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Broadly neutralizing human monoclonal JC polyomavirus VP1-specific antibodies as candidate therapeutics for
Ivan Jelcic1, Benoit Combaluzier2, Ilijas Jelcic1
1Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
Abstract:
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.
Insights
JC polyomavirus (JCPyV) can cause fatal progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. Researchers identified potent neutralizing antibodies from a PML survivor, offering hope for new JCPyV treatments.
Area of Science:
- Neurovirology
- Immunology
- Infectious Diseases
Background:
- JC polyomavirus (JCPyV) reactivation in immunocompromised individuals can lead to progressive multifocal leukoencephalopathy (PML), a severe and often fatal central nervous system infection.
- Current treatments for PML are lacking, highlighting the urgent need for therapeutic interventions.
- The role of JCPyV-specific humoral immunity in controlling infection and viral clearance from the brain remains incompletely understood.
Purpose of the Study:
- To investigate antibody responses against JC polyomavirus (JCPyV) major capsid protein VP1 variants in different patient cohorts.
- To explore the potential of memory B cells from recovered individuals as a source for broadly neutralizing antibodies against JCPyV.
- To identify promising antibody candidates for the development of a passive immunization treatment for progressive multifocal leukoencephalopathy (PML).
Main Methods:
- Analysis of antibody responses in serum and cerebrospinal fluid (CSF) from healthy donors, natalizumab-treated patients, and patients with PML.
- Generation and characterization of human monoclonal antibodies from memory B cells targeting JCPyV VP1 variants.
- Assessment of antibody binding affinity, cross-reactivity, recognition of PML-associated variants, and JCPyV neutralization capacity.
Main Results:
- CSF antibody responses against JCPyV VP1 variants exhibited 'recognition holes' before and during PML, but increased and recognized PML-associated variants upon immune reconstitution.
- Monoclonal antibodies derived from a PML survivor demonstrated potent JCPyV neutralization, high affinity, and broad recognition of PML-associated VP1 variants.
- Antibodies from the PML survivor showed exquisite specificity for JCPyV and cross-reactivity with BK polyomavirus, indicating potential therapeutic value.
Conclusions:
- Immune reconstitution following PML may involve the generation of antibodies capable of recognizing and potentially eliminating JCPyV.
- Memory B cells from individuals who recovered from PML are a valuable source for discovering broadly neutralizing antibodies against JCPyV.
- These identified JCPyV-specific monoclonal antibodies represent promising therapeutic candidates for treating progressive multifocal leukoencephalopathy (PML).
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