Chemistry: molecular biology and microbiology – Kit
Reexamination Certificate
2001-06-27
2004-01-06
Housel, James (Department: 1648)
Chemistry: molecular biology and microbiology
Kit
C435S004000, C435S005000, C435S007100, C435S007900, C435S007920, C435S007940, C435S007950, C436S828000
Reexamination Certificate
active
06673614
ABSTRACT:
TECHNICAL FIELD
This invention relates to the field of antibody detection, particularly rapid methods, devices and kits for detection and semi-quantitation of anti-adenovirus antibody.
BACKGROUND ART
The ability to detect antibodies to viruses such as adenovirus in a patient sample is increasingly becoming a prerequisite for optimal utilization of many modern health care technologies. This is especially relevant in two broad areas of health care: detection of infections based on presence of pathogen-specific antibodies, and “prepping” of patients for therapeutic agent administration.
The pathogenesis of the ubiquitous adenovirus is well-documented. Many relatively minor illnesses are associated with adenovirus infections, including acute febrile pharyngitis, pharyngoconjunctival fever, acute respiratory disease, pneumonia, epidemic keratoconjunctivitis, pertussis-like syndrome, acute hemorrhagic cystitis, gastroenteritis, hepatitis and persistence of virus in urinary tract. Fields, et al.,
Fields' VIROLOGY,
Vol. 2, p. 2155 (3rd Ed.). A vaccine for the most severe of these diseases has been developed using a wild-type unattenuated replicating polyvalent vaccine comprised of adenovirus types 4 and 7.
Detection of anti-adenovirus antibodies is an important aspect of optimizing the administration, and hence therapeutic effects, of new therapeutic tools. This phenomenon results from two factors. First, many of the new therapeutic tools involve the use of adenoviral vector constructs. Second, it is now clear that the full potential of the virus-based therapeutic tools, specifically those that exploit the gene delivery advantages of adenovirus vector constructs, is hampered by the recipient's immune response.
Adenoviruses also form the basis of some of the most innovative and potentially powerful disease-fighting tools. One such tool is gene therapy, in which a defective gene or sequence is supplanted with an exogenous sequence. This approach holds great potential in treating not only cancer, but many other diseases as well, including cystic fibrosis, anemia, hemophilia, diabetes, Hungtington's disease, AIDS, abnormally high serum cholesterol levels, certain immune deficiencies, and many forms of cancer.
Gene therapy generally requires a delivery vehicle for the exogenous sequence, such as a viral vector. Recombinant adenovirus is one of the newly-developed viral agents that may be effective vectors against these diseases. For reviews, see Kim et al. (1996)
Mol. Med. Today
12:519-527 and Smith et al. (1996)
Gene Therapy
3:496-502.
In addition, in the cancer context, specific attenuated replication-competent viral vectors have been developed, in which selective replication in cancer cells preferentially destroys those cells. Various cell-specific replication-competent adenovirus constructs, which preferentially replicate (and thus destroy) certain cell types, are described in, for example, WO 95/19434, WO 98/39465, WO 98/39467, WO 98/39466, WO 99/06576, WO 98/39464, WO 00/15820. Another attenuated replication-competent adenovirus is Onyx-015 adenovirus. Onyx-015 has a deletion in the E1B-55kDa protein, which normally inhibits the cellular p53 tumor suppressor protein. Onyx-015 can replicate in p53-deficient human cells, but does not replicate efficiently in p53-positive cells. Bischoff et al. (1996)
Science
274:373-376; Heise et al. (1997)
Nat. Med.
3:639-645.
The favorable factors that make adenoviruses a safe therapeutic agent include: (a) infection with adenovirus has minor clinical disease manifestations; (b) adenovirus has a stable well-described and characterized genome; (c) adenovirus is unable to integrate its viral DNA into host DNA; (d) adenovirus allows transient gene expression; (e) adenovirus is able to infect both dividing and non-dividing cells; (f) adenovirus can infect a variety of human cell types; (g) adenovirus is physically stable; and (h) adenovirus is amenable to high titer production.
There are 47 different serotypes of adenovirus, which are distinguishable by antibody reactivity to epitopes on the virion surface. Each serotype is assigned to one of five Subgroups (A-E). Members of a Subgroup can exchange genetic material (recombine) efficiently, but they do not recombine with members of a different Subgroup. Adenovirus types 1, 2, 5, and 6 are members of Subgroup C. Adenovirus type 5 (the type typically used in gene therapy and for other therapies) is associated with a self-limiting, febrile respiratory illness and ocular disease in humans. In long-term immunosuppressed individuals, adenovirus-5 is also associated with renal impairment, hepatic necrosis, and gastric erosions. Shields et al. (1985)
New England J. Med.
312:529-533; Zahradnik et al. (1980)
Am. J. Med.
68: 725-732. Adenovirus-5 and the other Subgroup C viruses have little or no oncogenic potential in mammals. Horowitz (1990) in
Virology,
(Raven Press, New York, 2
nd
Ed.) pp. 1679-1721.
While use of viral therapeutic agents such as adenovirus holds promise, there are a number of potentially significant barriers to their effectiveness. Two of the major limitations of virus-based vectors as therapeutic vehicles result from the subject's immune response to the presence of the viral agents, namely (a) the inactivation of virus by pre-existing circulating antibodies to the virus, and (b) the reduced efficacy of repeat dosage by primary or secondary induction of humoral immunity. For example, a recent serological survey indicates that 57% of the adult population in the U.S. has neutralizing antibodies to adenovirus-5 with titers ranging from 1:2 to 1:512. Schulick et al. (1997)
J. Clin. Invest.
99:209-219. Neutralizing antibodies are generated to specific antigenic determinants within 7-14 days following intravenous adenovirus injection. Zinkernagel (1996)
Science
271:173-178. These antibodies are typically specific for proteins on the virion, such as capsid proteins and various glycoproteins. George-Fries et al. (1984)
Virology
134(1):64-71; Fisher et al. (1997)
Nat. Med.
3(3): 306-12; Eing et al. (1989)
J. Med. Virol.
27(1):59-65; Highlander et al. (1987)
J. Virol.
61(11)3356-64; Durali et al. (1998)
J. Virol.
72(5):3547-53. Activation of CD4+ lymphocytes by adenovirus capsid proteins also leads to the up-regulation of MHC class 1 molecules in infected cells contributing to the production of neutralizing antibodies as well as the clearing of adenovirus infected cells by CTLs. Yang et al. (1995)
J. Virol.
69:2004-2015. For many patients, a therapeutic adenovirus will elicit an amnestic humoral response and a CTL response further decreasing the efficacy of repeat intravenous treatment with the same virus. Since the majority of the human population has been exposed to adenovirus during their lifetime, pre-existing immunity could be a major obstacle to the use of adenoviral vectors. Such high prevalence of neutralizing antibodies to adenovirus in adult humans could inhibit adenovirus dissemination (to distant tumor sites for example) and greatly limit the effectiveness of adenovirus-based therapy in vivo. More difficult to quantify is the potential non-neutralizing antibodies to inactivate adenovirus by opsonization.
The effect of antibodies on viral dissemination is a major issue in determining the success of viral therapy using parenteral administration, especially since intravenous administration may be desirable for treatment for metastatic disease. Although recent studies have indicated that pre-existing antibody may not reduce the efficiency of intratumoral viral administration (in terms of tumor regression), virus dissemination appears to be greatly impeded by pre-existing circulating antibodies. One group found that transgene expression in the liver of adenovirus-immune animals following intratumoral injection was reduced more than 1000-fold compared to the transgene expression found in näive mice. Bramson et al. (1997)
Gene Therapy
4:1069-1-76. In another example, in mice 90% of viral vectors is eliminated within 24 hours of intravenous
Charlton David
Henderson Daniel R.
Bozicevic Field & Francis LLP
Cell Genesys Inc.
Housel James
Judge Linda
Li Bao Qun
LandOfFree
Rapid methods and kits for detection and semi-quantitation... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Rapid methods and kits for detection and semi-quantitation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Rapid methods and kits for detection and semi-quantitation... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3251481