Steven Kozlowski
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The history of the protein therapeutics over the past decades can be divided into five main periods. Each stage along the
way has seen the development of new products, advances in science, and the evolution of quality regulations to adapt to those
changes. A review of this history can be instructive as we advance in an era of new dosage forms, follow-on biologics, and
unknown industry and regulatory challenges that have yet to arise.
PRE-1986: A STAR IS BORN
In the early 1950s, DNA was shown to transfer genetic information, and the double helix structure of DNA was resolved. By
1961, the genetic code was deciphered, paving the way to genetic engineering and biotechnology. These advances promised tremendous
benefits but generated a great deal of fear. To deal with the potential risks of this new technology, the National Institutes
of Health (NIH) issued guidelines on the use of recombinant DNA (now known as the NIH Guidelines for Research Involving Recombinant DNA Molecules) in 1976, and the following year, many bills were presented in Congress to limit the use of recombinant DNA technology. Between
1976 and 1986, however, fears about the use of DNA diminished, and genetic engineering allowed for the successful production
and marketing of human insulin and growth hormone, both of which were manufactured using recombinant bacterial expression
systems. These products were great successes. Although as a society we still worry about biotechnology, from genetically engineered
foods to fictional recombinant velociraptors (thanks to Hollywood films such as Jurassic Park), we have seen the benefits
of biotechnology-derived pharmaceuticals.
1986–1991: MORE BIOTECHNOLOGY SUCCESSES
Products: Interferon; The First Antibody; Hematopoetic Growth Factors
Staff from the Office of Biotechnology Products at work. Far left: Mate Tolnay reviews monoclonal antibodies and runs a laboratory
program. Center: Emanuela Lacana reviews therapeutic proteins. Above: Ashutosh Rao is an FDA-NCI fellow performing research
and review side-by-side (review page obscured).
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In 1986, interferon alfa was initially approved for the treatment of hairy cell leukemia, and other oncology and antiviral
indications followed. Also in 1986, muromonab-CD3, the first marketed monoclonal antibody, was approved for the treatment
of allograft rejection. This murine monoclonal antibody reversed acute renal rejection in greater than 90% of cases, and it
was the first marketed product made from an immortalized mammalian cell fusion. In 1987, alteplase was approved for the treatment
of acute myocardial infarctions; other therapeutic enzymes with cardiovascular indications followed. Alteplase production
used immortalized Chinese hamster ovary cells (CHO), further advancing the role of mammalian cell lines in the manufacture
of biotechnology products. From 1989 to 1991, the hematopoetic growth factors erythropoietin, granulocyte colony-stimulating
factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF, produced by recombinant yeast) were approved
for marketing in the United States. These products treat anemia by reducing transfusions or treat neutropenia by reducing
infections.
