Long-Lasting Protective Antiviral Immunity Induced by Passive Immunotherapies Requires both Neutralizing and Effector Functions of the Administered Monoclonal Antibody

Abstract

Using FrCasE retrovirus-infected newborn mice as a model system, we have shown recently that a longlasting antiviral immune response essential for healthy survival emerges after a short treatment with a neutralizing (667) IgG2a isotype monoclonal antibody (MAb). This suggested that the mobilization of adaptive immunity by administered MAbs is key for the success in the long term for the MAb-based passive immunotherapy of chronic viral infections. We have addressed here whether the anti-FrCas E protective endogenous immunity is the mere consequence of viral propagation blunting, which would simply give time to the immune system to react, and/or to actual immunomodulation by the MAb during the treatment. To this aim, we have compared viral replication, disease progression, and antiviral immune responses between different groups of infected mice: (i) mice treated with either the 667 MAb, its F(ab) 2 fragment, or an IgM (672) with epitopic specificity similar to that of 667 but displaying different effector functions, and (ii) mice receiving no treatment but infected with a low viral inoculum reproducing the initial viral expansion observed in their infected/667 MAb-treated counterparts. Our data show that the reduction of FrCas E propagation is insufficient on its own to induce protective immunity and support a direct immunomodulatory action of the 667 MAb. Interestingly, they also point to sequential actions of the administered MAb. In a first step, viral propagation is exclusively controlled by 667 neutralizing activity, and in a second one, this action is complemented by Fc␥R-bindingdependent mechanisms, which most likely combine infected cell cytolysis and the modulation of the antiviral endogenous immune response. Such complementary effects of administered MAbs must be taken into consideration for the improvement of future antiviral MAb-based immunotherapies.Although monoclonal antibodies (MAbs) principally have been considered for anticancer applications heretofore (62, 64), they now are increasingly being considered to treat severe acute and chronic viral infections (43,63,83). The best-studied antiviral MAbs are (i) pavalizumab, a humanized anti-respiratory syncytial virus (RSV) MAb approved by the FDA in 1998 for treating severe lower-respiratory-tract diseases in infants (45); (ii) several anti-human immunodeficiency virus (HIV) MAbs, which have been used in macaque preclinical infection models and in several human trials (4, 5, 19, 27-30, 32, 42, 50, 55, 57, 76-79); and (iii) a few anti-hepatitis C virus (HCV) MAbs, some of which currently are being tested in humans (9,22,40). However, other MAbs, some of them of human origin, also have been generated against other human viruses in recent years. Among them are antibodies against Ebola virus (75), West Nile virus (WNV) (48,53,54), cytomegalovirus (CMV) (11), avian and human influenza viruses (59,60,73,74), severe acute respiratory syndrome coronavirus (SARS CoV) (81), hepatitis B virus (HBV) (31, 35), Hanta virus (80, 82), and Nipah virus (80,82). These ...

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

“…[20][21][22][23][24] This has potentially important therapeutical consequences for the treatment of patients infected with life-threatening chronic viruses. In the present study, we report …”

“…We have previously reported a crucial role for the Fc␥R-binding function of 667 and ruled out a significant contribution for its complement-binding function in the induction of protective antiviral immunity. 23,24 Moreover, we have also described previously a critical role for the interaction between DCs and ICs involving infected cells in this effect. 24 It is therefore possible that enhanced activation of DCs by cellular ICs may not only favor the activation of antiviral CTLs, but also may tip the balance of CD4 ϩ Th/Treg cells toward Treg differentiation.…”

“…[20][21][22][23][24] Mice were examined daily for clinical signs of neurodegeneration or erythroleukemia. [20][21][22][23][24] Plasma anti-FrCas E serum Igs were assayed by ELISA as described previously. 20,27 For challenge experiments, mice were injected intravenously with a mixture containing 25 L of FrCas E suspension (5 ϫ 10 5 FFU/mL) and 1 ϫ 10 6 infected fresh splenocytes.…”

“…19 The direct effects of mAbs, such as inhibition of soluble effectors or of cell membrane signaling receptors, virus neutralization, and NK-dependent (antibody-dependent cell-mediated cytotoxicity) or complement-dependent cytolysis on their targets are, in general, well studied. 12 In addition, we have shown recently that short neutralizing mAb-based immunotherapies may exert immunomodulatory effects translating into life-long immune protection (see end of "Introduction"), [20][21][22][23][24] which has potentially important consequences for treating life-threatening viral diseases in humans. The recent demonstration that passive neutralizing mAbs could not only control viremia in young macaques infected with a hybrid simian HIV strain, but also enhance B-cell responses in a perinatal setting 16 further supports this concept.…”

Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity

“…The development of these immune responses is not the result of the direct reduction of the viral load by the mAb that would permit the immune system reaction, but of a bona fide immunomodulatory effect of the mAb through its interaction with the IgG Fc-receptors. 25,26 Indeed these longterm protective effects depend on two Fc-dependent mechanisms: (i) the activation of dendritic cells (DC) by cellular immune complexes composed of the administered mAb and infected cells 26 and (ii) the inhibition of the regulatory T cell expansion, which is normally observed in untreated animals. 27 Altogether, these data suggest that mAbs targeting TA or viral antigens in infected cells can interact with the host immune system in a Fc-dependent manner to induce an adaptive memory immune response for long-lasting protection in vivo ( Table 1).…”