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IBALIZUMAB SUSCEPTIBILITY IN PATIENT HIV ISOLATES RESISTANT TO ANTIRETROVIRALS
Steven Weinheimer1, Zvi Cohen2, Christian Marsolais2, Stanley Lewis1
1TaiMed Biologics USA, Irvine, CA, USA,2Theratechnologies, Inc, Montreal, QC, Canada
Ibalizumab (IBA) is a long-acting humanized IgG4 monoclonal antibody that blocks HIV entry into CD4 cells while preserving normal immunological function. IBA binds to domain 2 of the CD4 receptor, away from the MHC II binding site. IBA susceptibility of patient isolates was determined at Baseline for a 24-week, Phase 3 clinical trial (TMB-301) conducted in 40 heavily treatment-experienced patients with multi-drug resistant HIV-1. Susceptibility was compared for isolates that were sensitive and resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), enfuvirtide (ENF) and maraviroc (MVC).
Maximum Percent Inhibition (MPI) and ICHalfMax Fold Change (ICHMFC) from the dose-response curve were monitored as indicators of IBA susceptibility using the PhenoSense HIV Entry assay. MPI is the maximum level of inhibition achieved and ICHMFC occurs at the midpoint of the dose response curve.
IBA susceptibility at Baseline was determined for 38 of 40 patient isolates. The mean IBA MPI at Baseline was 91±14 (median of 97). Twenty-seven samples had MPI values of 90-100%, 6 had MPI values of 80-90%, and 5 had MPI values <80%. The mean ICHMFC was 1.2 ± 0.9 (median of 0.9). The mean IBA MPI for patient HIV isolates with wild-type susceptibility to NRTIs, NNRTIs, PIs, or INIs, was 81%, 98%, 89%, and 91%, respectively; the mean ICHMFC was 1.3, 0.9, 1.1, and 1.0, respectively. For isolates that were resistant to all NRTIs, NNRTIs, PIs, or INIs, the mean IBA MPI was 94%, 91%, 91%, and 92%, respectively; the mean ICHMFC was 1.2, 1.2, 1.3, and 1.1, respectively. 6 patients had HIV with reduced susceptibility to ENF at screening. 5 of these had IBA MPI values 84-99% with ICHMFC values 0.7-1.4, while 1 had HIV with reduced IBA susceptibility (MPI = 41%, ICHMFC = 6.2). Two patient isolates exhibited CCR5-dependent replication with reduced susceptibility to MVC – one was CCR5 tropic with MVC MPI = 58% and one was dual-mixed (DM) tropic with MVC MPI <0 . Both isolates were susceptible to inhibition by IBA with MPI = 94% and 100%, respectively. The mean MPI for CCR5, DM, and CXCR4 tropic isolates was 89%, 91%, and 92%, respectively.
IBA is effective despite resistance to other antiretrovirals. The present in vitro IBA susceptibility results correlate with the efficacy observed in the Phase 3 trial 7 days after functional monotherapy.