Abstract
Rabies virus is a prototypical neurotropic virus that causes one of the most dangerous zoonotic diseases in humans. Humanized or fully human monoclonal antibodies (mAb) that neutralize rabies virus would be the basis for powerful post-exposure prophylaxis of rabies in humans, having several significant benefits in comparison with human or equine rabies polyclonal immunoglobulins. The most advanced antibodies should broadly neutralize natural rabies virus isolates, bind with conserved antigenic determinants of the rabies virus glycoprotein, and show high neutralizing potency in assays in vivo. The antibodies should recognize nonoverlapping epitopes if they are used in combination. This review focuses on basic requirements for anti-rabies therapeutic antibodies. The urgency in the search for novel rabies post-exposure prophylaxis and methods of development of anti-rabies human mAb cocktail are discussed. The rabies virus structure and pathways of its penetration into the nervous system are also briefly described.
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Abbreviations
- AS:
-
antigenic site
- CHO:
-
Chinese hamster ovary tumor cells
- ERIG:
-
equine rabies immunoglobulin
- (H)RIG:
-
(human) rabies immunoglobulin
- IFN:
-
interferon
- mAb:
-
mono-clonal antibodies
- nACR:
-
nicotine acetylcholine receptor (n-cholinoreceptor)
- NBs:
-
Negri bodies
- NCAM:
-
neuronal cell adhesion molecule
- NGFR or p75NTR:
-
nerve growth factor (p75 neutrophin receptor)
- PEP:
-
post-exposure prophylaxis
- RABV:
-
rabies virus
- RIG:
-
rabies immunoglobulin
- STAT:
-
transcription factor
- TLRs:
-
toll-like receptors.
References
Banyard, A. C., Horton, D. L., Freuling, C., Muller, T., and Fooks, A. R. (2013) Control and prevention of canine rabies: the need for building laboratory-based surveillance capacity, Antiviral Res., 98, 357–364.
Baltimore, D. (1971) Expression of animal virus genomes, Bacteriol. Rev., 35, 235–241.
Johnson, N., Vos, A., Freuling, C., Tordo, N., Fooks, A. R., and Muller, T. (2010) Human rabies due to lyssavirus infection of bat origin, Vet. Microbiol., 142, 151–159.
Dietzgen, R. G., Calisher, C. H., Kurath, G., Kuzmin, I. V., Rodriguez, L. L., Stone, D. M., Tesh, R. B., Tordo, N., Walker, P. J., Wetzel, T., and Whitfield, A. E. (2011) Rhabdoviridae, in Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses (King, A. M. Q., Adams, M. J., Carstens, E. B., and Lefkowitz, E. J., eds.) Elsevier, Oxford, pp. 686-714.
Lafon, M. (2005) Rabies virus receptors, J. Neurovirol., 11, 82–87.
Wunner, W. H., Reagan, K. J., and Koprowski, H. (1984) Characterization of saturable binding sites for rabies virus, J. Virol., 50, 691–697.
Cox, J. H., Dietzschold, B., and Schneider, L. G. (1977) Rabies virus glycoprotein: II. Biological and serological characterization, Infect. Immun., 16, 754–759.
Celis, E., Ou, D., Dietzschold, B., and Koprowski, H. (1988) Recognition of rabies and rabies-related viruses by T cells derived from human vaccine recipients, J. Virol., 62, 3128–3134.
Shakin-Eshleman, S. H., Remaley, A. T., Eshleman, J. R., Wunner, W. H., and Spitalnik, S. L. (1992) N-linked glycosylation of rabies virus glycoprotein. Individual sequons differ in their glycosylation efficiencies and influence on cell surface expression, J. Biol. Chem., 267, 10690–10698.
Gaudin, Y., Tuffereau, C., Benmansour, A., and Flamand, A. (1991) Fatty-acylation of rabies virus proteins, Virology, 184, 441–444.
Marissen, W. E., Kramer, R. A., Rice, A., Weldon, W. C., Niezgoda, M., Faber, M., Slootstra, J. W., Meloen, R. H., Clijsters-van der Horst, M., Visser, T. J., Jongeneelen, M., Thijsse, S., Throsby, M., De Kruif, J., Rupprecht, C. E., Dietzschold, B., Goudsmit, J., and Bakker, A. B. (2005) Novel rabies virus-neutralizing epitope recognized by human monoclonal antibody: fine mapping and escape mutant analysis, J. Virol., 79, 4672–4678.
Prehaud, C., Coulon, P., Lafay, F., Thiers, C., and Flamand, A. (1988) Antigenic site II of the rabies virus glycoprotein: structure and role in viral virulence, J. Virol., 62, 1–7.
Benmansour, A., Leblois, H., Coulon, P., Tuffereau, C., Gaudin, Y., Flamand, A., and Lafay, F. (1991) Antigenicity of rabies virus glycoprotein, J. Virol., 65, 4198–4203.
Broughan, J. H., and Wunner, W. H. (1995) Characterization of protein involvement in rabies virus binding to BHK-21 cells, Arch. Virol., 140, 75–93.
Chen, J. F., Mandel, E. M., Thomson, J. M., Wu, Q., Callis, T. E., Hammond, S. M., Conlon, F. L., and Wang, D. Z. (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation, Nat. Genet., 38, 228–233.
Ugolini, G. (2011) Rabies virus as a transneuronal tracer of neuronal connections, Adv. Virus Res., 79, 165–202.
Ugolini, G. (2008) Use of rabies virus as a transneuronal tracer of neuronal connections: implications for the understanding of rabies pathogenesis, Dev. Biol. (Basel), 131, 493–506.
Lewis, P., Fu, Y., and Lentz, T. L. (2000) Rabies virus entry at the neuromuscular junction in nerve muscle cocultures, Muscle Nerve, 23, 720–730.
Lentz, T. L., Hawrot, E., and Wilson, P. T. (1987) Synthetic peptides corresponding to sequences of snake venom neurotoxins and rabies virus glycoprotein bind to the nicotinic acetylcholine receptor, Proteins, 2, 298–307.
Langevin, C., Jaaro, H., Bressanelli, S., Fainzilber, M., and Tuffereau, C. (2002) Rabies virus glycoprotein (RVG) is a trimeric ligand for the N-terminal cysteine-rich domain of the mammalian p75 neurotrophin receptor, J. Biol. Chem., 277, 37655–37662.
Superti, F., Hauttecoeur, B., Morelec, M. J., Goldoni, P., Bizzini, B., and Tsiang, H. (1986) Involvement of gangliosides in rabies virus infection, J. Gen. Virol., 67, 47–56.
Hornung, V., Ellegast, J., Kim, S., Brzozka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K. K., Schlee, M., Endres, S., and Hartmann, G. (2006) 5′-Triphosphate RNA is the ligand for RIG-I, Science, 314, 994–997.
Rieder, M., and Conzelmann, K. K. (2011) Interferon in rabies virus infection, Adv. Virus. Res., 79, 91–114.
Lahaye, X., Vidy, A., Pomier, C., Obiang, L., Harper, F., Gaudin, Y., and Blondel, D. (2009) Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: evidence that NBs are sites of viral transcription and replication, J. Virol., 83, 7948–7958.
Menager, P., Roux, P., Megret, F., Bourgeois, J. P., Le Sourd, A. M., Danckaert, A., Lafage, M., Prehaud, C., and Lafon, M. (2009) Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri bodies, PLOS Pathog., 5.
Vidy, A., El Bougrini, J., Chelbi-Alix, M. K., and Blondel, D. J. (2007) The nucleocytoplasmic rabies virus P protein counteracts interferon signaling by inhibiting both nuclear accumulation and DNA binding of STAT1, J. Virol., 81, 4255–4263.
Lafon, M. (2008) Immune evasion, a critical strategy for rabies virus, Dev. Biol. Stand., 131, 413–419.
Warrell, M. J. (2012) Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure, Travel Med. Infect. Dis., 10, 1–15.
Faber, M. (2014) Recombinant rabies virus vaccines, in Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention (Rupprecht, C. E., and Nagarajan, T., eds.) Elsevier Inc., Vol. 1, pp. 255-263.
Yusibov, V., Modelska, A., Steplewski, K., Agadjanyan, M., Weiner, D., Hooper, D. C., and Koprowski, H. (1997) Antigens produced in plants by infection with chimeric plant viruses immunize against rabies virus and HIV-1, Proc. Natl. Acad. Sci. USA, 94, 5784–5788.
Montgomery, D. L., and Prather, K. J. (2006) Design of plasmid DNA constructs for vaccines, Methods Mol. Med., 127, 11–22.
Both, L., Banyard, A. C., Van Dolleweerd, C., Horton, D. L., Ma, J. K., and Fooks, A. R. (2012) Passive immunity in the prevention of rabies, Lancet Infect. Dis., 12, 397–407.
Fernandes, A., Kaundinya, J. O., Daftary, G., Saxena, L., Banerjee, S., and Pattnaik, P. (2008) Chromatographic purification of equine immunoglobulin G F(ab′)2 from plasma, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 876, 109–115.
Meslin, F. X., Fishbein, D. B., and Matter, H. C. (1994) Rationale and prospects for rabies elimination in developing countries, Curr. Top. Microbiol. Immunol., 187, 1–26.
McKay, N., and Wallis, L. (2005) Rabies: a review of UK management, J. Emerg. Med., 22, 316–321.
World Health Organization (2013) WHO expert consultation on rabies: second report, World Health Organ. Tech. Rep. Ser., 982, 1–139.
Goudsmit, J., Marissen, W. E., Weldon, W. C., Niezgoda, M., Hanlon, C. A., Rice, A. B., Kruif, Jd., Dietzschold, B., Bakker, A. B., and Rupprecht, C. E. (2006) Comparison of an anti-rabies human monoclonal antibody combination with human polyclonal anti-rabies immune globulin, J. Infect. Dis., 193, 796–801.
Dietzschold, B., Gore, M., Casali, P., Ueki, Y., Rupprecht, C. E., Notkins, A. L., and Koprowski, H. (1990) Biological characterization of human monoclonal antibodies to rabies virus, J. Virol., 64, 3087–3090.
Both, L., Van Dolleweerd, C., Wright, E., Banyard, A. C., Bulmer-Thomas, B., Selden, D., Altmann, F., Fooks, A. R., and Ma, J. K. (2013) Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans, FASEB J., 27, 2055–2065.
De Benedictis, P., Minola, A., Rota Nodari, E., Aiello, R., Zecchin, B., Salomoni, A., Foglierini, M., Agatic, G., Vanzetta, F., Lavenir, R., Lepelletier, A., Bentley, E., Weiss, R., Cattoli, G., Capua, I., Sallusto, F., Wright, E., Lanzavecchia, A., Bourhy, H., and Corti, D. (2016) Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis, EMBO Mol. Med., 8, 407–421.
Tsekoa, T. L., Lotter-Stark, T., Buthelezi, S., Chakauya, E., Stoychev, S. H., Sabeta, C., Shumba, W., Phahladira, B., Hume, S., Morton, J., Rupprecht, C. E., Steinkellner, H., Pauly, M., Zeitlin, L., Whaley, K., and Chikwambaet, R. (2016) Efficient in vitro and in vivo activity of glyco-engineered plant-produced rabies monoclonal antibodies E559 and 62-71-3, PLoS One, 11, 1–15.
Matsumoto, T., Yamada, K., Noguchi, K., Nakajima, K., Takada, K., Khawplod, P., and Nishizono, A. (2010) Isolation and characterization of novel human monoclonal antibodies possessing neutralizing ability against rabies virus, Microbiol. Immunol., 54, 673–683.
Kramer, R. A., Marissen, W. E., Goudsmit, J., Visser, T. J., Clijsters-Van der Horst, M., Bakker, A. Q., De Jong, M., Jongeneelen, M., Thijsse, S., Backus, H. H., Rice, A. B., Weldon, W. C., Rupprecht, C. E., Dietzschold, B., Bakker, A. B., and De Kruif, J. (2005) The human antibody repertoire specific for rabies virus glycoprotein as selected from immune libraries, Eur. J. Immunol., 35, 2131–2145.
Sloan, S. E., Hanlon, C., Weldon, W., Niezgoda, M., Blanton, J., Self, J., Rowley, K. J., Mandell, R. B., Babcock, G. J., Thomas, W. D., Jr., Rupprecht, C. E., and Ambrosino, D. M. (2007) Identification and characterization of a human monoclonal antibody that potently neutralizes a broad panel of rabies virus isolates, Vaccine, 25, 2800–2810.
Zhao, X. L., Yin, J., Chen, W. Q., Jiang, M., Yang, G., and Yang, Z. H. (2008) Generation and characterization of human monoclonal antibodies to G5, a linear neutralization epitope on glycoprotein of rabies virus, by phage display technology, Microbiol. Immunol., 52, 89–93.
Lafon, M., Wiktor, T. J., and Macfarlan, R. I. (1983) Antigenic sites on the CVS rabies virus glycoprotein: analysis with monoclonal antibodies, J. Gen. Virol., 64, 843–851.
Muller, T., Dietzschold, B., Ertl, H., Fooks, A. R., Freuling, C., Fehlner-Gardiner, C., Kliemt, J., Meslin, F. X., Franka, R., Rupprecht, C. E., Tordo, N., Wanderler, A. I., and Kieny, M. P. (2009) Development of a mouse monoclonal antibody cocktail for post-exposure rabies prophylaxis in humans, PLoS Negl. Trop. Dis., 3, e542.
Kuzmina, N. A., Kuzmin, I. V., Ellison, J. A., and Rupprecht, Ch. E. (2013) Conservation of binding epitopes for monoclonal antibodies on the rabies virus glycoprotein, J. Antivir. Antiretrovir., 5, 37–43.
Kohler, G., and Milstein, C. (1975) Continuous cultures of fused cells secreting antibodies of predetermined specificity, Nature, 256, 495–497.
Benevolensky, S. V., Zatsepin, S. S., Klyachko, E. V., Morozkina, E. V., Pozdnyakova, L. P., Sveshnikov, P. G., Solopova, O. N., Shemchukova, O. B., and Yagudin, O. B. (2012) The humanized antigen-binding fragments (Fab) against the rabies virus, the isolated DNA fragment encoding Fab against the rabies virus, the yeast cell transformed by the DNA fragment, and the method of obtaining Fab against the rabies virus using yeast, Patent No. RU2440412 (C2).
Crucell Holland BV. A Randomized Phase II Trial to Compare the Safety and Neutralizing Activity of CL184 in Combination with Rabies Vaccine vs. HRIG or Placebo in Combination with Rabies Vaccine in Healthy Adult Subjects (https://clinicaltrials.gov/show/NCT00656097), registered on September 2011.
Crucell Holland BV. Randomized Phase II Trial on Safety and Neutralizing Activity of CL184 and Rabies Vaccine versus Human Rabies Immune Globulin (HRIG) and Rabies Vaccine in Children and Adolescents (https:// clinicaltrials.gov/show/NCT00708084), registered on March 2012.
Crucell Holland BV. Rabies Virus Neutralizing Activity and Safety of CL184, a Monoclonal Antibody Cocktail, in Simulated Rabies Post-exposure Prophylaxis in Healthy Adults (https://clinicaltrials.gov/ct2/show/study/NCT01228383), registered on April 2013.
Serum Institute of India Ltd. A Phase II/III, Randomized, Multi-Centric, Comparator-Controlled Study of the Safety and Neutralizing Activity of a Human Monoclonal Antibody to Rabies (SII RMAb) Administered in Conjunction with Rabies Vaccine for Post-exposure Prophylaxis in Patients Following Potential Rabies Exposure, CTRI/2012/05/002709 (http://www.ctri.nic.in/ Clinicaltrials/pmaindet2.php?trialid=4191), registered on November 2012.
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Original Russian Text © E. N. Ilina, M. V. Larina, T. K. Aliev, D. A. Dolgikh, M. P. Kirpichnikov, 2018, published in Biokhimiya, 2018, Vol. 83, No. 1, pp. 3-18.
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Ilina, E.N., Larina, M.V., Aliev, T.K. et al. Recombinant monoclonal antibodies for rabies post-exposure prophylaxis. Biochemistry Moscow 83, 1–12 (2018). https://doi.org/10.1134/S0006297918010017
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DOI: https://doi.org/10.1134/S0006297918010017