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THERAPEUTIC ACTIVITY OF PGT121 MONOCLONAL ANTIBODY IN HIV-INFECTED ADULTS
Kathryn E. Stephenson1, Boris Julg2, Jessica Ansel1, Stephen R. Walsh1, Chen S. Tan1, Lori Maxfield1, Peter Abbink1, Huub C. Gelderblom3, Frances Priddy3, Allan C. deCamp4, Roberto Arduino5, Edwin DeJesus6, Georgia Tomaras7, Michael S. Seaman1, Dan Barouch1
1Beth Israel Deaconess Medical Center, Boston, MA, USA,2Massachusetts General Hospital, Boston, MA, USA,3International AIDS Vaccine Initiative, New York, NY, USA,4Fred Hutchinson Cancer Research Center, Seattle, WA, USA,5University of Texas at Houston, Houston, TX, USA,6Orlando Immunology Center, Orlando, FL, USA,7Duke University, Durham, NC, USA
PGT121 is a recombinant human IgG1 mAb that targets a V3 glycan-dependent epitope region of HIV Env. PGT121 is a potent neutralizing antibody in vitro and has been shown to prevent and treat simian-human immunodeficiency virus in rhesus monkeys. Here we present safety, pharmacokinetic (PK) and antiviral efficacy data from the first-in-human phase 1 clinical trial of PGT121 conducted in the United States.
The first part of the study was a randomized, double blinded, dose escalation, placebo-controlled trial of PGT121 in adults who were HIV-uninfected (HIV-, N=20) and HIV-infected on ART (HIV+/ART+, N=15). PGT121 was given once at 3, 10, and 30 mg/kg IV and 3 mg/kg SC (N=5/group, 4:1 Ab/placebo). The second part of the study was an open label trial of PGT121 given once at 30 mg/kg IV in HIV-infected adults not on ART with high VL (3.3-4.8 log cp/ml, N=9) and low VL (2-2.6 log cp/ml, N=3). All participants were monitored for reactogenicity for 3 days and adverse events (AEs) for 56 days. PK and virologic assessments were performed through 6 months. The lower limit of quantification (LLOQ) of VL was 1.6 log cp/ml.
PGT121 was safe and well-tolerated with no related mod/severe AEs. The elimination half-life of PGT121 was ~22 days in HIV- and HIV+/ART+ groups, with variation by dose and route. In viremic HIV+ individuals not on ART, PGT121 showed antiviral efficacy in 5/9 participants in the high VL group with a median drop in VL of 1.7 log cp/ml (1.3-2.1) by d10. These individuals showed PGT121 sensitive virus at baseline but developed rebound by d28 with emergence of resistance. In the low VL group, PGT121 decreased VL to <LLOQ by d7 in 3/3 participants. Two of these individuals showed prolonged ART-free virologic suppression following 1 infusion with PGT121, with 1 individual experiencing rebound only at 6 months. The second individual's VL is still <LLOQ at 6 months, despite PGT121 levels that have declined to <0.86 ug/ml.
In this Phase 1 study, PGT121 was safe and well-tolerated with a favorable PK profile. PGT121 led to a median 1.7 log drop in VL in viremic HIV+ participants with PGT121-sensitive virus and high VL at baseline. Surprisingly, a single infusion of PGT121 led to >5 months of viral suppression to <lower limit of quantification in 2 participants with the lowest VL at baseline. Follow up is ongoing to determine PGT121-induced changes to host immunity, as well as the ultimate duration of ART-free virologic remission in suppressed participants.