Publication Date:
2015-04-10
Description:
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Caskey, Marina -- Klein, Florian -- Lorenzi, Julio C C -- Seaman, Michael S -- West, Anthony P Jr -- Buckley, Noreen -- Kremer, Gisela -- Nogueira, Lilian -- Braunschweig, Malte -- Scheid, Johannes F -- Horwitz, Joshua A -- Shimeliovich, Irina -- Ben-Avraham, Sivan -- Witmer-Pack, Maggi -- Platten, Martin -- Lehmann, Clara -- Burke, Leah A -- Hawthorne, Thomas -- Gorelick, Robert J -- Walker, Bruce D -- Keler, Tibor -- Gulick, Roy M -- Fatkenheuer, Gerd -- Schlesinger, Sarah J -- Nussenzweig, Michel C -- HHSN261200800001E/PHS HHS/ -- U19AI111825-01/AI/NIAID NIH HHS/ -- UL1 TR000043/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 25;522(7557):487-91. doi: 10.1038/nature14411. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. ; 1] First Department of Internal Medicine, University Hospital of Cologne, D-50924 Cologne, Germany [2] Clinical Trials Center Cologne, ZKS Koln, BMBF 01KN1106, University of Cologne, Cologne, Germany. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Albert Ludwigs University of Freiburg, 79085 Freiburg, Germany. ; 1] First Department of Internal Medicine, University Hospital of Cologne, D-50924 Cologne, Germany [2] German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Division of Infectious Diseases, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Celldex Therapeutics, Inc., Hampton, New Jersey 08827, USA. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Ragon Institute of MGH, MIT and Harvard, Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA. ; Division of Infectious Diseases, Weill Medical College of Cornell University, New York, New York 10065, USA. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855300" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Amino Acid Sequence
;
Antibodies, Monoclonal/administration &
;
dosage/immunology/pharmacokinetics/therapeutic use
;
Antibodies, Neutralizing/administration & dosage/adverse
;
effects/*immunology/pharmacology/therapeutic use
;
Antigens, CD4/metabolism
;
Binding Sites
;
Case-Control Studies
;
Evolution, Molecular
;
Female
;
HIV Antibodies/administration & dosage/adverse
;
effects/*immunology/pharmacology/therapeutic use
;
HIV Envelope Protein gp120/chemistry/immunology
;
HIV Infections/immunology/*therapy/virology
;
HIV-1/chemistry/drug effects/*immunology
;
Humans
;
Immunization, Passive/methods
;
Male
;
Middle Aged
;
Molecular Sequence Data
;
Time Factors
;
Viral Load/drug effects/*immunology
;
Viremia/immunology/*therapy/virology
;
Young Adult
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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