Читать книгу Successful Drug Discovery, Volume 5 - Группа авторов - Страница 27

In 1975, César Milstein, University of Cambridge, and his postdoctoral fellow Georges Jean Franz Köhler [88] first described the generation of monoclonal antibodies from hybridoma cells. Their high specificity and strong affinity quickly suggested that this concept may very well be suited for drug development. This discovery earned both of them the Nobel Prize for Medicine in 1984.

In 1980, a surface antigen of B‐cells was described [89], which was isolated and further described and termed CD20 in 1988 [90]. CD20 is present on almost all differentiation states of B‐cells, except the immature ones, and found on cancerous as well as healthy B cells. A treatment targeting CD20 would accordingly eliminate all B‐cells, but the immature ones, which then could form a new population after treatment, is finished.

Lee Nadler at Dana Farber Cancer Institute in Harvard University described and cloned the first antibody targeting a cancer‐associated antigen called CD20. In a historic proof of principle study [91], he treated a first patient with this antibody. A transient response was observed, providing first evidence that targeting CD20 with monoclonal antibodies could be a viable therapeutic option to treat B‐cell lymphomas.

Shortly after, the technology of generating chimeric antibodies was established, representing another milestone in the establishment of antibody therapies. Scientists at the University of Toronto and Columbia University demonstrated [92] that it was possible to generate antibodies bearing the human F_c region and bearing the mouse variable region. These antibodies were significantly less immunogenic, thus improving therapeutic prospects significantly.

Ronald Levy at Stanford University discovered that B‐cell lymphomas were composed of monoclonal cell populations and, influenced by the work of Köhler and Milstein, he directed his research toward development of personalized monoclonal antibody therapy to target these lymphomas [93].

As early as 1982, a first patient was treated [94]. The promising results lead to formation of a start‐up company called IDEC, which later turned into Biogen. The approach of developing personalized antibodies turned out too laborious and costly, instead CD20 was selected as a selective B‐cell marker. As a direct result, rituximab [95], a chimeric monoclonal antibody targeted against CD20, was discovered. In the following clinical trial [96], tumor regression could be observed in about 50 % of the patients. This antibody represents a hallmark in the treatment of cancer and was the first antibody drug to be approved by the FDA for treatment of cancer in 1997. It was licensed to Roche and is used for treatment of various cancers like non‐Hodgkin's lymphoma.