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Antibody Engineering: A Renaissance for Mab Therapeutics

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses the emergence of engineered monoclonal antibodies (Mabs) in the 1990s. The failure of Centoxin to gain FDA approval prompted many in the biotechnology and pharmaceutical ... More

This chapter discusses the emergence of engineered monoclonal antibodies (Mabs) in the 1990s. The failure of Centoxin to gain FDA approval prompted many in the biotechnology and pharmaceutical industry as well as the financial world to view Mab drugs as a lost cause. However, things began to change in 1994 with the approval of ReoPro. The drug signified a major engineering revolution in Mabs after the 1980s, when various competitive and complementary engineering methods began to be developed in the academic and corporate worlds. The first Mabs—known as murine Mabs—were produced by fusing myeloma tumor cells taken from mice with spleen cells derived from other mice or rats previously immunized with an antigen. While these could be made to target almost any antigen and in vast quantities, they were considered foreign by the human body, causing patients treated with murine Mabs to experience immune reactions. This also led to the rapid destruction and clearance of the Mab from the body before it could have its full therapeutic effect. Faced with these obstacles, scientists turned to genetic engineering to transform animal antibodies into human ones.Less

Hunting for the Elusive “Magic Bullet”

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter traces the history of the discovery of antibodies, from the late nineteenth-century theories of immunity to the development of monoclonal antibodies (Mabs) in 1975—a breakthrough that ... More

This chapter traces the history of the discovery of antibodies, from the late nineteenth-century theories of immunity to the development of monoclonal antibodies (Mabs) in 1975—a breakthrough that was made possible by the coming together of knowledge and techniques developed in many different geographic locations, laboratories, and disciplines, as well as at the bedside. The process was far from linear not only because of these logistical obstacles, but also because the evolving science was subject to the personal and theoretical rivalries among scientists. In many ways, the history of Mabs is as much about how substances, originally invisible to the naked eye, were imagined and then transformed into material entities.Less

Breakthroughs at the Bench

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses how monoclonal antibodies (Mabs) opened new frontiers in research well beyond immunology and transformed the way scientists analyzed biological phenomena in the early 1980s. ... More

This chapter discusses how monoclonal antibodies (Mabs) opened new frontiers in research well beyond immunology and transformed the way scientists analyzed biological phenomena in the early 1980s. Some of the earliest discoveries made possible by Mabs were related to the brain and the central nervous system. Yet these advances were just the tip of the iceberg as scientists began to realize the power of Mabs for exploring the vast number of human differentiation antigens, proteins located on the cell surface of immune cells. Before the arrival of Mabs, scientists had little knowledge of the surface of immune cells. Their subsequent investigations into human differentiation antigens would not only advance understandings about the network of interactions that govern the immune response, but also help identify new targets for diagnostic and therapeutic interventions that would have profound implications for human health.Less

Joy, Disappointment, Determination: Early Clinical Tests

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter considers the development of monoclonal antibodies (Mabs) for cancer treatment. In the early 1980s, many scientists were optimistic that Mabs would defeat cancer. In 1982, John Minna of ... More

This chapter considers the development of monoclonal antibodies (Mabs) for cancer treatment. In the early 1980s, many scientists were optimistic that Mabs would defeat cancer. In 1982, John Minna of the U.S. National Cancer Institute (NCI) predicted that Mabs would revolutionize cancer diagnosis within five years. The adoption of Mabs as probes for targeting and identifying the multitude of antigens on different cell types seemed to herald their use in detecting and classifying tumors on a hitherto unthinkable scale. Mabs also promised to deliver more precisely powerful tumor-cell-killing agents, such as chemotherapeutic drugs, radioactive isotopes, or toxins, and to provide a way of harnessing a patient's immune system to attack tumors. However, work in the cancer field proved less straightforward than anticipated, partly because much of the initial endeavor was undertaken by researchers in academic laboratories and clinics with limited resources. Funded by government and charitable sources, their work had only minimal support from industry. In addition, new cancer drugs faced stiff regulatory and ethical tests.Less

The DNA of Biotechnology

Michael Kinch

in Prescription for Change: The Looming Crisis in Drug Development

This chapter relates the birth of the biotechnology industry, whose origins can be traced back to the Spanish flu and which would later revolutionize both fundamental understanding of life as well as ... More

This chapter relates the birth of the biotechnology industry, whose origins can be traced back to the Spanish flu and which would later revolutionize both fundamental understanding of life as well as create new and improved products. We then relate how the birth of biotechnology transitioned from St Louis, Missouri to San Francisco largely based on the inspiration of one man and how this controversial revolution was almost upended by popular culture. Our story then turns to the creation of one of the earliest biotechnology companies, Genentech, and why the creation of this company was mired by criticism that cost two key inventors of DNA research the Nobel prize. Genentech and other companies would soon come to embrace a technology, known as monoclonal antibodies, which allowed for selective targeting analogous to the use of modern smart bombs and create its own conflicts with the rise of aggressive patenting. The opportunities arising from the technologies inspired many government and academic investigators to become entrepreneurs, foster companies such as MedImmune to develop revolutionary new therapies to prevent a major killer of premature infants, Respiratory Syncytial Virus (RSV).Less

The First Medical Applications

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter describes the early clinical applications of monoclonal antibodies (Mabs). The technology offered so many different possibilities that it was difficult to know where to start. Many of ... More

This chapter describes the early clinical applications of monoclonal antibodies (Mabs). The technology offered so many different possibilities that it was difficult to know where to start. Many of Mabs' early applications appeared to have little overall pattern or logic, but their most effective uses were quickly established. In this process new relationships were forged between research scientists and industry, and Mabs' influence came to extend well beyond the confines of the small-scale laboratory. Researchers sought a wide range of applications for Mabs, including in the areas of immunology, parasitology, virology, bacteriology, oncology, endocrinology, hematology, pharmacology, and embryology. Mabs generated some of the greatest excitement in their potential to help purify natural substances and for blood and tissue typing.Less

A Quiet Revolution: The Legacy of Monoclonal Antibodies

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses legacy of monoclonal antibodies (Mabs). Mab therapeutics are some of the best-selling drugs in the world today. As of 2012 there were over thirty Mab drugs on the world market. ... More

This chapter discusses legacy of monoclonal antibodies (Mabs). Mab therapeutics are some of the best-selling drugs in the world today. As of 2012 there were over thirty Mab drugs on the world market. Of these, ten had achieved blockbuster status, generating profits of more than $1 billion. These included three marketed for cancer by the Roche Group: bevacizumab (Avastin), rituximab (Rituxan), and trastuzumab (Herceptin), which collectively raised $17 billion in annual revenue in 2009. Mabs have helped advance cancer research and treatment; transformed the management of autoimmune disorders; provided a major tool for understanding the onset and progression of autoimmune diseases and revealed new therapeutic possibilities; and facilitated a paradigm shift in the treatment of autoimmune diseases away from just treating symptoms to targeting and preventing their cause. Mabs were also instrumental historically in the identification and utilization of hematopoietic stem cells (HSCs), immature cells found in bone marrow, to improve the treatment of leukemia.Less

The Wild West of Antibody Commercialization

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses the pioneers who commercialized monoclonal antibodies (Mabs) from the late 1970s. Those who did so were entering totally uncharted territory. Not only was the technique still ... More

This chapter discusses the pioneers who commercialized monoclonal antibodies (Mabs) from the late 1970s. Those who did so were entering totally uncharted territory. Not only was the technique still in its infancy, but how it could be used also remained unknown. The enterprise was full of risk, because the scientists needed both to raise capital and to meet the regulatory criteria. Among these profit-seekers were both experienced entrepreneurs and novices who were united by a sense of adventure and excitement about what the technology promised and its potential to make money. David Murray, who founded Sera-Lab in 1971, was the first to engage in the marketing of Mabs; he began to distribute Milstein's cells commercially starting in February 1977. Other notable players in the industry include Hybritech, a company designed to sell Mabs for research; and Centocor, whose funders sought to use Mabs as a means to break into the immunodiagnostics market and eventually into therapeutics. By the late 1980s, as Hybritech and Sera-Lab began to fade from view, Centocor was one of the very few monoclonal antibody companies making a profit.Less

Blockbuster Mab Drugs

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter explores the development of rituximab and infliximab, two of the best-selling monoclonal antibody (Mab) therapeutics today. The evolution of these drugs not only illustrates how a single ... More

This chapter explores the development of rituximab and infliximab, two of the best-selling monoclonal antibody (Mab) therapeutics today. The evolution of these drugs not only illustrates how a single Mab therapeutic came to be used for multiple indications, but shows the significant role that Mabs have played in fostering new understandings of the causes of cancer and autoimmune disorders, thereby opening avenues to more effective care. Their stories also show how the development of Mab drugs shifted from prioritizing rare diseases to treating more lucrative common illnesses. Although each drug took a different path to the clinic, they encountered similar hurdles along the way. These included not only the challenge of scaling up production for newly engineered antibodies, and getting Mabs through clinical trials and regulatory approval, but also securing enough funding. All of this required a complex alliance among academic researchers, industry leaders, and financiers as well as the consent of patients.Less

Levers in a Specific Industry—Biotechnology

in The Patent Crisis and How the Courts Can Solve It

This chapter presents preliminary assessments of the economics of biotechnology, and describes how policy levers can and do apply in biotechnology. Taking the biotechnology industry as the case ... More

This chapter presents preliminary assessments of the economics of biotechnology, and describes how policy levers can and do apply in biotechnology. Taking the biotechnology industry as the case study, it examines the use—and perhaps the misuse—of patent tailoring by the courts. The courts in the monoclonal antibody cases made implicit policy judgments designed to encourage patenting, tweaking the legal doctrines to achieve what seemed to be desirable results for innovation. It is suggested that the risk of anticommons in biotechnology patents remains a concern, and can be best avoided by proper modulation of obviousness and disclosure. As biotechnology changes and develops, the availability of additional policy levers will be important to tailor patent law to its changing innovation profile.Less

The Challenge of Monoclonal Antibody Drugs

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses the efforts to develop monoclonal antibody (Mab) therapeutics. The quick commercialization of Mab diagnostics prompted many to assume that Mab therapeutics would soon reach the ... More

This chapter discusses the efforts to develop monoclonal antibody (Mab) therapeutics. The quick commercialization of Mab diagnostics prompted many to assume that Mab therapeutics would soon reach the market. These high expectations were given a boost in June 1986 when the FDA approved Ortho Diagnostic Systems' Orthoclone (muromonab-CD3) in order to prevent kidney rejection in transplant patients. Orthoclone was the first Mab approved anywhere for use as a drug in humans. Yet Orthoclone was not without problems. Between 5 and 10 percent of patients on it experienced significant side effects, including fevers, thromboses, and anaphylactic shock. Other Mab therapies tested in this period also led to complications. Part of the problem was that the antibodies were derived from mice or rats, which the human immune system treated as foreign and attacked. Such antibodies also only survived for between fifteen and thirty hours in humans, so the drugs had to be infused in high and frequent doses. Moreover, their recognition of human receptors was poor.Less

A Hesitant Start: Patents, Politics, and Process

Lara V. Marks

in The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare

This chapter discusses how the dissemination of monoclonal antibodies (Mabs) involved complex negotiations between actors in numerous scientific laboratories across the world, negotiations that also ... More

This chapter discusses how the dissemination of monoclonal antibodies (Mabs) involved complex negotiations between actors in numerous scientific laboratories across the world, negotiations that also played out on the political stage. Central questions arose over who possessed rights to the technology, and whether those rights should be protected. Much of the debate about rights was shaped by whether scientists believed the technique was revolutionary or merely part of a long chain of scientific discoveries. In 1975, Mabs were not particularly new either theoretically or conceptually because similar antibodies had been produced before. The difference was essentially one of scale. While British immunologist César Milstein and other experts recognized the technology's potential early, the National Research and Development Corporation (NRDC) initially expressed doubts regarding the application of Mabs, and thus refused to patent the technique. The eventual collaboration between Sera-Lab and Milstein's laboratory provided the first commercial channel for the global dissemination of Mabs, and established an important foundation for future research in the field.Less

The British Response

Geoffrey Owen and Michael M. Hopkins

in Science, the State, and the City: Britain's Struggle to Succeed in Biotechnology

The chapter describes the chain of events that led to the creation, with government support, of the UK’s first biotech firm, Celltech, in 1980. There followed a wave of start-ups as scientists and ... More

The chapter describes the chain of events that led to the creation, with government support, of the UK’s first biotech firm, Celltech, in 1980. There followed a wave of start-ups as scientists and entrepreneurs sought to build biotech firms on the US model. Thanks in part to the pro-entrepreneur policies of the Thatcher government, the venture capital industry grew strongly during the 1980s. With the stock market opening to loss-making biotech firms in the early 1990s, capital flowing into the sector increased and the prospects for future growth looked bright. However a series of setbacks in leading companies—most spectacularly the collapse of British Biotech, previously regarded as the flagship of the sector—undermined investor confidence. By the end of the decade the sector, as one executive put it, was still in its teenage years, still a long way behind the US and still waiting for a big success.Less

Sep-Con Articulation Process in Creative Discovery

Albert Rothenberg

in Flight from Wonder: An Investigation of Scientific Creativity

Verbatim descriptions are given of the use of the sep-con articulation process in creative discovery by Werner Arber on DNA restriction and modification, David Baltimore on reverse transcriptase, ... More

Verbatim descriptions are given of the use of the sep-con articulation process in creative discovery by Werner Arber on DNA restriction and modification, David Baltimore on reverse transcriptase, Baruj Benacerraf on immune responsiveness genes, Paul Berg on recombinant DNA, Allan Cormack on the CAT scan, Sheldon Glashow on the charm quark and electroweak theory, David Hubel in ocular orientation selectivity, Georges Köhler on the monoclonal antibody, Jean-Marie Lehn on supramolecular structure, Max Delbrück on genetic replication, Ivar Giaever on superconductor tunneling, Christiane Nüsslein-Volhard on segmentation pairs, Salvador Luria on the Lurian distribution, and Norman Ramsey on the separated oscillatory field method in atomic clocks.Less

Biotechnological Inventions

Philip W. Grubb, Peter R. Thomsen, Tom Hoxie, and Gordon Wright

in Patents for Chemicals, Pharmaceuticals, and Biotechnology

This chapter considers the law governing the patentability of biological inventions, including microbiological inventions, recombinant DNA technology, and monoclonal antibody technology. Patent ... More

This chapter considers the law governing the patentability of biological inventions, including microbiological inventions, recombinant DNA technology, and monoclonal antibody technology. Patent protection for biotechnological inventions is of immense commercial importance. But patent law and practice have been unable to keep up with the rapid scientific progress in this field; issues such as inventive step, sufficiency of disclosure, and permissible breadth of claims have proved troublesome. There has been much litigation of biotech patents and courts have found it difficult in such a rapidly moving field to determine what was the general knowledge of the skilled person at the time that the invention was made. Another problem is the opposition of special interest groups to anything related to genetic engineering, particularly the existence of patents in this area. Less

A New Way of Making Medicines

Geoffrey Owen and Michael M. Hopkins

in Science, the State, and the City: Britain's Struggle to Succeed in Biotechnology

This chapter introduces the term biotechnology and explains why it has been the subject of intense interest on the part of governments and investors around the world. It reviews the scientific ... More

This chapter introduces the term biotechnology and explains why it has been the subject of intense interest on the part of governments and investors around the world. It reviews the scientific advances, including the deciphering of DNA by Watson and Crick, which paved the way for the emergence of biotechnology, and describes the two key breakthroughs—recombinant DNA and monoclonal antibodies—which took place in the US and Britain in the 1970s. It draws some comparisons between biotechnology and semiconductors, noting the important role played in both sectors by newly formed entrepreneurial firms, and the dominance of the US. It also discusses the changing relationship between the new biotechnology firms and the established pharmaceutical companies.Less