Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1998-01-21
2000-12-05
Budens, Robert D.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4351885, 530412, 530413, C12P 2100, C12P 2108, C07K 1610
Patent
active
061565415
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to treatment of HIV infection and associated pathologies. In particular, catalytic (proteolytic) antibodies, or derivative thereof, are provided, which catalyze the hydrolysis of the HIV gp120 protein.
BACKGROUND OF THE INVENTION
The envelope glycoproteins of HIV-1 are initially synthesized as a single 160 kD precursor, gp160, which is cleaved at the Arg511-Ala512 bond by a cellular protease, producing gp120 and the integral membrane protein gp41 (Kido, H., et al., J. Biol. Chem. 268:13406-13413 (1993)). The biological activity of gp120 is a key ingredient in initial binding of host cells by HIV-1, propagation of the virus and its toxic effects on uninfected neurons and other cells (Kieber-Emmons, T., et al., Biochim. Biophys. Acta. 989:281-300, (1987); Capon et al., Ann. Rev. Immunol. 9:649-678). Thus, gp120 is a target of passive and active immunization against AIDS (Kahn, J. O., et al., J. Infec. Dis. 170:1288-1291 (1994); Birx, D. L., et al., Curr. Opin. Immunol. 5:600-607 (1993); Berman, P. W., et al., Proc. Natl. Acad. Sci. USA 85:5200-5204 (1988)). Binding of a conformational epitope of gp120 to CD4 receptors on host cells is the first step in HIV-1 infection. Individual amino acids constituting this epitope appear to be located in the second (C2), third (C3), and fourth (C4) conserved gp120 segments (Olshevsky, T. J., et al., J. Virol. 64:5701-5705 (1990)). These are gp120 residues 256, 257, 368-370, 421-427 and 457. Monoclonal antibodies that bind the CD4 binding site have been described (Thali, M., et al., J. Virol. 65:6188-6193 (1991); Thali, M., et al., J. Virol. 66:5635-5641 (1992)). Since the CD4 binding site is a conformational epitope, distant residues that are not themselves constituents of the epitope may be important in maintaining the ability to bind CD4. Gp120 interactions with other host cell proteins are also essential for virus propagation. For example, binding of gp120 by calmodulin may be involved in HIV-1 infectivity, as revealed by the inhibitory effect of calmodulin antagonists (Srinivas, R. V., et al., AIDS Res. Hum. Retroviruses 108:1489-1496 (1994). Asp180 located between the V1 and V2 regions of gp120 is critical for viral replication (Wang, W-K., et al., J. Virol. 69:538-542 (1995)). Similarly, the V3 loop is essential for infectivity (Ivanoff, L. A., et al., Virology 187:423-432 (1992)). It is clear, therefore, that structural determinants in gp120 other than those constituting the CD4 binding site are likely to be necessary for virus genome replication, coat protein synthesis and virus particle packaging.
Shedding of gp120 by virus particles and infected cells has been proposed as a factor in the pathogenesis of AIDS (Gelderblom, H. R. et al., Lancett ii:1016-1017 (1985)). Purified gp120 is toxic for cultured neurons (Brenneman, D. E. et al., Nature 335:639-642 (1988); Muller, W. E. G. et al., Eur. J. Pharmacol 226:209-214 (1992)). Uninfected T-lymphocytes coated with gp120 can be lysed by antibody-dependent monocytes (Hober, D. et al., FEMS Immunol. Med. Microbiol. 10:83-92 (1995)). Uninfected CD4+ cells can die because binding of the gp120-gp41 complex induces apoptosis (Laurent-Crawford, A. G. et al., Res. Virol 146:5-17 995)). Gp120 also binds complement components (Stoiber, H. et al., AIDS 9:19-26 (1995)).
There has been considerable interest in the possibility that gp120 contributes to neural damage observed in AIDS patients (Everall, I. P et al., J. Neuropathol. Exp. Neurol. 52:561-566 (1993)). Productive infection in the brain occurs in a relatively small number of cells, which include microglia, multinucleated giant cells and blood-derived macrophages (Epstein. L. G et al., Ann. Neurol. 33:429-436 (1993)). Yet, there is wide-spread brain damage at areas that are not infected by the virus. This has lead to suggestions that soluble gp120 shed by the virus and cytokines produced by infected cells may be responsible for the damage (Lipton, S. A., Brain Pathol. 1:193-199 (1991), Giulian, D. et al., Science 250:1593-15
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Kalaga Ravishankar
Paul Sudhir
Budens Robert D.
The Board of Regents of the University of Nebraska
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