Alemtuzumab is a monoclonal antibody that targets CD52 positive T-cells and B-cells, and is used to treat relapsing remitting multiple sclerosis. However, despite humanization and depletion of peripheral T and B cells, alemtuzumab generates the highest frequency of binding and neutralizing antibodies of all humanized antibodies currently in clinical use. In some individuals, antibody neutralization appears to be sufficiently severe to allow disease-breakthrough.
The objective of this report is to highlight a need to re-evaluate how we approach and monitor anti-drug antibodies to alemtuzumab during treatment of patients with multiple sclerosis.
This is a presentation of a case report of a 40 year old woman with a history of MS who was started on alemtuzumab in June 2015.
She had breakthrough disease activity in September 2018, so received her third cycle of alemtuzumab in December 2018. In July 2019 she developed right eye blurry vision and bilateral lower extremity weakness. MRIs demonstrated longitudinally extensive right optic neuritis, 17 enhancing lesions throughout the cerebral hemispheres, corpus callosum, and brainstem, five enhancing cervical cord lesions, and two enhancing thoracic cord lesions. Review of her records revealed that her lymphocytes did not deplete following the third cycle of alemtuzumab. A novel serum assay was performed which demonstrated a very high titer of binding and neutralizing alemtuzumab anti-drug antibodies (>7.7 x 105 Lux) compared to an untreated serum sample (1.22 x 104 Lux).
We concluded that her new lesions were secondary to her multiple sclerosis, unchecked as a result of alemtuzumab depletion failure. We are additionally concerned that depletion failure was secondary to the presence of alemtuzumab neutralizing antibodies. We propose that following lymphocyte counts in the months following treatment should be routine if not imperative, with the goal of monitoring for treatment failure. More pro-actively, it may be appropriate to evaluate for neutralizing antibodies before considering administration of third or fourth cycles of treatment.