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Abstract
Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.
Highlights
IntroductionMonoclonal antibodies (mAbs) constitute the largest class of biomedical proteins [1]
Monoclonal antibodies constitute the largest class of biomedical proteins [1]
We showed that a short 667 Monoclonal antibodies (mAbs) treatment prevents infected animals from developing erythroleukemia by comparing FrCasE-infected, 667 mAb-treated mice to 3 control groups: (i) infected mice not treated with 667, (ii) infected mice treated with an isotypematched control mAb and (iii) non-infected mice receiving 667. 667 was administered 3 times: 1 hour after virus inoculation, which is a time sufficient for the establishment of infection, and 2and 5 days later
Summary
Monoclonal antibodies (mAbs) constitute the largest class of biomedical proteins [1]. One can cite neutralizing mAbs against Ebola- [3], West Nile (WNV)- [4], cytomegalo (CMV)- [5], avian H5N1- [6] and human influenza- [6,7], severe acute respiratory syndrome (SARS)- [8], respiratory syncytial (RSV)[9], hepatitis B (HBV)- [10], hepatitis C (HCV)- [11] and human immunodeficiency virus (HIV) [1,12] that have shown antiviral activity in preclinical studies. Certain viral antigens expressed at the surface of infected cells, such as envelope glycoproteins (Env) of immunodeficiency-inducing viruses, like HIV, or of cancer-inducing viruses, Author Summary
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