Alemtuzumab depletion failure can occur in multiple sclerosis

Abstract

Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.

The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies

“…While alemtuzumab (CAMPATH-1H) was originally designed to reduce the immunogenicity of the parent CAMPATH-1G rat immunoglobulin (1)(2)(3)21) with alemtuzumab, ironically this appears not the case, as seen in this comparison among antibody therapies used in MS ( Table 2). Moreover, alemtuzumab (36-60 mg Q52W) induces binding ADA in about 85% of cases within 24 months (n = 811), and about 92% of those develop neutralizing ADA (12,13). In the phase III studies, it was evident that, despite substantial lymphocyte depletion, over 60% of pwMS developed ADA within the first month of infusion (12,13).…”

“…Moreover, alemtuzumab (36-60 mg Q52W) induces binding ADA in about 85% of cases within 24 months (n = 811), and about 92% of those develop neutralizing ADA (12,13). In the phase III studies, it was evident that, despite substantial lymphocyte depletion, over 60% of pwMS developed ADA within the first month of infusion (12,13). Furthermore, in the phase II extension study (Maximum n = 232), with three cycles of alemtuzumab administered, nearly all of the pwMS eventually developed ADA (8) ( Table 1).…”

“…This is unlike cladribine and ocrelizumab that are administered again 2-4 weeks after the initial dose (23,29). As such, pwMS who do not deplete lymphocytes effectively after the first dose are more likely to subsequently develop ADA (13,15); (b) alemtuzumab targets antigen-presenting cells, which include dendritic cells, and B cells, due to their expression of CD52 (Figure 1). Although transiently depleted, monocytes repopulate within a month while circulating antibody is probably still present, and so could rapidly present antigen to remaining antigen-specific lymphocytes, as could any antigen presenting cell that escaped depletion (15,34).…”

“…The occurrence of binding antibodies (BAbs) received limited mention and notably neutralizing antibodies (NAbs) were not discussed in the published reports (5,6,11) of the pivotal trials leading to the licensing and commercial development in MS. The first mention of neutralizing antibodies did not occur until we reported on them in 2017 (12,13). They were described as "inhibitory antibodies" within the regulatory submissions (5,6).…”

“…According to the Food and Drug Administration (FDA), their effect on the clinical efficacy and safety profile was of unclear clinical significance. We are concerned that the effect of alemtuzumab anti-drug antibodies (ADA) on efficacy has yet to be adequately addressed (12,14,15), and may have safety implications (6,13,16,17). Although ADA against alemtuzumab have been reported as being without clinical significance (14,15), the dosing at intervals of 12 months or longer may have aided development of alemtuzumab by allowing ADA to subside ( Table 1).…”