Monoclonal antibodies and progressive multifocal leukoencephalopathy

Abstract

Since their introduction, monoclonal antibodies have found an ever expanding role in the treatment of a wide number of disorders. However, the perturbation of the immune system that attends their use may also increase the risk for the development of disorders that arise in the setting of immunosuppressive conditions, such as, opportunistic infection and malignancy. In this paper, we address the association between some monoclonal antibodies and the development of a rare demyelinating disease of the brain, progressive multifocal leukoencephalopathy (PML). PML results from infection with a ubiquitous polyoma virus, JC virus, and typically occurs in the setting of impaired immunity, most commonly, AIDS. It was first recognized as a potential complication of monoclonal antibody therapy in patients with multiple sclerosis and Crohn disease being treated with natalizumab, an alpha 4 beta1 and alpha 4 beta 7 integrin inhibitor. Subsequently, efalizumab, a monoclonal antibody used in the treatment of psoriasis, was also demonstrated to be associated with PML. An increased risk has been suggested for rituximab, although most of the patients developing PML with that monoclonal antibody have been treated for B-cell disorders that predispose to the development of PML. Based on our current understanding of the biology of JC virus and the pathogenesis of PML, we propose an explanation for the increased risk for PML that is observed with natalizumab and certain other monoclonal antibodies.

Figure 1

Genesis of the neurotropic Strain of JC Virus. (Adapted from Jensen and Major85). The JC virus genome is depicted on the left. The genes coding for its three structural proteins and three regulatory proteins (here) are highly conserved, but not the non-coding control region which dictates whether the virus can bind to a cells NF-1X DNA binding proteins. The archetype virus' non-coding control region is at the top; at the bottom, is the 98 bp tandem repeat sequence seen in the virus isolated from brains with PML. This is the mutation that must occur.