Alemtuzumab

Alemtuzumab, is a recombinant DNA-derived humanised monoclonal antibody directed against the 21-28 kD cell surface glycoprotein CD52. Alemtuzumab is an IgG1 kappa antibody with human variable framework and constant regions, and complementary-determining regions from a murine (rat) monoclonal antibody. The antibody has an approximate molecular weight of 150 kD.

Alemtuzumab binds to CD52, a cell surface antigen present at high levels on T (CD3+) and B (CD19+) lymphocytes, and at lower levels on natural killer cells, monocytes, and macrophages. There is little or no CD52 detected on neutrophils, plasma cells, or bone marrow stem cells. Alemtuzumab acts through antibody-dependent cellular cytolysis and complement-mediated lysis following cell surface binding to T and B lymphocytes.

The mechanism by which alemtuzumab exerts its therapeutic effects in MS is not fully elucidated. However, research suggests immunomodulatory effects through the depletion and repopulation of lymphocytes, including:

• Alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment
• Increased representation of regulatory T cell subsets
• Increased representation of memory T- and B-lymphocytes
• Transient effects on components of innate immunity (i.e., neutrophils, macrophages, NK cells)

The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation, may reduce the potential for relapse, which ultimately delays disease progression.

Pharmacodynamic effects

Alemtuzumab depletes circulating T and B lymphocytes after each treatment course with the lowest observed values occurring 1 month after a course of treatment (the earliest post-treatment time point in phase 3 studies). Lymphocytes repopulate over time with B-cell recovery usually completed within 6 months. CD3+ and CD4+ lymphocyte counts rise more slowly towards normal, but generally do not return to baseline by 12-months post-treatment. Approximately 40% of patients had total lymphocyte counts reaching the lower limit of normal (LLN) by 6 months after each treatment course, and approximately 80% of patients had total lymphocyte counts reaching the LLN by 12 months after each course.

Neutrophils, monocytes, eosinophils, basophils, and natural killer cells are only transiently affected by alemtuzumab.

The pharmacokinetics of alemtuzumab were evaluated in a total of 216 patients with RRMS who received intravenous infusions of either 12 mg/day or 24 mg/day on 5 consecutive days, followed by 3 consecutive days 12 months following the initial treatment course. Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. Administration of 12 mg/day resulted in a mean C_max of 3014 ng/ml on day 5 of the initial treatment course, and 2276 ng/ml on day 3 of the second treatment course. The alpha half-life approximated 4-5 days and was comparable between courses leading to low or undetectable serum concentrations within approximately 30 days following each treatment course.

Alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.

Conclusions cannot be made with available data on the effect of race and gender on the pharmacokinetics of alemtuzumab. The pharmacokinetics of alemtuzumab in RRMS has not been studied in patients aged 55 years and older.

Carcinogenesis and mutagenesis

There have been no studies to assess the carcinogenic or mutagenic potential of alemtuzumab.

Fertility and reproduction

Treatment with intravenous alemtuzumab at doses up to 10 mg/kg/day, administered for 5 consecutive days (AUC of 7.1 times the human exposure at the recommended daily dose) had no effect on fertility and reproductive performance in male huCD52 transgenic mice. The number of normal sperm was significantly reduced (<10%) relative to controls and the percent abnormal sperm (detached heads or no heads) were significantly increased (up to 3%). However, these changes did not affect fertility and were therefore considered to be non-adverse.

In female mice dosed with intravenous alemtuzumab up to 10 mg/kg/day (AUC of 4.7 times the human exposure at the recommended daily dose) for 5 consecutive days prior to cohabitation with wild-type male mice, the average number of corpora lutea and implantation sites per mouse were significantly reduced as compared to vehicle treated animals. Reduced gestational weight gain relative to the vehicle controls was observed in pregnant mice dosed with 10 mg/kg/day.

A reproductive toxicity study in pregnant mice exposed to intravenous doses of alemtuzumab up to 10 mg/kg/day (AUC 2.4 times the human exposure at the recommended dose of 12 mg/day) for 5 consecutive days during gestation resulted in significant increases in the number of dams with all conceptuses dead or resorbed, along with a concomitant reduction in the number of dams with viable foetuses. There were no external, soft tissue, or skeletal malformations or variations observed at doses up to 10 mg/kg/day.

Placental transfer and potential pharmacologic activity of alemtuzumab were observed during gestation and following delivery in mice. In studies in mice, alterations in lymphocyte counts were observed in pups exposed to alemtuzumab during gestation at doses of 3 mg/kg/day for 5 consecutive days (AUC 0.6 times the human exposure at the recommended dose of 12 mg/day). Cognitive, physical, and sexual development of pups exposed to alemtuzumab during lactation were not affected at doses up to 10 mg/kg/day alemtuzumab.