Treating Multiple Sclerosis With Monoclonal Antibodies

Mathias Buttman, MD; Peter Rieckmann, MD, FRCPC

Disclosures

Expert Rev Neurother. 2008;8(3):433-455. 

In This Article

Development of Therapeutic Monoclonal Antibodies: From Mice to Men

In 1975, Georges Köhler and César Milstein published a method allowing the production of large quantities of prespecified identical Abs.[17] Their method followed a simple principle: fusion of spleen cells from a mouse immunized with an antigen of interest with nonsecretory murine myeloma cells resulted in continuous hybridoma cell lines, combining a desired property of B cells, that is, Ab production, with a desired property of tumor cells, such as unlimited cell division. By clonal expansion of a single hybridoma cell, selected for production of an Ab of interest, large amounts of identical Abs could be produced. This method provided invaluable research tools and rapidly revolutionized immunology and molecular biology. Together with Niels Jerne, Georges Köhler and César Milstein were awarded the Nobel Prize in Physiology or Medicine in 1984.

In their original publication, Köhler and Milstein emphasized the potential of mAbs for the treatment of human diseases.[17] However, first attempts to treat humans with murine mAbs in the 1980s, when it became possible to produce sufficient quantities of clinical grade mAbs, were rather discouraging, since Abs of murine origin proved to be rather ineffective and toxic by inducing severe anti-idiotypic humoral immune responses in the majority of patients, especially when injected repeatedly. These human antimouse Abs induced rapid intrinsic clearance of murine therapeutic Abs by complex formation and additionally decreased their efficacy by blocking the murine antigen-recognizing domain.[18]

Most early Phase I trials in MS patients with murine mAbs, targeted against various human immune cell differentiation markers, such as CD6, CD2, CD3 and CD4, and designed for immune cell depletion, faced these problems of high toxicity and low efficacy (reviewed in[19]). To reduce the immuno-genicity of murine Abs, therapeutic mAbs more similar to human Abs had to be developed. The production of chimeric Abs was an important step in this direction: the variable regions of a mouse Ab were combined with the constant regions of a human Ab, thereby retaining the original binding specificity (not necessarily affinity) of the Ab but reducing its immuno-genicity.[20,21] A further reduction of immuno-genicity was achieved by the production of humanized Abs, where only the antigen-recognizing, complementarity-determining regions were derived from a murine Ab and combined with human variable region frameworks as well as human constant regions.[22] The latest generation of therapeutic Abs is completely human. However, even fully human Abs may induce neutralizing Abs (nAbs) in a significant proportion of treated patients.[23]

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