Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-10-06
2002-06-18
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C424S140100, C424S233100, C424S131100, C424S159100, C424S278100, C424S093100, C530S351000, C514S885000
Reexamination Certificate
active
06406861
ABSTRACT:
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
Not applicable.
1. Technical Field
This invention relates to the field of administration of viral immunogenic therapeutic agents, particularly diminishing host humoral immune response to such administration.
2. Background Art
A broad spectrum of human disease involves genetic aberrations at the cellular level. Some of these diseases include cystic fibrosis, anemia, hemophilia, diabetes, Huntington's Disease, AIDS, abnormally high serum cholesterol levels, and certain immune deficiencies. In particular, a disease that has touched almost everyone's lives is cancer. In spite of massive research efforts, only limited progress has been made in treating any of these diseases.
A number of new potentially promising therapies are currently under development. Gene therapy, in which a defective gene or sequence is supplanted with an exogenenous sequence, may be useful in treating not only cancer, but all of the previously listed diseases. Gene therapy generally requires a delivery vehicle for the exogenous sequence such as a viral vector. Newly developed viral agents that may be effective vectors against these diseases include retroviruses and recombinant adenoviruses. For review see Kim et al. (1996)
Mol. Med. Today
12:519-527) and Smith et al. (1996)
Gene Therapy
3:496-502. Other viral vectors that are potentially useful as therapeutic agents include Moloney mouse leukemia virus (MoMLV), Pox virus, Herpes virus, HIV and Adeno-associated viruses (AAV).
In addition, in the cancer context, more 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 commonly-owned U.S. patent application Ser. Nos. 09/033,555, 09/033,333, 60/076,545, and 09/033,556. Another attenuated replication-competent adenovirus is Onyx-015 adenovirus. Onyx-015 has a deletion in the E1B-55 kDa 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 contributing to adenovirus as 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.
The adenovirus type 5 genome is a double-stranded DNA molecule of 35,935 base pairs containing short inverted terminal repeats. Chroboczek et al. (1992)
Virology
186:280-285; Garon et al. (1972)
Proc. Natl. Acad. Sci. USA
69:2391-2395. Expression of the genome is a regulated cascade which is arbitrarily divided into early (E) and late (L) phases, with viral DNA replication required for maximal L gene expression. Related RNA transcripts are grouped according to the region of the genome from which they are transcribed as well as by the timing (E or L) of their expression. The E3 region is not essential for replication in tissue culture and this region is deleted from most first-generation therapeutic adenovirus.
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.
Use of viral therapeutic agents such as adenovirus holds promise, but there are a number of significant barriers to their effectiveness. Two of the major limitations of virus-based vectors as therapeutic vehicles are (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, with respect to adenovirus, 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); 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 I 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 viral 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 type 5-based therapy in vivo.
The effect of neutralizing 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 or non-discrete tumors. 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 naive 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 injection. Worgall et al. (1997)
Hum. Gene Ther.
8:37-44. This finding was confirmed by quantitative analysis of viral DNA in liver, spleen and lung using Southern analysis over the first 70 hours post injection demonstrating a 90% elimination of vector. Christ et al. (1997)
Immunology Letters
57:19-25. Schulick et al. (1997) found if rats are immunized by prior intravenous exposure to adenovirus, a second intravenous injection of an adenovirus vector gave no evidence o
Chen Yu
Henderson Daniel R.
Yu De Chao
Bozicevic Field & Francis LLP
Brown Stacy S.
Cell Genesys Inc.
Park Hankyel T.
Sherwood Pamela J.
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