Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults

Abstract

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log(10)) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4(+) T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4(+) T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.

Figures

FIG. 1.

Mean changes in viral loads from baseline. Shown are mean HIV-1 load (log10 HIV-1 copies/ml) changes from baseline in study arms A (10 mg/kg) (filled squares), B (10 mg/kg plus 6 mg/kg) (open triangles), and C (25 mg/kg) (filled diamonds). The data were derived from weekly viral-load measurements obtained for all patients in the study. The last administration of ibalizumab (arrowheads) occurred at week 8 (arm C) or 9 (arms A and B).

FIG. 2.

Mean changes in CD4+ counts from baseline. Shown are mean CD4+ T-cell count changes from baseline in study arms A (10 mg/kg) (filled squares), B (10 mg/kg plus 6 mg/kg) (open triangles), and C (25 mg/kg) (filled diamonds). The data were derived from weekly CD4+ T-cell counts obtained for all patients in the study. The last administration of ibalizumab (arrowheads) occurred at week 8 (arm C) or 9 (arms A and B).

FIG. 3.

Ibalizumab susceptibilities of patient HIV isolates at baseline and week 9. Shown are results from Phenosense HIV Entry and Trofile assays performed at Monogram Biosciences. (A) Representative dose-response curves used to determine in vitro susceptibilities to ibalizumab for patient HIV isolates taken at baseline (upper graph) and week 9 after the dosing interval (lower graph); the IC50 is indicated by a dashed vertical line. (B) PMIs of all patient HIV isolates from baseline (top) and week 9 (bottom) patient samples. Target cells for the HIV Entry assay dually expressed CCR5 and CXCR4 coreceptors. Virus coreceptor tropism (Trofile) is indicated as R5 (CCR5 tropic), DM (dual-mixed tropic), or X4 (CXCR4 tropic). Two R5 isolates at baseline could not be phenotyped at week 9 (NP). Samples are grouped by dose regimen: 10 mg/kg weekly (arm A), 10 mg/kg weekly plus 6 mg/kg biweekly (arm B), and 25 mg/kg weekly (arm C).