Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds bacterium or component thereof or substance produced...
Reexamination Certificate
1997-12-31
2001-06-12
Swartz, Rodney P. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds bacterium or component thereof or substance produced...
C424S009100, C424S130100, C424S150100, C424S164100, C424S248100, C435S007100, C435S007200
Reexamination Certificate
active
06245331
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention in the fields of microbiology and medicine relates to methods for rapid early detection of mycobacterial disease in humans based on the presence of antibodies to particular “early” mycobacterial antigens which have not been previously recognized for this purpose. Assay of such antibodies on select partially purified or purified mycobacterial preparations containing such early antigens permits diagnosis of TB earlier than has been heretofore possible. Also provided is a surrogate marker for screening populations at risk for TB, in particular subjects infected with human immunodeficiency virus (HIV).
2. Description of the Background Art
Recent estimates by the World Health Organization (WHO) suggest that approximately 90 million new cases of tuberculosis (“TB”) will occur during this decade leading to about 30 million deaths (Raviglione, M. C. et al., 1995,
JAMA.
273:220-226). The spread of HIV in populations already having a high incidence of TB related to socioeconomic factors and malnutrition has resulted in a resurgence of TB all over the world (Raviglione, M. C. et al., 1992,
Bull World Health Organ
70:515-526; Harries A. D., 1990,
Lancet.
335:387-390). This resurgence has renewed interest in developing improved vaccines, diagnostics, drugs and drug delivery regimens for TB. Furthermore, the immune dysfunction caused by HIV infection leads to a high rate of reactivation of latent TB, increased susceptibility to primary disease, as well as an accelerated course of disease progression (Raviglione et al., 1992, supra; 1995, supra; Shafer R. W. et al., 1996,
Clin. Infect. Dis.
22:683-704; Barnes P. F. et al., 1991,
N. Engl. J. Med.
324:1644-1650; Selwyn P. A. et al., 1989,
N. Engl. J Med.
320:545-550).
It is well established that cellular immunity is critical for protection against TB. Much of the work in this field is focused on defining the antigens of the causative bacterium,
Mycobacterium tuberculosis
(
M. tuberculosis
; also abbreviated herein as “Mt”) that can elicit effective immunity and on understanding the role of various cell populations in host-pathogen interactions (Andersen, P. et al., 1992, Scand. J. Immunol. 36:823-831; Havlir, D. V. et al., 1991,
Infect. Immun.
59:665-670; Orme, I. M. et al., 1993, J. Infect. Dis. 167:1481-1497).
Delayed hypersensitivity measured as cutaneous immune reactivity to a purified protein derivative of Mt (abbreviated “PPD”) is the only marker available for detection of latent infection with Mt. However, the sensitivity of the PPD skin test is substantially reduced during HIV infection (Raviglione et al., 1992, supra, 1995, supra; Graham N. M. H. et al., 1991,
JAMA
267:369-373; Huebner R. E. et al., 1994,
Clin. Infect. Dis.
19:26-32; Huebner R. E. et al., 1992,
JAMA
267:409-410; Caiaffa W. T. et al., 1995,
Arch. Intern. Med.
155:2111-2117). Furthermore, vaccination with a closely related mycobacterium designated Bacillus Calmette-Guerin (BCG) or previous exposure to other mycobacterial species can lead to false positive results in a PPD skin test. Not only does PPD reactivity fail to distinguish active, subclinical disease from latent infection, but the time between a positive skin test and development of clinical disease may range from months to several years (Selwyn P. A. et al., supra).
Because of the susceptibility of immunocompromised individuals to TB, the U.S. Centers for Disease Control and Prevention recommends preventive isoniazid therapy for all HIV seropositive (HIV
+
), PPD-positive (PPD
+
) individuals. However, the optimal time for such therapy is not clear and, ideally, should coincide with replication of previously latent bacteria. Unnecessary therapy must be minimized because prolonged isoniazid treatment can have serious toxic side effects (Shafer et al., supra). The impact of such treatment on emergence of drug resistant bacteria is still unclear. The use of preventive therapy in developing countries is seriously limited by the high frequency of PPD
+
individuals coupled with the lack of adequate medico-social infrastructure and economic resources. High risk populations are also found in the United States, primarily intravenous drug users, homeless people, prison inmates and residents of slum areas (Fitzgerald, J. M. et al., 1991,
Chest
100:191-200; Graham, N. M. H. et al., 1992,
JAMA
267:369-373; Friedman, L. N. et al., 1996,
New Engl. J. Med
334:828-833). Thus, discovery of additional surrogate markers for early detection and prompt treatment of active, subclinical TB in such high risk populations is urgently required.
Antibody responses in TB have been studied for several decades primarily for the purpose of developing serodiagnostic assays. Although some seroreactive antigens/epitopes have been identified, interest in antibody responses to
M. tuberculosis
has waned because of the lack of progress in simple detection of corresponding antibodies. Studies using crude antigen preparations revealed that healthy individuals possess antibodies that cross-react with several mycobacterial antigens. Such antibodies are believed to have been elicited by exposure to commensal and environmental bacteria and vaccinations (Bardana, E. J. et al., 1973,
Clin. Exp. Immunol.
13:65-77; Das, S. et al., 1992,
Clin. Exp. Immunol.
89:402-406; Del Giudice, G. et al., 1993,
J. Immunol.
150:2025-2032; Grange, J. M., 1984,
Adv. Tuberc. Res.
21:1-78; Havlir, D. V. et al., supra; Ivanyi, J. et al., 1989,
Brit. Med. Bull.
44:635-649; Verbon, A. et al., 1990,
J. Gen. Microbiol.
136:955-964). During the last decade, several mycobacterial antigens have been isolated and characterized (Young, D. B. et al., 1992,
Mol. Microbiol.
6:133-145), including the 71 kDa DnaK, 65 kDa GroEL, 47 kDa elongation factor tu, 44 kDa PstA homologue, 40 kDa L-alanine dehydrogenase, 38 kDa PhoS, 23 kDa superoxide dismutase, 23 kDa outer membrane protein, 12 kDa thioredoxin, and the 14 kDa GroES. However, a majority of the antigens identified so far bear significant homology to the analogous proteins in other mycobacteria and non-mycobacterial prokaryotes (Andersen, A. B. et al., 1992,
Infect. Immun.
60:2317-2323; Andersen, A. B. et al., 1989,
Infect. Immun.
57:2481-2488; Braibant, M. et al., 1994,
Infect. Immun.
62:849-854; Carlin, N. I. A. et al., 1992,
Infect. Immun.
60:3136-3142; Garsia, R. J. et al., 1989,
Infect. Immun.
57:204-212; Hirschfield, G. R. et al., 1990,
J. Bacteriol.
172:1005-1013; Shinnick, T. M. et al., 1989,
Nucl. Acids Res.
17:1254; Shinnick, T. M. et al., 1988,
Infect. Immun.
56:446-451; Wieles, B. et al., 1995,
Infect. Immun.
63:4946-4948; Young, D. B. et al., supra; Zhang, Y. et al., 1991,
Mol. Microbiol.
5:381-391). Thus, almost all individuals (healthy or diseased) have antibodies to epitopes of conserved regions of these antigens. These antibodies are responsible for the uninformative (and possibly misleading) cross-reactivity observed with crude Mt antigen preparations (Davenport, M. P. et al., 1992,
Infect. Immun.
60:1170-1177; Grandia, A. A. et al, 1991,
Immunobiol.
182:127-134; Meeker, H. C. et al., 1989,
Infect. Immun.
57:3689-3694; Thole, J. et al., 1987,
Infect. Immun.
55:1466-1475).
Because such cross-reactive antibodies would mask the presence of antibodies specific for Mt antigens, some of the purified antigens such as the 38 kDa PhoS, the 30/31 kDa “antigen 85” (discussed in more detail below), 19 kDa lipoprotein, 14 kDa GroES and lipoarabinomannan have been prepared and tested (Daniel, T. et al., 1985
Chest.
88:388-392; Drowart, L. et al., 1991,
Chest.
100:685-687; Jackett, P. S. et al., 1988,
J. Clin. Microbiol.
26:2313-2318; Ma, Y. et al., 1986,
Am. Rev. Respir. Dis.
134:1273-1275; Sada, E. et al., 1990,
J. Clin. Microbiol.
28:2587-2590; Sada, E. D. et al., 1990,
J. Infect. Dis.
162:928-931; Van Vooren, J. P. et al., 1991,
J. Clin. Microbiol.
29:2348-2350). It is noteworthy that the choice of which antigen to test was dictated primarily by (a) its availabil
Belisle John T.
Laal Suman
Zolla-Pazner Susan
Livnat Shmuel
New York Univ. Medical Center
Swartz Rodney P.
Venable
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