Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Abstract

SummaryAlemtuzumab, a humanized anti‐CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post‐treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti‐alemtuzumab antibodies, including inhibitory antibodies, during the 2‐year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti‐alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

“…By comparison, CD52 encodes a membrane glycoprotein present at varying levels on the surface of various leukocytes but not hematopoietic cells 21 . In addition, alemtuzumab is a monoclonal anti-CD52 (αCD52) antibody that results in preferential and prolonged depletion of circulating T and B cells 22,23 and is FDA approved for the treatment of B-cell chronic lymphocytic leukemia [24][25][26] and relapsing remitting multiple sclerosis [27][28][29] . Because of its biological role in immune cells relevant to asthma as well as its potential translational implications, we, therefore, prioritized CD52 as a strong causal positional candidate gene for functional validation (Fig.…”

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

“…These findings not only point to a novel pathway for development of asthma but may also have potential translational implications. For example, we demonstrated that treatment of mice with an α CD52 antibody mimicked the immune cell-depleting activity of alemtuzumab in the circulation in humans 33,34 . We readily observed depletion of immune cells in spleen, which in mice is considered as accurately reflecting the pool of peripheral immune cells 64 .…”

“…By comparison, CD52 encodes a membrane glycoprotein present at high levels on the surface of various immune cells, including lymphocytes, monocytes, and dendritic cells. In addition, alemtuzumab is a monoclonal anti-CD52 (αCD52) antibody that results in preferential and prolonged depletion of circulating T and B cells 33,34 and is FDA approved for the treatment of relapsing remitting multiple sclerosis [35][36][37] and B-cell chronic lymphocytic leukemia [38][39][40] . Because of its biological role in immune cells relevant to asthma as well as its potential translational implications, we therefore prioritized CD52 as a strong causal positional candidate gene for functional validation (Fig.…”

“…4A). 33,34 , the mouse α CD52 antibody efficiently depleted CD4 + and CD8 + T cells as well as CD19 + B cells in both the lung and spleen (Supplemental Figs. 4B-E and 5).…”

Guide to Immunopharmacology: a database to boost immunology education, research and therapy

“…In conclusion, Immunology and our sister journal Clinical and Experimental Immunology are strongly committed to publishing high-quality research relating to new therapeutics [9][10][11][12][13][14][15][16] as well as to the provision of educational resources, and therefore we recommend the GtoImmuPdb database as a novel tool to accelerate research, education and drug discovery in immunology, infection and inflammation.…”