Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?
2015; Elsevier BV; Volume: 23; Issue: 10 Linguagem: Inglês
10.1016/j.tim.2015.07.005
ISSN1878-4380
AutoresMireia Pelegrín, Mar Naranjo‐Gómez, Marc Piechaczyk,
Tópico(s)CAR-T cell therapy research
ResumoAntiviral monoclonal antibodies (mAbs) are promising, high-added-value biotherapeutics. During recent years, the number of antiviral mAbs developed against both acute and chronic viruses has grown exponentially, some of them being currently tested in clinical trials. Antiviral mAbs can be used to blunt viral propagation through direct effects. They can also engage the host's immune system, leading to the induction of long-lasting protective vaccine-like effects. The assessment of mechanisms at play in the induction of vaccine-like effects by antiviral mAbs will help in improving antiviral treatments. Exploiting this effect will translate into therapeutic benefit for patients. The benefit will also help healthcare systems through the reduction of treatment costs. Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems. Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems. Although mAbs currently constitute the main class of biotherapeutics, the possibility of using them to treat viral infections has received limited attention until recently. This contrasts with cancer and inflammatory diseases against which they are now widely utilized [1Beck A. et al.Strategies and challenges for the next generation of therapeutic antibodies.Nat. Rev. Immunol. 2010; 10: 345-352Crossref PubMed Scopus (714) Google Scholar, 2Reichert J.M. 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Finally, antiviral mAbs have already demonstrated partial efficacy when administered after HIV, HCV, or Ebola virus established infections [11Qiu X. et al.Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp.Nature. 2014; 514: 47-53Crossref PubMed Scopus (819) Google Scholar, 23Barouch D.H. et al.Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys.Nature. 2013; 503: 224-228Crossref PubMed Scopus (535) Google Scholar, 24de Jong Y.P. et al.Broadly neutralizing antibodies abrogate established hepatitis C virus infection.Sci. Transl. Med. 2014; 6: 254ra129Crossref PubMed Scopus (187) Google Scholar], fueling the idea that they represent promising, high-added-value therapeutic agents. mAb therapy is a form of passive immunotherapy (see Glossary) that is classically intended to blunt viral infections via direct and rapid targeting of the infectious agent rather than via the triggering of a long-term immune response against it. This therapeutic approach contrasts with vaccine approaches that aim to stimulate the endogenous immune response of the host, in order to provide sustained protective immunity. mAbs can diminish viral dissemination by direct action involving both their antigen-binding activity and the effector functions borne by their Fc fragment. So far, most antiviral mAbs with therapeutic potential have initially (and logically) been selected for their ability to neutralize virions via the recognition of viral surface antigens essential for receptor binding and/or entry into host cells. Furthermore, direct recognition has also been shown to inhibit cell–cell transmission of virions in certain settings. Most antiviral mAbs studied to date are immunoglobulin Gs (IgGs), that is, antibodies efficiently recognized by both the complement and the Fcγ receptors (FcγRs) borne by many cells of the immune system. In addition to complement-mediated inactivation of viral particles, and/or their phagocytosis, this also permits complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC) to eliminate infected cells displaying viral antigens at their surface (Figure 1A) . This, for instance, is the case of mAbs targeting the envelope glycoprotein (Env) of HIV (and other lenti-/retroviruses) that is exposed at the surface of virus-producing cells. Finally, Fc–FcγR interactions can also directly impact viral propagation via a mechanism called antibody-dependent, cell-mediated virus inhibition (ADCVI) (see [19Euler Z. Alter G. Exploring the potential of monoclonal antibody therapeutics for HIV-1 eradication.AIDS Res. Hum. Retroviruses. 2014; 31: 13-24Crossref Scopus (42) Google Scholar, 25Forthal D.N. Moog C. Fc receptor-mediated antiviral antibodies.Curr. Opin. HIV AIDS. 2009; 4: 388-393Crossref PubMed Scopus (128) Google Scholar, 26Hessell A.J. Haigwood N.L. Neutralizing antibodies and control of HIV: moves and countermoves.Curr. HIV/AIDS Rep. 2012; 9: 64-72Crossref PubMed Scopus (21) Google Scholar, 27Su B. Moog C. Which antibody functions are important for an HIV vaccine?.Front. Immunol. 2014; 5: 289Crossref PubMed Scopus (43) Google Scholar] for more information on direct Fc-mediated antiviral effects). Thus, during immunotherapies, mAbs can impact viral propagation via a variety of direct mechanisms, possibly varying according to the virus, the viral antigen recognized and the antibody itself. However, there is now accumulating evidence that antiviral mAbs, upon interaction with different components of the immune system, can also operate via indirect mechanisms, that is, engagement of the host immune response, with effects lasting well beyond the treatment itself. Thus, similarly to vaccine approaches, mAb treatment could lead to the stimulation of the endogenous humoral and cellular immune responses in such a manner as to provide protective immunity ('vaccine-like effects'). During the immunotherapy period, antiviral mAbs form immune complexes (ICs) with virions and, in some cases, infected cells. Such ICs can then be recognized by antigen-presenting cells (APCs) such as dendritic cells (DCs), which are central for any adaptive immune responses (Figure 1B). Surprisingly, until recently, the scientific and medical communities have largely failed to take into consideration that this could impact the endogenous immunity (i.e., the enhancement of antibody responses as well as cytotoxic T-cell responses) of infected, immunotherapy-treated patients. This is all the more puzzling as positive immunomodulatory (vaccine-like) effects, which strengthen the patients' immune defenses against viral infections, would translate into obvious benefits, not only for the patients, but also for healthcare systems that would benefit from both reduced cost and duration of treatment. Several objective reasons might explain this situation. First, most antiviral mAbs (if not all) were initially selected on the basis of their blunting effects on viral propagation. Second, models of viral infections in immunocompetent animals, allowing in-depth analyses of endogenous immune responses in the context of passive mAb-based immunotherapies, are scarce. This is especially true for relevant models of chronic infections by viruses such as HIV or HCV, against which most antiviral mAbs available to date were raised. Indeed, anti-HIV (and to a lesser extent anti-HCV) mAb activity was assessed mainly in immunocompromized, humanized mice reconstituting only partially the human immune system [28Akkina R. New generation humanized mice for virus research: comparative aspects and future prospects.Virology. 2013; 435: 14-28Crossref PubMed Scopus (140) Google Scholar, 29Brehm M.A. et al.Generation of improved humanized mouse models for human infectious diseases.J. Immunol. Methods. 2014; 410: 3-17Crossref PubMed Scopus (110) Google Scholar, 30Klein F. et al.Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants.J. Exp. Med. 2014; 211: 2361-2372Crossref PubMed Scopus (69) Google Scholar, 31Lux A. Nimmerjahn F. Of mice and men: the need for humanized mouse models to study human IgG activity in vivo.J. Clin. 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Despite this apparently unfavorable context, however, evidence gained in various animal models has recently demonstrated that vaccine-like effects can be induced by short mAb therapies. These experiments are reviewed below before potential improvements of the approach are discussed. FrCasE retrovirus is a murine leukemia virus (MLV). FrCasE infection of newborn mice is reminiscent of perinatal infection by HIV, in that viral expansion occurs in an organism with developing immunity. It provides one of the rare models of chronic viral infection, in an immunocompetent animal, for which neutralizing mAbs of the same species (mouse) are available [33Portis J.L. et al.Neurodegenerative disease induced by the wild mouse ecotropic retrovirus is markedly accelerated by long terminal repeat and gag-pol sequences from nondefective Friend murine leukemia virus.J. Virol. 1990; 64: 1648-1656PubMed Google Scholar]. It was the first experimental system to permit the unambiguous demonstration of the possibility of inducing vaccine-like effects by mAb-based immunotherapy [34Gros L. et al.Induction of long-term protective antiviral endogenous immune response by short neutralizing monoclonal antibody treatment.J. Virol. 2005; 79: 6272-6280Crossref PubMed Scopus (18) Google Scholar, 35Gros L. et al.Endogenous cytotoxic T-cell response contributes to the long-term antiretroviral protection induced by a short period of antibody-based immunotherapy of neonatally infected mice.J. Virol. 2008; 82: 1339-1349Crossref PubMed Scopus (15) Google Scholar, 36Michaud H.A. et al.A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.PLoS Pathog. 2010; 6: e1000948Crossref PubMed Scopus (44) Google Scholar, 37Nasser R. et al.Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody.J. Virol. 2010; 84: 10169-10181Crossref PubMed Scopus (24) Google Scholar]. When inoculated into 8-day-old pups, FrCasE induces a fatal erythroleukemia (or neurodegeneration if inoculated earlier) associated with weak non-protective humoral and cellular antiviral immune responses. However, short treatments (a few days) with a neutralizing IgG2a (equivalent to IgG1 in humans) mAb, recognizing viral Env, shortly after infection allow infected mice to survive in good health and with a normal lifespan. Survival is associated with decreased viral propagation and, importantly, is strictly dependent on the development of a life-long protective endogenous antiviral immune response. This immunity is of the Th1 type with a humoral arm directed against the virus and a cytotoxic T-cell arm directed against infected/leukemic cells, both of them displaying strong memory responses in challenge experiments. Detailed analyses indicate that the induction of protective immunity is not the mere result of the reduction of the viral load during the immunotherapy but the consequence of a genuine immunomodulatory action of the therapeutic mAb involving various FcγR-dependent mechanisms [36Michaud H.A. et al.A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.PLoS Pathog. 2010; 6: e1000948Crossref PubMed Scopus (44) Google Scholar, 37Nasser R. et al.Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody.J. Virol. 2010; 84: 10169-10181Crossref PubMed Scopus (24) Google Scholar]. In particular, the mAb induces Env-expressing infected cell lysis through a natural killer (NK) cell-dependent ADCC mechanism. This most likely provides an inflammatory environment favoring the induction of the antiviral immune response. Moreover, ICs formed with infected cells are more efficiently captured by DCs than infected cells alone, leading to stronger functional DC activation and elicitation of a potent antiviral cytotoxic T lymphocyte (CTL) response (Figure 2, Key Figure). Importantly, the endogenous antiviral antibodies generated by the immunotherapy allow containment of viral propagation and contribute to the maintenance of a T-cell memory response once the therapeutic antibody has been eliminated from treated mice [36Michaud H.A. et al.A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.PLoS Pathog. 2010; 6: e1000948Crossref PubMed Scopus (44) Google Scholar, 37Nasser R. et al.Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody.J. Virol. 2010; 84: 10169-10181Crossref PubMed Scopus (24) Google Scholar]. A third FcγR-dependent effect described is the inhibition of the expansion of regulatory T cells (Treg), which is essential for the induction of protective immunity [38Nasser R. et al.Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies.Blood. 2013; 121: 1102-1111Crossref PubMed Scopus (19) Google Scholar] (Figure 2). Such a finding is, in fact, not surprising as Treg expansion is associated with all types of chronic viral infections and leads to dampening of the antiviral immune response, promoting chronicity and subsequent pathologic manifestations. Thus, the FrCasE model has provided the proof of concept that short mAb-based antiviral therapies can induce life-long protective immunity permitting an infected organism to survive in good health. Yet, a number of issues are still pending. In particular, it will be crucial to identify all of the cell types and molecular effectors involved in this process as well as to elucidate the mechanisms whereby long-term immunity is maintained in order to apply it to the treatment of human disease. Antiviral immune responses induced, or strengthened, by antiviral mAb-based immunotherapies have also been observed in various chronic and acute life-threatening human viruses (see summary in Table 1). This is most notable in preclinical NHP models of HIV infection using second-generation, broadly neutralizing antibodies (bnAbs). Such observations are all the more important now that these mAbs are being tested in clinical trials.Table 1Antiviral Immune Responses Induced by Antiviral Monoclonal Antibodies (mAbs) Against Life-Threatening Human VirusesaAbbreviations: ADCVI, antibody-dependent cell-mediated viral inhibition; CTL, cytotoxic T lymphocyte; IL-4, interleukin-4; IFN-γ: interferon-γ; i.p., intraperitoneal; i.v., intravenous; nAbs, neutralizing antibodies; N.D., not determined; RSV, respiratory syncytial virus; SIVIG/SHIV, highly neutralizing polyclonal immune globulin prepared from hyperimmune SIV/SHIV-infected animals; s.c., subcutaneous; Tfh, follicular helper T cells.Animal ModelVirusTherapeutic AntibodyAdministrationClinical OutcomeCellular ResponseHumoral ResponseRefsRhesus monkeys(Macaca mulatta)SIV smE660(i.v.)SIVIGi.v.(1 and 14 days post-infection)Delayed disease, increased survival rate;control of viremia (5-year follow-up)No difference in CD4+ T-cell counts,30% animals develop an antiviral CTL responseAcceleration of de novo nAb production39Haigwood N.L. et al.Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies.J. Virol. 2004; 78: 5983-5995Crossref PubMed Scopus (92) Google ScholarRhesus monkeys(Macaca mulatta)SIV mac239(intramuscular)SIVIGi.v.(7 days post-infection)Reduction of viral loadsPolyfunctional Gag-specific T-cell responseTransient nAb response40Yamamoto T. et al.Polyfunctional CD4+ T-cell induction in neutralizing antibody-triggered control of simian immunodeficiency virus infection.J. Virol. 2009; 83: 5514-5524Crossref PubMed Scopus (39) Google Scholar, 41Yamamoto H. et al.Post-infection immunodeficiency virus control by neutralizing antibodies.PLoS ONE. 2007; 2: e540Crossref PubMed Scopus (40) Google ScholarPigtail macaques(Macaca nemestrina)SHIVSF162P3(oral)SHIVIG + IgG1b12s.c.(24 h before challenge)Transient reduction in plasma viremia(6 months)No difference in CD4+ T-cell countsRapid appearance of nAb43Ng C.T. et al.Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques.Nat. Med. 2010; 16: 1117-1119Crossref PubMed Scopus (125) Google ScholarRhesus monkeys(Macaca mulatta)SHIVSF162P3(oral)SHIVIGs.c.(24 h before challenge)Protection from diseaseNo difference in total Gag-specific CD8+ T-cell responsePreservation of B cells: de novo nAb production(ADCVI)44Jaworski J.P. et al.Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques.J. Virol. 2013; 87: 10447-10459Crossref PubMed Scopus (36) Google ScholarRhesus monkeys(Macaca mulatta)SHIVSF162P3(Intrarectal)PGT121+3BNC117+b12;PGT121+3BNC117;PGT121i.v.(9 months post-infection)Decline in plasma viremiaImproved functionality of Gag-specific T-cell responsede novo nAb to SHIV-SF162P323Barouch D.H. et al.Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys.Nature. 2013; 503: 224-228Crossref PubMed Scopus (535) Google ScholarRhesus monkeys(Macaca mulatta)SHIV-1157ipEL-p(Intrarectal)HGN194i.v.(1 day beforeinfection and 7 days post-infection)Aviremia,protection not reportedGag-specific T-cell responseN.D.46Watkins J.D. et al.An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV.PLoS ONE. 2011; 6: e18207Crossref PubMed Scopus (70) Google ScholarBALB/c miceRSV r19F(Intranasal)131-2G mAbi.p.(2 days before infection)Decreased virus replicationIncreased Thf counts;decreased IL4, increased IFN-γ+ T cells;high counts of virus-specific CD8+ T cellsEnhanced humoral response47Boyoglu-Barnum S. et al.Prophylaxis with a respiratory syncytial virus (RSV) anti-G protein monoclonal antibody shifts the adaptive immune response to RSV rA2-line19F infection from Th2 to Th1 in BALB/c mice.J. Virol. 2014; 88: 10569-10583Crossref PubMed Scopus (46) Google ScholarAfrican Green monkeys(Chlorocebus aethiops)HeV(Intratracheally)m102.4i.v.(10 h, 24 h or 72 h post-infection and 48 h later)Reduced viral loadsN.D.Anti-HeV humoral response50Bossart K.N. et al.A neutralizing human monoclonal antibody protects African Green monkeys from hendra virus challenge.Sci. Transl. Med. 2011; 3: 105ra103Crossref PubMed Scopus (120) Google ScholarAfrican Green monkeys(Chlorocebus aethiops)NiV(Intratracheally)m102.4i.v.(24 h, 72 h, 60 h post-infection and 48 h later)ProtectionN.D.Antiviral humoral response51Geisbert T.W. et al.Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody.Sci. Transl. Med. 2014; 6: 242ra282Crossref Scopus (103) Google Scholara Abbreviations: ADCVI, antibody-dependent cell-mediated viral inhibition; CTL, cytotoxic T lymphocyte; IL-4, interleukin-4; IFN-γ: interferon-γ; i.p., intraperitoneal; i.v., intravenous; nAbs, neutralizing antibodies; N.D., not determined; RSV, respiratory syncytial virus; SIVIG/SHIV, highly neutralizing polyclonal immune globulin prepared from hyperimmune SIV/SHIV-infected animals; s.c., subcutaneous; Tfh, follicular helper T cells. Open table in a new tab Infection of macaques by different strains of SIV is widely used in NHP models of HIV infection, as well as in immunotherapy experiments. Several reports now indicate that short treatments of SIV-infected macaques with neutralizing antibodies can lead to enhanced antiviral immunity [39Haigwood N.L. et al.Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies.J. Virol. 2004; 78: 5983-5995Crossref PubMed Scopus (92) Google Scholar, 40Yamamoto T. et al.Polyfunctional CD4+ T-cell induction in neutralizing antibody-triggered control of simian immunodeficiency virus infection.J. Virol. 2009; 83: 5514-5524Crossref PubMed Scopus (39) Google Scholar]. However, these experiments were performed with SIV-specific, highly neutralizing, polyclonal immune globulins (SIVIG) prepared from SIV-infected animals and not mAbs. In a first study, the SIVIG treatment could both significantly delay disease onset and increase the survival rate of SIVsmE660-infected Macaca mulatta macaques, with the long-term survivors showing accelerated de novo production of anti-SIV-neutralizing antibodies [39Haigwood N.L. et al.Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies.J. Virol. 2004; 78: 5983-5995Crossref PubMed Scopus (92) Google Scholar]. In another set of experiments, rhesus macaques treated with SIVIG shortly after SIVmac239 infection resulted in transiently detectable neutralizing-antibody responses followed by reduction in viral loads as compared to untreated macaques [41Yamamoto H. et al.Post-infection immunodeficiency virus control by neutralizing antibodies.PLoS ONE. 2007; 2: e540Crossref PubMed Scopus (40) Google Scholar]. Interestingly, a virus-specific polyfunctional CD4+ T-cell response was also induced during the acute phase of infection and maintained elevated during the following chronic phase together with a CD8+ T-cell antiviral response measured by the appearance of CTLs specific to capsid (Gag). Intriguingly, no neutralizing antibodies could be measured during the latter phase (i.e., after SIVIG had disappeared) [40Yamamoto T. et al.Polyfunctional CD4+ T-cell induction in neutralizing antibody-triggered control of simian immunodeficiency virus infection.J. Virol. 2009; 83: 5514-5524Crossref PubMed Scopus (39) Google Scholar], underlining a striking difference with the M. mulata macaque and FrCasE models for reasons that will have to be elucidated. Moreover, DCs stimulated in vitro with SIVIG-preincubated SIV were shown to activate virus-specific CD4+ T lymphocytes in an Fc-dependent manner, suggesting that enhanced T-cell priming during the immunotherapy period is dependent on antibody-mediated virion uptake by these APCs [41Yamamoto H. et al.Post-infection immunodeficiency virus control by neutralizing antibodies.PLoS ONE. 2007; 2: e540Crossref PubMed Scopus (40) Google Scholar]. Such a conclusion is consistent with a former observation that MHC class I-restricted cross-presentation of SIV capsid protein (Gag) is enhanced by anti-Gag antibodies to generate stronger Gag-specific CD8+ T-cell responses in SIV-infected macaques [42Villinger F. et al.Evidence for antibody-mediated enhancement of simian immunodeficiency virus (SIV) Gag antigen processing and cross presentation in SIV-infected rhesus macaques.J. Virol. 2003; 77: 10-24Crossref PubMed Scopus (46) Google Scholar]. Thus, taken together, these experiments suggest that the administration of neutralizing antibodies can strengthen the antiviral immunity of lentivirus-infected organisms. Some of them also po
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