PMID- 26400911 OWN - NLM STAT- MEDLINE DCOM- 20160708 LR - 20181113 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 7 IP - 306 DP - 2015 Sep 23 TI - Broadly neutralizing human monoclonal JC polyomavirus VP1-specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy. PG - 306ra150 LID - 10.1126/scitranslmed.aac8691 [doi] AB - In immunocompromised individuals, JC polyomavirus (JCPyV) may mutate and gain access to the central nervous system resulting in progressive multifocal leukoencephalopathy (PML), an often fatal opportunistic infection for which no treatments are currently available. Despite recent progress, the contribution of JCPyV-specific humoral immunity to controlling asymptomatic infection throughout life and to eliminating JCPyV from the brain is poorly understood. We examined antibody responses against JCPyV major capsid protein VP1 (viral protein 1) variants in the serum and cerebrospinal fluid (CSF) of healthy donors (HDs), JCPyV-positive multiple sclerosis patients treated with the anti-VLA-4 monoclonal antibody natalizumab (NAT), and patients with NAT-associated PML. Before and during PML, CSF antibody responses against JCPyV VP1 variants show "recognition holes"; however, upon immune reconstitution, CSF antibody titers rise, then recognize PML-associated JCPyV VP1 variants, and may be involved in elimination of the virus. We therefore reasoned that the memory B cell repertoire of individuals who recovered from PML could be a source for the molecular cloning of broadly neutralizing antibodies for passive immunization. We generated a series of memory B cell-derived JCPyV VP1-specific human monoclonal antibodies from HDs and a patient with NAT-associated PML-immune reconstitution inflammatory syndrome (IRIS). These antibodies exhibited diverse binding affinity, cross-reactivity with the closely related BK polyomavirus, recognition of PML-causing VP1 variants, and JCPyV neutralization. Almost all antibodies with exquisite specificity for JCPyV, neutralizing activity, recognition of all tested JCPyV PML variants, and high affinity were derived from one patient who had recovered from PML. These antibodies are promising drug candidates for the development of a treatment of PML. CI - Copyright (c) 2015, American Association for the Advancement of Science. FAU - Jelcic, Ivan AU - Jelcic I AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Combaluzier, Benoit AU - Combaluzier B AD - Neurimmune Holding AG, 8952 Schlieren, Switzerland. FAU - Jelcic, Ilijas AU - Jelcic I AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Faigle, Wolfgang AU - Faigle W AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Senn, Luzia AU - Senn L AD - Neurimmune Holding AG, 8952 Schlieren, Switzerland. FAU - Reinhart, Brenda J AU - Reinhart BJ AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Stroh, Luisa AU - Stroh L AD - Interfaculty Institute of Biochemistry, University of Tubingen, 72076 Tubingen, Germany. FAU - Nitsch, Roger M AU - Nitsch RM AD - Neurimmune Holding AG, 8952 Schlieren, Switzerland. Division of Psychiatry Research, University of Zurich, 8952 Schlieren, Switzerland. FAU - Stehle, Thilo AU - Stehle T AD - Interfaculty Institute of Biochemistry, University of Tubingen, 72076 Tubingen, Germany. Vanderbilt University School of Medicine, Nashville, TN 37232, USA. FAU - Sospedra, Mireia AU - Sospedra M AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Grimm, Jan AU - Grimm J AD - Neurimmune Holding AG, 8952 Schlieren, Switzerland. roland.martin@usz.ch jan.grimm@neurimmune.com. FAU - Martin, Roland AU - Martin R AD - Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. roland.martin@usz.ch jan.grimm@neurimmune.com. LA - eng GR - P01 NS065719/NS/NINDS NIH HHS/United States GR - P01-NS065719/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150923 PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) SB - IM MH - Antibodies, Monoclonal/*immunology MH - Antibodies, Neutralizing/*immunology MH - Antibodies, Viral/*immunology MH - Antibody Formation MH - Humans MH - JC Virus/*immunology MH - Leukoencephalopathy, Progressive Multifocal/*therapy PMC - PMC4820754 MID - NIHMS772250 COIS- Competing interests: B.C., Ivan J., R.M., and J.G. are listed as inventors on a patent of the human monoclonal antibodies against JCPyV VP1 for the treatment of PML. J.G. and R.N. are employees and shareholders of Neurimmune. B.C. and L. Senn are employees of Neurimmune. The remaining authors declare no competing interests. EDAT- 2015/09/25 06:00 MHDA- 2016/07/09 06:00 PMCR- 2016/04/05 CRDT- 2015/09/25 06:00 PHST- 2015/06/25 00:00 [received] PHST- 2015/08/27 00:00 [accepted] PHST- 2015/09/25 06:00 [entrez] PHST- 2015/09/25 06:00 [pubmed] PHST- 2016/07/09 06:00 [medline] PHST- 2016/04/05 00:00 [pmc-release] AID - 7/306/306ra150 [pii] AID - 10.1126/scitranslmed.aac8691 [doi] PST - ppublish SO - Sci Transl Med. 2015 Sep 23;7(306):306ra150. doi: 10.1126/scitranslmed.aac8691. Epub 2015 Sep 23.