Phase I study of safety and pharmacokinetics of a human anticytomegalovirus monoclonal antibody in allogeneic bone marrow transplant recipients.

This study examined the safety and pharmacokinetic profile of a potentially therapeutic and fully human anti-CMV monoclonal antibody (SDZ MSL-109) in a phase I dose escalation trial in patients receiving allogeneic bone marrow transplants. Fifteen adult marrow transplant patients, twelve with chronic myelogenous leukemia and three with acute nonlymphocytic leukemia, in cohorts of five patients each, were administered monoclonal antibody intravenously at doses of 50, 250, and 500 micrograms/kg at approximately three-week intervals for six months. Administration of the monoclonal antibody was associated with minimal side effects and no dose-related toxicity. Antibody elimination curves in all dose groups were consistent with a two-compartment model with an alpha half-life at the low, middle, and high dose groups of 1.03, 0.82, and 0.79 days, and a beta half life of 13.9, 14.0, and 16.5 days, respectively. The volume of distribution decreased with repetitive dosing to approximate the plasma volume in each patient and the pharmacokinetic profile was comparable to that of human IgG. There was no host antiidiotypic or antiallotypic antibody formation, indicating that MSL-109 was not immunogenic. Further studies are warranted to assess the potential efficacy of human monoclonal anti-CMV disease in marrow transplant recipients and other patients with immunodeficiency disorders.

Pharmacokinetics of cytomegalovirus specific IgG antibody following intravenous immunoglobulin in bone marrow transplant patients.

Cytomegalovirus (CMV) associated interstitial pneumonitis is a major cause of death among bone marrow transplant patients. A variety of intravenous immunoglobulin (IVIg) preparations have shown some promise in preventing this complication. As part of a multicenter trial of Sandoglobulin, the pharmacokinetics of CMV specific IgG was measured in order to guide future dosing schedules. A dose of 500 mg/kg was administered weekly beginning 1 week before transplant and continuing until day 98 following transplant. The half-life of CMV specific IgG was measured by an ELISA method after the first, third and fifth doses of IVIg. CMV seronegative patients received only screened CMV negative blood products, which permitted assessment of the half-life of IVIg CMV antibody. Peak titers achieved were comparable to those of the CMV seropositive patients averaging 1:2702 (range 1:596-1:10 514). Total IgG levels rose to a peak of about 75% above baseline. After the first dose of IVIg, the half-life of CMV IgG antibody was 3.4 +/- 2.0 (SD) days, although it lengthened to 6.1 +/- 5.1 days after the fifth dose of IVIg. The half-life of total IgG was estimated to be between 5 and 10 days, depending on the assumptions made regarding endogenous production. If high levels of IVIg are necessary for protection from CMV associated interstitial pneumonitis, weekly dosing will be important in order to maintain sufficient levels to be protective.