would pioneer in 1975 the seminal technique for the production of Mabs and demonstrate their clinical application. The procedure for producing Mabs involves injecting a mouse with a specific antigen to stimulate its production of antibodies. These antibodies are then harvested from the mouse’s spleen and fused with an immortal myeloma cancer cell to make what is called a hybrid cell, or hybridoma, which secretes Mabs. Each Mab is identical and can be reproduced (p.xiii) endlessly either by injecting the hybridoma into the abdominal cavity of mice, or, as is increasingly the case today, by its artificial growth in a culture medium.

Armed with the technique to produce unlimited quantities of Mabs and at minimum cost, scientists have developed a vast array of uses for the technology since 1975. In the diagnostics field, Mabs have opened the means to detect numerous diseases previously impossible to identify until they had reached an advanced stage. Similarly, diagnostic tests, which took days if not weeks before the arrival of Mabs, now take just minutes to complete and have also greatly enhanced the accuracy of diagnostics and reduced their cost.

On the therapeutic front, Mabs have radically altered the treatment of more than fifty major diseases, many considered untreatable before. Mab therapies are used for a broad range of conditions today, including organ transplants, cancer, inflammatory and autoimmune diseases, cardiovascular and infectious diseases, allergies, and ophthalmic disorders. In addition to offering a host of new drugs to fight disease, Mabs have provided the means to monitor a patient’s response to therapy and helped lead the way in personalized medicine.

Despite the prevalence of Mabs, few know of their existence outside the scientific and medical community. Their emergence is often overshadowed by the 1973 discovery in the United States of recombinant DNA, or gene cloning, which inspired the creation of Genentech, the world’s first company dedicated to biotechnology. Although recombinant DNA set the stage for a major breakthrough in manufacturing and production techniques that enabled the development of cheaper and more effective treatments for disease, I argue in this book that Mabs have had just as much, if not more, of a far-reaching effect on our society and daily life. The history of Mabs provides fresh insight into the beginnings of the biotechnology revolution usually missed by previous studies of the biotechnology industry. Looking back, perhaps this historical oversight is not surprising. Mabs did not transform healthcare overnight or with major fanfare. Instead they quietly brought about new understandings of the pathways of disease and slipped unobserved into routine clinical diagnostics on a large scale. Unnoticed at the time, Mabs brought with them new treatment possibilities often taken for granted and considered mundane today.

(p.xiv) This book is very much a tale of the complexities and difficulties inherent in science and its practical application. Milstein and Köhler’s breakthrough in 1975 was rooted in scientists’ quest from the late nineteenth century to unravel the mechanism behind the diversity of antibodies made by the body’s immune system and to find new treatments to fight infectious diseases. Their work was not a linear process, and it was subject to both controversy and intense national rivalry. What helped galvanize the field was a theory put forward in the 1890s by Paul Ehrlich, a German physician. Ehrlich conceptualized all cells as having a wide variety of special receptors that acted as gatekeepers or locks, permitting entry only to substances like antibodies whose structure matched such receptors. He was convinced that antibodies bind to specific receptors found on antigens in the same way as a key fits a lock and that one day scientists would be able to create antibodies that could act as magic bullets, seeking out and destroying specific disease-causing microorganisms without harming the rest of the body.

Ehrlich’s theory came under attack in the ensuing decades. Many scientists found it puzzling how the immune system could produce antibodies with such high levels of specific affinity to match the wide diversity of antigens. The debate about antibody formation twisted and turned for many years as scientists worked to see how antibodies might be applied clinically. Diphtheria was one of the first diseases to be successfully treated with antibodies. The treatment, developed in the 1890s, entailed injecting patients with blood serum taken from animals immunized against diphtheria. This serum, known as antisera, contained highly potent antibodies which targeted diphtheria and helped boost the immune system to fight the disease. By the 1930s serum therapy had become a common treatment for many infectious diseases, and antisera had become an important agent in immunobased tests. Such diagnostics exploited the lock and key mechanism, in which antibodies attached to specific cell receptors, facilitated the analysis and identification of different cell types. (The antibodies acted as markers for locating and measuring cells in biological samples.) The first immunobased test developed was for typhoid in 1896.

Despite their utility for therapeutics and diagnostics, antisera had major limitations. The supply of antisera depended on an individual animal’s lifetime and varied between batches, which made it difficult to (p.xv) standardize. Consequently, some scientists looked for ways to create artificial antibodies to specific antigens. Although they had come close to achieving this by 1970, artificial antisera were difficult to reproduce so were limited in quantity and had a short half-life. Milstein and Köhler’s innovation in 1975 heralded a new era by introducing the means to produce unlimited quantities of standardized antibodies specific to any antigen.

Milstein and Köhler’s procedure, however, was not adopted overnight. Many scientists failed to grasp its significance at first, and the technique was not patented by the British National Research Development Corporation, which could not foresee its having any commercial application. Transforming Mabs, which had started life as a laboratory tool, into something that could be of use to the outside world was neither straightforward or inevitable. Yet within a few years many scientists had become interested in the technology. This interest was in part fueled by Milstein, who collaborated with researchers in disciplines different from his own to demonstrate the utility of Mabs. One of his first collaborators was Claudio Cuello, a fellow Argentinian émigré. Together Milstein and Cuello proved the validity of Mabs for immunobased tests that by the 1970s were being routinely used for diagnosis in parasitology, virology, immunology, cancer, and other fields. Their work marked a major breakthrough for scientists who previously had struggled to reproduce (and compare) the results of their diagnostic tests that relied on antisera. Moreover, Milstein and Cuello extended the reach of immunobased diagnostics by demonstrating how Mabs, used as probes, could enhance the pathological investigation of the brain and the central nervous system.

In addition to Cuello, Milstein launched projects with many other scientists. Foremost among these was a partnership with Alan Williams and Andrew McMichael, two immunologists based at Oxford University. Together the collaborators discovered the potency of Mabs for identifying and distinguishing different markers found on the surface of cells. By laying the basis for a whole new field of investigation into immune cells and the immune response’s regulatory network, their work opened up new targets for diagnostic and therapeutic intervention.

As the interest in Mabs began to gain momentum outside the confines of Cambridge, Milstein found it increasingly difficult to satisfy the (p.xvi) avalanche of demands for his cells. Fortunately in February 1977 he received an unexpected visit from David Murray, founder of Sera-Lab, a British company producing and marketing antisera as reagents for the scientific community. Learning of Milstein’s difficulties, Murray quickly agreed to distribute Milstein’s cells through Sera-Lab, an arrangement that marked the first commercialization of Mabs. How Sera-Lab came to be a pioneer in the market is an unusual tale. Unlike American startups, which dominate the traditional histories told of the commercialization of biotechnology, Sera-Lab was founded with no venture capital funding or outside support.

That a British company spearheaded the first marketing of Mabs, a technology devised in a British laboratory by an émigré Argentinian scientist with his German colleague, highlights the international nature of biotechnology commercialization. Sera-Lab’s venture to sell Mabs took place in the midst of the excitement generated by the founding of Genentech in 1976. The emergence of Genentech, which had been set up to market recombinant DNA products, galvanized numerous alliances among academics, entrepreneurs, and venture capitalists to launch new companies to commercialize biotechnology. Most of the early enterprises set up in the wake of Genentech’s birth were dedicated to exploiting recombinant DNA for the mass production of natural products such as interferon and insulin for drugs. But the early germination of the modern biotechnology industry did not rest solely on recombinant DNA. By the 1970s a number of pioneering companies were developing Mab products, including Sera-Lab and two startups: Hybritech in San Diego and Centocor in Philadelphia. Entrepreneurs who risked entry into the field had no guarantee of success and were entering totally uncharted territory. Such individuals faced major financial, personal, professional, and regulatory challenges as well as a great deal of hostility, pessimism, and litigation.

Among the stories told in this book is that of David Murray, who set up Sera-Lab to earn his living after being forced to abandon his position as general manager of his father’s cabaret club, a place notorious as a result of the part played by one of its dancers, Christine Keeler, in the British political scandal known as the Profumo affair. Murray’s endeavors are told alongside those of Hubert Schoemaker, a young Dutch immigrant who, after completing a biochemistry doctorate at Massachusetts (p.xvii) Institute of Technology, became involved in commercializing Mabs out of his desire to relieve the suffering of the sick, a passion awakened by the birth of his profoundly disabled daughter. At much the same time Ivor Royston, a British immigrant who had settled in America as a child, began hunting for a more effective treatment for his cancer patients when he attained a clinical position in oncology at Stanford University. Risktaking was part of the bloodline for these men. During World War II, Murray had been a saboteur in occupied Europe, Schoemaker’s father had participated in the Dutch underground resistance, and Royston’s father had fought with the Polish army and then alongside Field Marshall Montgomery in Italy.

When starting on their adventure, little did these intrepid individuals realize how much Mabs would change the world. For example, Mabs played a critical role in the purification of recombinant interferon, which is often hailed as one of early successes of modern biotechnology. After this success with interferon, Mabs were used to purify many other commercial drug products. Mabs were also soon adopted as a means to improve blood typing and grouping. Mabs critically helped shift the process of blood typing away from its dependency on human blood, providing a reagent that was easier to standardize, cheaper to produce, and suitable for use in automated blood-grouping machines.

The use of Mabs for blood typing and the purification of drugs was just the start of medical applications explored for the technology. By the late 1970s, many clinicians had great expectations that Mabs could transform cancer therapy. Yet Mabs proved more difficult to deploy in cancer diagnostics and therapeutics than originally anticipated. The first marketed Mab drug was not for cancer, but for the prevention of acute kidney rejection in transplant patients in 1986. No more Mab drugs were approved over the next seven years. Indeed, by the early 1990s many had become despondent about its therapeutic potential. The downfall of Centoxin in 1992 is illustrative of some of the difficulties that entrepreneurs faced in bringing Mab therapeutics to market. Not only did they encounter the difficulties inherent in the science of drug development, but they also had to satisfy financial stakeholders. Centocor’s failure to win U.S. regulatory approval for Centoxin not only brought its developer to the brink of bankruptcy, but also cast a long shadow over the viability of Mab therapeutics as a whole.

(p.xviii) Although much of the optimism surrounding Mab therapeutics of the early 1980s had dissipated by the end of the decade, new protein engineering techniques developed in these years helped improve the efficacy and safety of Mabs and stimulated a renaissance of Mab therapeutics in the 1990s. In 1993, Abciximab (ReoPro), developed by Centocor for reducing blood clots in heart attack patients, was approved and became the first reengineered Mab to reach market, marking a significant breakthrough. Other reengineered Mabs soon followed suit, and gained momentum from 1996. Many of these drugs started as treatments for rare diseases where profit margins were minimal, but were then soon approved for more common conditions, bringing the possibility of $1 million in revenue. The rise of blockbuster drugs shows how far reengineering had improved the safety and efficacy of Mabs and how much the knowledge of the immune system and the utility of Mabs had advanced since the early days.

Mabs have had their strongest therapeutic impact in the field of cancer. The first Mab to reach the market for cancer was edrecolomab (Panorex), which was granted German regulatory approval in 1995 for the treatment of postoperative colorectal cancer. Developed by Centocor in partnership with the Wistar Institute, it was withdrawn in 2001 because of its poor efficacy in comparison with other drugs. Since 1997, however, the U.S. Food and Drug Administration (FDA) has approved twelve Mab drugs for cancer treatment, including rituximab (Rituxan), approved in 1998 for the treatment of non-Hodgkin’s lymphoma. By 2012 there were over 160 candidates in clinical trials for cancer, with seventy of them in phase III trials, the stage before a drug is submitted for regulatory approval.

One of the advantages of Mab drugs is that they can specifically target cancer cells while avoiding healthy cells. This means they cause fewer debilitating side effects than more conventional chemotherapy or radiotherapy. In addition, Mabs have enabled the identification and characterization of cancerous tumors previously difficult to detect and differentiate from other tumors, thereby providing a better understanding of cancer. They have also opened a path to more personalized medical treatment. Trastuzumab (Herceptin), for example, was specifically developed to target HERM2/neu, a protein overexpressed by tumors found in 25 percent of newly diagnosed breast-cancer patients. Tumors expressing (p.xix) HER2/neu are known to grow more aggressively and therefore to have more fatal outcomes. Trastuzumab was explicitly approved in 2000 together with a companion diagnostic to detect HERM2/neu.

Aside from cancer, Mabs have aided the treatment of other previously untreatable diseases, most notably autoimmune and inflammatory diseases. The first Mab marketed for the treatment of such disorders was infiliximab (Remicade). Initially approved for Crohn’s disease (gut wall disorder) in 1998, the drug rapidly became a blockbuster drug, being used for chronic inflammatory conditions such as psoriasis (a noncontagious skin disease), rheumatoid arthritis (a joint disease), ulcerative colitis (a large intestine disorder), and ankylosing spondylitis (a spine disease). Overall, Mabs have shifted the treatment paradigm for autoimmune disorders away from merely ameliorating their painful symptoms to targeting and disrupting their cause.

Mabs are now marketed not only for cancer and autoimmune disorders, but also for a range of other diseases, including allergic conditions such as asthma, age-related macular degeneration (an eye disorder), multiple sclerosis (a neurological disorder), and osteoporosis (brittle bones). They are also being investigated for central nervous system disorders such as Alzheimer’s disease (a degenerative brain disease), metabolic diseases such as diabetes, and the prevention of migraines. Today, the growth and profitability of Mabs are outstripping those of earlier types of biotechnology drugs and more traditional pharmaceutical ones. Indeed their expansion is among the fastest in the global pharmaceutical world. In part this reflects the sectors’ embrace of Mabs as an answer to dwindling drugs in the pipeline and reduced revenue streams in the face of the expiration of key patents and the growth of generic medicines.

Although Mab drugs have brought untold relief to patients with previously untreatable illnesses, they are not a total elixir. Such therapies do not offer a total cure and can cause complications. Moreover, they come with a very high price tag, which since the 1990s has raised important questions about the cost-effectiveness of Mab therapeutics and has put them at the heart of debates over the rising cost of healthcare provision and whether and how innovative drugs should be made universally available.

Mabs have come a long way since their development as a tool to answer a basic scientific research question. Indeed, as the possible uses of (p.xx) Mabs continue to unfold and their dominance in healthcare continues to strengthen, it is easy to forget scientists’ initial struggle to produce sustainable and reproducible antibodies in the laboratory—and how the ability to produce antibodies was just the first chapter in how this technology continues to transform health care. Today we are on the brink of exciting new engineering discoveries which will enhance the potency and safety of Mab therapeutics and may make it possible to lower the dose given to patients and reduce costs. In no area are these developments more important than in the fight against infectious diseases, which to date has gained little traction in the Mab therapeutic sector. Because Mabs boost a host’s immune response rather than kill microbes directly, they could provide a pivotal tool in the fight against the rising tide of drug resistance ushered in with the antibiotic era.