Keliximab

Keliximab studies have provided evidence of the therapeutic potential of a non-depleting CD4 monoclonal antibody (mAb) in the treatment of rheumatoid arthritis (RA). Clenoliximab, an immunoglobulin G4 derivative of keliximab, has substantially reduced potential to deplete CD4 cells. In initial studies of clenoliximab, we investigated the hypothesis that the decrease in cell surface CD4 is the result of antibody-mediated stripping from the cell surface.

Patients received single or multiple intravenous infusions of clenoliximab as follows: 0.05, 0.2, 1, 5, 10 or 15 mg/kg (n=3-5/group); 150 or 350 mg weekly x 4; or 350 or 700 mg every other week x 2 (n=12/group). Blood was collected for up to 16 weeks and pharmacokinetic and pharmacodynamic assessments were conducted using immunoassay and flow cytometry.

CD4 count was largely unaffected by clenoliximab treatment. Dose-dependent CD4 coating, down-modulation and stripping were observed. Maximal down-modulation persisted for an increasing period as dose increased, while soluble CD4-clenoliximab complexes accumulated. The amount of CD4 in soluble complex was as much as 20 times the amount of cell-associated CD4. For the same total dose, administration of higher doses, less frequently, resulted in pharmacodynamic profiles similar to those of lower doses administered more frequently.

Decrease in the density of CD4 on the T-lymphocyte surface is caused by antibody-mediated stripping.

Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a preand postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (F0) with keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of preand postnatal development designed in accordance with ICH Guidelines.