Phase 1 trial evaluating safety and pharmacokinetics of HIV-1 broadly neutralizing mAbs 10E8VLS and VRC07-523LS
Seemal F. Awan, Amarendra Pegu, Larisa Strom, Cristina A. Carter, Cynthia S. Hendel, LaSonji A. Holman, Pamela J. Costner, Olga Trofymenko, Renunda Dyer, Ingelise J. Gordon, Ro Shauna S. Rothwell, Somia P. Hickman, Michelle Conan-Cibotti, Nicole A. Doria-Rose, Bob C. Lin, Sarah O’Connell, Sandeep R. Narpala, Cassandra G. Almasri, Cuiping Liu, Sungyoul Ko, Young D. Kwon, Aryan M. Namboodiri, Janardan P. Pandey, Frank J. Arnold, Kevin Carlton, Jason G. Gall, Peter D. Kwong, Edmund V. Capparelli, Robert T. Bailer, Adrian B. McDermott, Grace L. Chen, Richard A. Koup, John R. Mascola, Emily E. Coates, Julie E. Ledgerwood, Martin R. Gaudinski, the VRC 610 study team
Seemal F. Awan, Amarendra Pegu, Larisa Strom, Cristina A. Carter, Cynthia S. Hendel, LaSonji A. Holman, Pamela J. Costner, Olga Trofymenko, Renunda Dyer, Ingelise J. Gordon, Ro Shauna S. Rothwell, Somia P. Hickman, Michelle Conan-Cibotti, Nicole A. Doria-Rose, Bob C. Lin, Sarah O’Connell, Sandeep R. Narpala, Cassandra G. Almasri, Cuiping Liu, Sungyoul Ko, Young D. Kwon, Aryan M. Namboodiri, Janardan P. Pandey, Frank J. Arnold, Kevin Carlton, Jason G. Gall, Peter D. Kwong, Edmund V. Capparelli, Robert T. Bailer, Adrian B. McDermott, Grace L. Chen, Richard A. Koup, John R. Mascola, Emily E. Coates, Julie E. Ledgerwood, Martin R. Gaudinski, the VRC 610 study team
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Clinical Research and Public Health AIDS/HIV Clinical trials

Phase 1 trial evaluating safety and pharmacokinetics of HIV-1 broadly neutralizing mAbs 10E8VLS and VRC07-523LS

Abstract

BACKGROUND Broadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODS In this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non–HIV-infected individuals.RESULTS Eight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION 10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATION Clinicaltrials.gov, accession no. NCT03565315.FUNDING Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.

Authors

Seemal F. Awan, Amarendra Pegu, Larisa Strom, Cristina A. Carter, Cynthia S. Hendel, LaSonji A. Holman, Pamela J. Costner, Olga Trofymenko, Renunda Dyer, Ingelise J. Gordon, Ro Shauna S. Rothwell, Somia P. Hickman, Michelle Conan-Cibotti, Nicole A. Doria-Rose, Bob C. Lin, Sarah O’Connell, Sandeep R. Narpala, Cassandra G. Almasri, Cuiping Liu, Sungyoul Ko, Young D. Kwon, Aryan M. Namboodiri, Janardan P. Pandey, Frank J. Arnold, Kevin Carlton, Jason G. Gall, Peter D. Kwong, Edmund V. Capparelli, Robert T. Bailer, Adrian B. McDermott, Grace L. Chen, Richard A. Koup, John R. Mascola, Emily E. Coates, Julie E. Ledgerwood, Martin R. Gaudinski, the VRC 610 study team

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Figure 6

Binding to preadipocytes and adipocytes by 10E8VLS and VRC01LS followed by IL-5 secretion.

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Binding to preadipocytes and adipocytes by 10E8VLS and VRC01LS followed ...
(A) Binding of 10E8VLS or VRC01LS to primary human preadipocytes — or in vitro–differentiated adipocytes derived from 3 healthy donors at concentrations of 50, 25, and 12.5 mg/mL — was detected using an HRP-conjugated secondary antibody. The OD450 values indicative of binding are shown for each antibody concentration tested for each donor; the bar denotes the mean, with the error bars representing the SEM. (B) Primary human preadipocytes and adipocytes from 3 healthy donors were incubated with 50, 25, and 12.5 mg/mL 10E8VLS or VRC01LS. Culture supernatant was taken after a 4.5-hour incubation and assayed for secreted cytokine levels by a multiplex assay. The IL-5 levels are shown for each antibody concentration tested for each donor; the bar denotes the mean, with the error bars representing the SEM. For statistical analysis, a 2-way ANOVA using the Šidák multiple-comparison test was performed. ****P < 0.0001.