- Email: [email protected]
Perspectives for the utilization of neutralizing human monoclonal antibodies as anti-HCV drugs
Journal of Hepatology 49 (2008) 299–302 www.elsevier.com/locate/jhep
Journal Clubs Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Perspectives for the utilization of neutralizing human monoclonal antibodies as anti-HCV drugs q Roberto Burioni*, Mario Perotti, Nicasio Mancini, Massimo Clementi Laboratorio di Microbiologia e Virologia, Universita` Vita-Salute San Raffaele, Istituto Scientifico San Raffaele, San Raffaele Diagnostica e Ricerca, Milan, Italy
Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI, Ball JK, McKeating JA, Kneteman NM, Burton DR. A major problem in hepatitis C virus (HCV) immunotherapy or vaccine design is the extreme variability of the virus. We identified human monoclonal antibodies (mAbs) that neutralize genetically diverse HCV isolates and protect against heterologous HCV quasispecies challenge in a human liver-chimeric mouse model. The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable. [Abstract reproduced by permission of Nat Med 2008;14:25–27]. The hepatitis C virus (HCV) is characterized by a great variability, due to its ability to evade the host immune response and to establish a persistent infection. Virus replication seems unaffected by strong antibody responses in persistently infected patients and subjects who have recovered from acute infection can be readily reinfected suggesting the concept that humoral immune
q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +39 02 2643 3023; fax: +39 02 2643 4288. E-mail address: [email protected] (R. Burioni).
response is not a key element in protection against HCV. Law et al. [1] passively administered to mice, genetically engineered to support the transplant of a large population of human liver cells, a dose of a recombinant human monoclonal antibody endowed with pseudovirus neutralizing activity and recognizing a conserved discontinuous epitope of the HCVE2 envelope glycoprotein, called AR3. Intravenous challenge of these mice with serum derived from a HCV-infected patient showed how passive immunization could protect the animal from inoculation with a heterologous HCV quasispecies. The antibody protective effect was still present in 5 of 6 mice six weeks after passive immunization, when antibody concentration was less than 10% of the initial level. These results indicate how selected anti-HCV antibodies are able, within the limitations of this experimental setting, to provide protection even against infection from a viral quasispecies present in the patient serum used to infect mice in this experiment. This clearly indicates that conserved regions, crucial for viral replication, can be targeted by antibodies and that such antibodies are produced after natural infection. Some considerations arise from the above finding. It is known that useful neutralizing antibody clones coexist with other clones that are not necessarily protective [2]. The overall inefficiency of the anti-HCV antibody response can be due to the final balance of the whole response, as recently demonstrated by data reporting how patients showing a strong HCV neutralizing antibody response in the early phase of infection can have better virus control [3]. Furthermore, in a well-characterized single-source outbreak, viral clearance was
300
Journal Clubs / Journal of Hepatology 49 (2008) 299–302
clearly associated to a rapid induction of a broad-range neutralizing antibodies in the early phase of infection, while inability to eradicate the virus was characterized by low neutralizing antibody titers at the same time points [4]. Collectively, these data indicate that production of a broad-range neutralizing humoral response can be crucial for viral clearance, in line with findings in HIV infection, in which neutralizing antibodies act in concert with cellmediated responses for the control of infection [5]. Several well-characterized human monoclonal antibodies (mAb) endowed with broad-range neutralizing activity at very low concentrations and recognizing the AR3 epitope have been described and are available today [6,7]. Each of these molecules is a potential new tool for prevention and treatment of HCV infection. Indeed, prophylaxis with a single mAb or with a mixture of synergic mAbs, can protect from infection; however, this should be tested in the experimental chimpanzee model of HCV infection. Moreover definition of conserved B-cell epitopes able to elicit protective immunity can be a key element for the design of more effective vaccines. Conserved regions, such as the one identified by Law et al., are particularly attractive as their mutation can be detrimental to the HCV life cycle. Passive administration of human monoclonal antibodies directed against these conserved epitopes would force the virus to mutate in functionally important regions, and this may represent a novel therapeutic approach in those patients who did not respond to current treatments. Antiviral compounds targeting crucial viral proteins have been demonstrated to be effective in inducing a modification of the viral replication capacity as well as the pathogenic potential of rapidly evolving RNA viruses [8]. Human mAbs directed against conserved HCV epitopes with broad-range neutralization activity are promising
antiviral compounds that, through their unique mechanism of action, could be useful in preventing and treating HCV infection. References [1] Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 2008;14:25–27. [2] Burioni R, Matsuura Y, Mancini N, Tani H, Miyamura T, Varaldo PE, et al. Diverging effects of human recombinant anti-hepatitis C virus (HCV) antibody fragments derived from a single patient on the infectivity of a vesicular stomatitis virus/HCV pseudotype. J Virol 2002;76:11775–11779. [3] Lavillette D, Morice Y, Germanidis G, Donot P, Soulier A, Pagkalos E, et al. Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection. J Virol 2005;79:6023–6034. [4] Pestka JM, Zeisel MB, Blaser E, Schurmann P, Bartosch B, Cosset FL, et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 2007;104:6025–6030. [5] Igarashi T, Brown C, Azadegan A, Haigwood N, Dimitrov D, Martin MA, et al. Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell-free virions from blood plasma. Nat Med 1999;5:211–216. [6] Keck ZY, Machida K, Lai MM, Ball JK, Patel AH, Foung SK. Therapeutic control of hepatitis C virus: the role of neutralizing monoclonal antibodies. Curr Top Microbiol Immunol 2008;317:1–38. [7] Perotti M, Mancini N, Diotti RA, Tarr AW, Ball JK, Owsianka A, et al. Identification of a broadly cross-reacting and neutralizing human monoclonal antibody directed against the hepatitis C virus E2 protein. J Virol 2008;82:1047–1052. [8] Clementi M, Burioni R. Is reduction of viral fitness a valid antiviral approach? Drug Discov Today: Ther Strategies 2008. doi:10.1016/ j.ddstr.2007.12.001.
doi:10.1016/j.jhep.2008.05.008
Liver and heart: A new link? q Stefano Bellentani1,*, Giorgio Bedogni1,2, Claudio Tiribelli2 1
Centro Studi Nutrizione e Fegato, Ospedale ‘‘Ramazzini’’ Carpi – Azienda USL di Modena, Via G. Molinari, 2 Carpi 42100, Italy 2 CSF – Bassovizza and University of Trieste, Italy
Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M. q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +39 059 659370; fax: +39 059 851762. E-mail addresses: [email protected], s.bellentani@ ausl.mo.it (S. Bellentani).
Alanine aminotransferase (ALT) is a marker of nonalcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50–75 years, at baseline. The
Journal Clubs Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Perspectives for the utilization of neutralizing human monoclonal antibodies as anti-HCV drugs q Roberto Burioni*, Mario Perotti, Nicasio Mancini, Massimo Clementi Laboratorio di Microbiologia e Virologia, Universita` Vita-Salute San Raffaele, Istituto Scientifico San Raffaele, San Raffaele Diagnostica e Ricerca, Milan, Italy
Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI, Ball JK, McKeating JA, Kneteman NM, Burton DR. A major problem in hepatitis C virus (HCV) immunotherapy or vaccine design is the extreme variability of the virus. We identified human monoclonal antibodies (mAbs) that neutralize genetically diverse HCV isolates and protect against heterologous HCV quasispecies challenge in a human liver-chimeric mouse model. The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable. [Abstract reproduced by permission of Nat Med 2008;14:25–27]. The hepatitis C virus (HCV) is characterized by a great variability, due to its ability to evade the host immune response and to establish a persistent infection. Virus replication seems unaffected by strong antibody responses in persistently infected patients and subjects who have recovered from acute infection can be readily reinfected suggesting the concept that humoral immune
q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +39 02 2643 3023; fax: +39 02 2643 4288. E-mail address: [email protected] (R. Burioni).
response is not a key element in protection against HCV. Law et al. [1] passively administered to mice, genetically engineered to support the transplant of a large population of human liver cells, a dose of a recombinant human monoclonal antibody endowed with pseudovirus neutralizing activity and recognizing a conserved discontinuous epitope of the HCVE2 envelope glycoprotein, called AR3. Intravenous challenge of these mice with serum derived from a HCV-infected patient showed how passive immunization could protect the animal from inoculation with a heterologous HCV quasispecies. The antibody protective effect was still present in 5 of 6 mice six weeks after passive immunization, when antibody concentration was less than 10% of the initial level. These results indicate how selected anti-HCV antibodies are able, within the limitations of this experimental setting, to provide protection even against infection from a viral quasispecies present in the patient serum used to infect mice in this experiment. This clearly indicates that conserved regions, crucial for viral replication, can be targeted by antibodies and that such antibodies are produced after natural infection. Some considerations arise from the above finding. It is known that useful neutralizing antibody clones coexist with other clones that are not necessarily protective [2]. The overall inefficiency of the anti-HCV antibody response can be due to the final balance of the whole response, as recently demonstrated by data reporting how patients showing a strong HCV neutralizing antibody response in the early phase of infection can have better virus control [3]. Furthermore, in a well-characterized single-source outbreak, viral clearance was
300
Journal Clubs / Journal of Hepatology 49 (2008) 299–302
clearly associated to a rapid induction of a broad-range neutralizing antibodies in the early phase of infection, while inability to eradicate the virus was characterized by low neutralizing antibody titers at the same time points [4]. Collectively, these data indicate that production of a broad-range neutralizing humoral response can be crucial for viral clearance, in line with findings in HIV infection, in which neutralizing antibodies act in concert with cellmediated responses for the control of infection [5]. Several well-characterized human monoclonal antibodies (mAb) endowed with broad-range neutralizing activity at very low concentrations and recognizing the AR3 epitope have been described and are available today [6,7]. Each of these molecules is a potential new tool for prevention and treatment of HCV infection. Indeed, prophylaxis with a single mAb or with a mixture of synergic mAbs, can protect from infection; however, this should be tested in the experimental chimpanzee model of HCV infection. Moreover definition of conserved B-cell epitopes able to elicit protective immunity can be a key element for the design of more effective vaccines. Conserved regions, such as the one identified by Law et al., are particularly attractive as their mutation can be detrimental to the HCV life cycle. Passive administration of human monoclonal antibodies directed against these conserved epitopes would force the virus to mutate in functionally important regions, and this may represent a novel therapeutic approach in those patients who did not respond to current treatments. Antiviral compounds targeting crucial viral proteins have been demonstrated to be effective in inducing a modification of the viral replication capacity as well as the pathogenic potential of rapidly evolving RNA viruses [8]. Human mAbs directed against conserved HCV epitopes with broad-range neutralization activity are promising
antiviral compounds that, through their unique mechanism of action, could be useful in preventing and treating HCV infection. References [1] Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 2008;14:25–27. [2] Burioni R, Matsuura Y, Mancini N, Tani H, Miyamura T, Varaldo PE, et al. Diverging effects of human recombinant anti-hepatitis C virus (HCV) antibody fragments derived from a single patient on the infectivity of a vesicular stomatitis virus/HCV pseudotype. J Virol 2002;76:11775–11779. [3] Lavillette D, Morice Y, Germanidis G, Donot P, Soulier A, Pagkalos E, et al. Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection. J Virol 2005;79:6023–6034. [4] Pestka JM, Zeisel MB, Blaser E, Schurmann P, Bartosch B, Cosset FL, et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 2007;104:6025–6030. [5] Igarashi T, Brown C, Azadegan A, Haigwood N, Dimitrov D, Martin MA, et al. Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell-free virions from blood plasma. Nat Med 1999;5:211–216. [6] Keck ZY, Machida K, Lai MM, Ball JK, Patel AH, Foung SK. Therapeutic control of hepatitis C virus: the role of neutralizing monoclonal antibodies. Curr Top Microbiol Immunol 2008;317:1–38. [7] Perotti M, Mancini N, Diotti RA, Tarr AW, Ball JK, Owsianka A, et al. Identification of a broadly cross-reacting and neutralizing human monoclonal antibody directed against the hepatitis C virus E2 protein. J Virol 2008;82:1047–1052. [8] Clementi M, Burioni R. Is reduction of viral fitness a valid antiviral approach? Drug Discov Today: Ther Strategies 2008. doi:10.1016/ j.ddstr.2007.12.001.
doi:10.1016/j.jhep.2008.05.008
Liver and heart: A new link? q Stefano Bellentani1,*, Giorgio Bedogni1,2, Claudio Tiribelli2 1
Centro Studi Nutrizione e Fegato, Ospedale ‘‘Ramazzini’’ Carpi – Azienda USL di Modena, Via G. Molinari, 2 Carpi 42100, Italy 2 CSF – Bassovizza and University of Trieste, Italy
Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M. q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +39 059 659370; fax: +39 059 851762. E-mail addresses: [email protected], s.bellentani@ ausl.mo.it (S. Bellentani).
Alanine aminotransferase (ALT) is a marker of nonalcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50–75 years, at baseline. The