Casadevall. lymphocytes to secrete immunosuppressive molecules (3), (viii) promote dysregulation in cytokine production (46, 52, 53), and (ix) inhibit phagocytosis (24). For all of these reasons, the capsular polysaccharide of is usually a major virulence factor that interferes with host defense mechanisms from clearing this organism from the bloodstream and infected tissues. Administration of antibodies directed against capsular polysaccharide to infected mice has prolonged survival (9, 16, 35, 37, 38), reduced the tissue fungal burden, and enhanced granuloma formation (10). Also, antibodies to capsular polysaccharide enhanced the killing of by amphotericin B (8, 15, 39), fluconazole (36), and flucytosine (11) in mice and by isolated leukocytes in vitro (34). On the basis of these promising preliminary data, we carried out a phase I, multi-institution, open-label, nonrandomized, dose-escalation study of a murine-derived anticryptococcal antibody (monoclonal antibody [MAb] 18B7) in HIV-infected subjects who had been successfully treated for cryptococcal meningitis. This is the first application of MAb therapy for the treatment of a fungal disease in humans. The trial was designed to determine the maximum tolerated dose of MAb 18B7 and to assess the impact of a single dose of this antibody around the serum and CSF CrAg titers. MATERIALS AND METHODS Study subjects met the following inclusion characteristics: (i) they were HIV infected and 18 years of age; (ii) they had a history of culture-proven cryptococcal meningitis; (iii) they had successfully completed at least 6 weeks of therapy for cryptococcal meningitis, with resolution of all signs and symptoms of cryptococcal meningitis; and (iv) they had Purvalanol A a negative posttreatment CSF culture for (5a). A response to the antibody infusion was inferred from changes in serum CrAg titers, which were measured at the baseline, at 4 and 24 h, and then at 7, 14, 28, 56, and Purvalanol A 70 days after Purvalanol A the MAb 18B7 infusion. Serum was assayed for the MAb 18B7 concentration at 5 min before the initiation of the infusion; at 15, 30, and 60 min and 2 h into the infusion; at 4, 6, 8, Mouse monoclonal to KIF7. KIF7,Kinesin family member 7) is a member of the KIF27 subfamily of the kinesinlike protein and contains one kinesinmotor domain. It is suggested that KIF7 may participate in the Hedgehog,Hh) signaling pathway by regulating the proteolysis and stability of GLI transcription factors. KIF7 play a major role in many cellular and developmental functions, including organelle transport, mitosis, meiosis, and possibly longrange signaling in neurons. and 12 h after the start of the infusion; and on days 7, 14, 28, 56, and 70 after the infusion. Lumbar puncture for CSF collection was performed 4 to 6 6 h after the initiation of MAb 18B7 infusion for CrAg titer and antibody measurement. The samples were tested for the presence of human anti-mouse antibodies (HAMAs) at the baseline and at days 7, 14, 28, 56, and 70. The CrAg titer was measured by a latex agglutination assay (Immuno-Mycologics, Inc., Norman, Okla.). Serum and CSF specimens were sent overnight to the central laboratory on wet ice, and titers were Purvalanol A measured within 24 to 48 h of collection. Samples were then placed in batches and stored frozen at ?70C until they were thawed and the titers were measured at the conclusion of study by latex agglutination assay and enzyme-linked immunoabsorption assay (Meridian, Cincinnati, Ohio). The MAb 18B7 and HAMA levels were measured by radioimmunoassays (I125) at the central laboratory at the conclusion of the study (22, 23). Quantitative HIV RNA assays were performed at the central laboratory, while CD4 and CD8 lymphocyte counts were measured at each site. The peak concentration in serum (= 0.02). The MRT for MAb 18B7 molecules within the body was estimated to be 73 h, giving an MRT-calculated.
