4.6 Article

Alemtuzumab depletion failure can occur in multiple sclerosis

Journal

IMMUNOLOGY
Volume 154, Issue 2, Pages 253-260

Publisher

WILEY
DOI: 10.1111/imm.12879

Keywords

antibodies; CD52; immunotherapy; multiple sclerosis; tolerance

Categories

Funding

  1. Sanofi-Genzyme
  2. Takeda
  3. Genzyme-Sanofi
  4. Merck Serono
  5. Novartis
  6. Teva
  7. Biogen
  8. Pfizer
  9. AbbVie Biotherapeutics
  10. Canbex
  11. Ironwood
  12. Merck
  13. Roche
  14. Sanofi Genzyme
  15. Synthon
  16. Vertex
  17. AbbVie
  18. Bayer HealthCare
  19. Genzyme
  20. Sanofi-Aventis
  21. BIAL
  22. Cytokinetics

Ask authors/readers for more resources

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 06% 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available