A clinical trial of non-invasive imaging with an anti-HIV antibody labelled with copper-64 in people living with HIV and uninfected controls
James H. McMahon,
Jennifer M. Zerbato,
Jillian S.Y. Lau,
Jaclyn L. Lange,
Michael Roche,
Carolin Tumpach,
Ashanti Dantanarayana,
Ajantha Rhodes,
Judy Chang,
Thomas A. Rasmussen,
Charlene A. Mackenzie,
Karen Alt,
Michelle Hagenauer,
Janine Roney,
Jessica O‘Bryan,
Alexandra Carey,
Richard McIntyre,
Paul Beech,
Graeme J. O'Keefe,
Christian W. Wichmann,
Fiona E. Scott,
Nancy Guo,
Sze-Ting Lee,
Zhanqi Liu,
Marina Caskey,
Michel C. Nussenzweig,
Paul S. Donnelly,
Gary Egan,
Christoph E. Hagemeyer,
Andrew M. Scott,
Sharon R. Lewin
Affiliations
James H. McMahon
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia; Department of Infectious Diseases, Monash Health, Melbourne, Australia; Corresponding author at: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
Jennifer M. Zerbato
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Jillian S.Y. Lau
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
Jaclyn L. Lange
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
Michael Roche
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Carolin Tumpach
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Ashanti Dantanarayana
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Ajantha Rhodes
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Judy Chang
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Thomas A. Rasmussen
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Charlene A. Mackenzie
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Karen Alt
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
Michelle Hagenauer
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
Janine Roney
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
Jessica O‘Bryan
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia; Department of Infectious Diseases, Monash Health, Melbourne, Australia
Alexandra Carey
Monash Biomedical Imaging, Monash University, Melbourne, Australia
Richard McIntyre
Monash Biomedical Imaging, Monash University, Melbourne, Australia
Paul Beech
Monash Biomedical Imaging, Monash University, Melbourne, Australia
Graeme J. O'Keefe
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Christian W. Wichmann
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Fiona E. Scott
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Nancy Guo
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Sze-Ting Lee
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Zhanqi Liu
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Marina Caskey
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, United States
Michel C. Nussenzweig
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, United States; Howard Hughes Medical Institute, The Rockefeller University, New York, NY, United States
Paul S. Donnelly
School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia
Gary Egan
Monash Biomedical Imaging, Monash University, Melbourne, Australia
Christoph E. Hagemeyer
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
Andrew M. Scott
Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia
Sharon R. Lewin
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia; The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Background: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH). Methods: Unmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and 64Cu (64Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial 64Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg 64Cu-3BNC117) and trace (<5mg 64Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for 64Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract). Findings: Comparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that 64Cu-3BNC117 remained intact in vivo. Interpretation: In PLWH on or off ART, the intervention of infusing 64Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo. Funding: Funded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (U19AI096109). JHM and SRL are supported by the Australian National Health and Medical Research Council.
