Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

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.

JC Polyomavirus Attachment and Entry: Potential Sites for PML Therapeutics

“…These findings further demonstrate that VP1 is a key target for antivirals and activation of humoral and cell-mediated immunity [31]. Recent studies have focused on vaccine or mAb therapies in combination with treatments to boost VP1-specific immunity (Table 1).…”

“…This treatment led to JCPyV clearance with an undetectable viral load and patient recovery [30]. Interestingly, sera isolated from PML patients can effectively neutralize wild-type JCPyV, yet does not neutralize virus with PML-associated mutations, while sera from healthy patients can neutralize wild-type and PML variants [29, 31]. These findings suggest that patients who develop PML have antibody “recognition holes” during immunosuppression, and their antibodies cannot neutralize variants with PML-associated mutations such as L55F, S266F, and S269F [29, 31].…”

“…As there are currently limited treatment options to manage JCPyV and PML, the development of an effective anti-JCPyV therapy would represent a major breakthrough. Several treatment strategies have been developed in recent years as potential methods to reduce PML disease burden including vaccines [29, 30], broadly neutralizing anti-JCPyV VP1 antibodies [31], and small molecule inhibitors [22, 32, 33]. This review summarizes the findings on JCPyV attachment, entry, and trafficking and illuminates the development of potential therapeutics targeted to block these early steps in the virus life cycle to prevent or treat PML.…”

Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

“…The high frequency of amino acid mutations in VP1 close to or at the receptor binding site in isolates of JCV from PML patients suggests that subtle changes in binding affinity for sialylated receptors can significantly affect viral pathogenicity (70). Recent evidence indicates that mutations in VP1 may serve to enable escape from neutralizing JCV antibodies (71,72). PML nonsurvivors had selectively impaired JCV-specific CD8 T cell responses (16,73).…”

Exposing the Molecular Machinery of BK Polyomavirus

“…Such antibodies could either be induced through vaccination or administered as recombinant monoclonals (mAbs). The first human mAbs capable of binding BKV virions were reported late last year (Jelcic et al, 2015). It is not yet clear whether the mAbs are capable of neutralizing the infectivity of BKV.…”