CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

1062 A PHASE 1 TRIAL OF THE COMBINATION OF 3BNC117 AND 10-1074 IN HIV-UNINFECTED ADULTS Yehuda Z. Cohen 1 , Allison Butler 1 , Rebeka Levin 1 , Katrina Millard 1 , Maggi Pack 1 , Shiraz A. Belblidia 1 , Juan P. Dizon 1 , Irina Shimeliovich 1 , Kelly Seaton 2 , Nicole L. Yates 2 , Georgia Tomaras 2 , Marshall Zingg 3 , Michael S. Seaman 3 , Michel Nussenzweig 1 , Marina Caskey 1 1 The Rockefeller University, New York, NY, USA, 2 Duke Human Vaccine Institute, Durham, NC, USA, 3 Beth Israel Deaconess Medical Center, Boston, MA, USA Background: Broadly neutralizing anti-HIV-1 antibodies are currently being developed for the treatment and prevention of HIV infection. It has been postulated that effective broadly neutralizing antibody therapy or prophylaxis will necessitate the combination of multiple antibodies, akin to the use of multiple drugs in antiretroviral therapy. This trial was designed to evaluate the safety and pharmacokinetic profile of the combination of the broadly neutralizing antibodies 3BNC117 and 10-1074, which target different epitopes on the HIV-1 envelope. Methods: This placebo-controlled, double blind, randomized trial (NCT02824536) consisted of 3 groups of 8 participants. Group 1 received a single dose of both antibodies at 10 mg/kg. Groups 2 and 3 received 3 doses of both antibodies 8 weeks apart at 3 mg/kg and 10 mg/kg, respectively. Participants in each group were randomized 3:1 to receive the study products or placebo, administered by intravenous infusion. Results: Twenty-four participants were enrolled. The infusions were generally well tolerated, with no serious adverse events considered related to infusion. Overall, the safety profile of the antibody combination was similar to the safety profile of either antibody administered individually. Serum 3BNC117 and 10-1074 levels were measured by anti-idiotype ELISA, and serum neutralizing activity was evaluated by TZM.bl assay. Preliminary pharmacokinetic measurements performed by non-compartmental analysis demonstrate a half-life for 3BNC117 and 10-1074 of 18 and 24 days, respectively. These results are similar to previously published half-lives for each antibody administered alone. Serum neutralizing activity against selected viral strains correlated with measured antibody levels. Conclusion: The broadly neutralizing antibodies 3BNC117 and 10-1074 were well tolerated when administered in combination. Additionally, no reduction in half-life was observed for either antibody. These results support the continued development of combinations of broadly neutralizing antibodies for the treatment and prevention of HIV-1 infection. 1063 PHASE 1 TRIAL TO ASSESS SAFETY AND ANTIVIRAL ACTIVITY OF MB66 VAGINAL FILM Susan Cu-Uvin 1 , Kenneth H. Mayer 2 , Thomas Moench 3 , Karen T. Tashima 1 , Jai G. Marathe 4 , Joseph A. Politch 4 , Tara J. Nyhuis 5 , Larry Zeitlin 3 , Hans M. Spiegel 6 , Kevin Whaley 3 , Deborah Anderson 4 1 Brown University, Providence, RI, USA, 2 Harvard University, Cambridge, MA, USA, 3 Mapp Biopharmaceutical, Inc, San Diego, CA, USA, 4 Boston University, Boston, MA, USA, 5 University of Colorado Boulder, Boulder, CO, USA, 6 NIH, Bethesda, MD, USA Background: Monoclonal antibodies (mAbs) show promise as multipurpose prevention technology because their specificity and diversity enable broad- spectrum activity. The MB66 product comprises a combination of anti-HIV and anti-HSV mAbs, produced in Nicotiana (N), to provide protection against two incurable viral infections with high and synergistic morbidity. We sought to assess in women the safety and antiviral effects (ex vivo) of MB66 film antibodies when delivered vaginally. Methods: The MB66 film contains 10 mg of VRC01-N (anti-HIV-1 mAb) and 10 mg of HSV8-N (anti-HSV-2 mAb). Eight healthy and sexually abstinent women without evidence of genital tract infections were enrolled. A study clinician manually inserted the MB66 film in the clinic. Visits and clinical sampling occurred at baseline, 1, 4, 24 hrs and 6-10 days post dose. Adverse events were documented based on DAIDS adverse event grading. Aliquots of cervicovaginal lavage samples (CVLs) were assayed by Luminex for 15 cytokines that have been associated with HIV transmission, by TZM-bl assay for HIV neutralization [HIV strains: Q23-17 (R5 clade A, transmitter/founder strain), BaL (R5 clade B), and LAI (X4 clade B)], and by Plaque Reduction Neutralization Test for HSV-2 neutralization [HSV-2 strain G]. Results: There were four reported adverse events: Grade 1 (cramping, spotting and rash on chest) and Grade 2 (vaginal itching). Only the spotting was deemed related to product. Levels of proinflammatory or other cytokines were not significantly increased in CVLs from the 24hr and 6-10 day time points compared

1061 A PHASE I DOSE-ESCALATION STUDY OF MONOCLONAL ANTIBODY VRC07- 523LS IN HEALTHY ADULTS Martin R. Gaudinski 1 , Katherine V. Houser 1 , Grace Chen 1 , Ro Shauna Rothwell 1 , Pamela Costner 1 , Lasonji Holman 1 , Ingelise Gordon 1 , Robert Bailor 1 , Margarita G. Lorenzo 1 , Richard A. Koup 1 , Edmund V. Capparelli 2 , Barney S. Graham 1 , John R. Mascola 1 , Julie Ledgerwood 1 1 NIH, Bethesda, MD, USA, 2 University of California San Diego, La Jolla, CA, USA Background: Human monoclonal antibodies that potently and broadly neutralize HIV-1 (bnMAbs) are under development for prevention and treatment of HIV-1 infection. The VRC01 class of bnMAbs targets the CD4-binding site of the HIV-1 envelope protein. VRC01, the first member of this antibody class, is currently being evaluated for prevention of HIV infection in two phase 2b efficacy trials. VRC07-523LS is an engineered clonal variant of VRC01 that is approximately 10 fold more potent than VRC01 and active against 96% of diverse HIV-1 strains, including clade C. The -LS mutation in the antibody Fc region is designed to lengthen its half-life by increasing binding affinity to the neonatal Fc receptor. This change extended terminal half-life and improved protection in the NHP challenge model. These qualities make VRC07-523LS an attractive candidate for a bnMAb prevention strategy. Methods: VRC07-523LS was administered to healthy adults in an ongoing phase 1 trial (clinicaltrials.gov NCT03015181) to determine its safety, tolerability, and pharmacokinetics (PK). VRC07-523LS has been infused once at doses of 1mg/kg, 5mg/kg, 20mg/kg, and 40mg/kg intravenously (IV) or 5mg/kg subcutaneously (SC), and will be administered three times at 12 week intervals to a subset of subjects receiving 20mg/kg IV or 5mg/kg SC. Serum neutralization activity and detection of anti-drug antibodies will also be examined. Results: A total of 25 subjects have enrolled in the study. Local and systemic reactogenicity was mild to moderate when reported. No serious adverse events or dose-limiting toxicities have occurred to date. Herein we report PK data through 4 weeks post-infusion for 18 subjects who have received a single administration of VRC07-523LS. Maximum (Cmax) and 4 weeks post-infusion serum concentrations increased proportionally with antibody dose (Table 1). At 4 weeks post-infusion, subjects who received 1mg/kg IV, 5mg/kg IV, 20mg/ kg IV, or 5mg/kg SC had mean (±SD) serum concentrations of 14±8 mcg/mL (n=3), 57±12 mcg/mL (n=3), 207±69 mcg/mL (n=6), and 32±8 mcg/mL (n=6), respectively. Conclusion: VRC07-523LS has been safe and well-tolerated at all doses and routes examined to date. Serum concentrations 4 weeks post-infusion demonstrated greater persistence and were more than 4 times higher than levels from prior studies of wildtype VRC01. The potent neutralizing activity, breadth, and extended half-life of VRC07-523LS make this antibody a leading candidate for inclusion in HIV-1 prevention and therapeutic strategies.

Poster Abstracts

CROI 2018 407