Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-04-26
2004-08-10
Wehbé, Anne M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000, C424S093200, C424S130100, C536S023500
Reexamination Certificate
active
06774119
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
1. Field of the Invention
The present invention is related to the medical arts, particularly to the field of gene therapy.
2. Discussion of the Related Art
Viruses have been tested for their ability to treat various types of malignancies in animals and humans. The proposed therapeutic mechanisms of viral tumor therapy in the prior art include: (i) producing new antigens on the tumor cell surface to induce immunologic rejection, called “xenogenization,” and (ii) direct killing of the tumor cell by a virus, called “oncolysis.”
Several animal models and animal types of malignant tumor have been used to study oncolysis with wild-type viruses. (Moore,
Ann. Rev. Microbiol.
8: 393 [1954]; Moore,
Progr. Exp. Tumor Res.
1:411 [1960]). At least nine viruses have been shown to be capable of inducing some degree of tumor regression of a variety of tumors in animals. A major drawback found in these early studies, however, was systemic infection of the patient by the virus.
Later in the quest for a viral therapy for cancer, clinical trials employing herpes viral vector therapy were approved in the United States to treat human tumors. (Culver,
Clin. Chem.
40: 510 [1994]). These studies employed replication-incompetent or defective viruses to potentially overcome the problem of systemic infection by the virus. However, the use of replication-defective herpes viruses for treating malignant tumors requires producer cells because each replication-defective herpes virus particle can enter only a single cell and cannot productively infect others thereafter. Thus, due to their inability to replicate, replication-defective herpes viruses cannot spread to other tumor cells, they are unable to penetrate a deep, multilayered tumor in vivo. (Markert et al.,
Neurosurg.
77: 590 [1992]).
On the other hand, the herpes simplex virus type 1 (HSV-1) appears to be particularly well suited for use in the treatment of malignancies. Mutation of several of the viral genes involved in DNA replication, including UTPase and thymidine kinase- render the virus replication-defective in normal postmitotic cells, like neurons, but replication-competent in dividing cells, which can complement the defect. In addition, the HSV-thymidine kinase (TK) gene product can convert the anti-herpes drugs gancyclovir or acyclovir to nucleotide analogs which block both viral and cellular replication, thereby killing dividing tumor cells.
The need for a safe and effective HSV-1-derived vector is especially acute with respect to malignant tumors of the central nervous system. These malignancies are usually fatal, despite recent advances in the areas of neurosurgical techniques, chemotherapy and radiotherapy. In particular, there are no standard therapeutic modalities that can substantially alter the prognosis for patients with malignant tumors of the brain, cranium, and spinal cord. For example, high mortality rates persist for patients diagnosed with malignant medulloblastomas, malignant meningiomas, malignant neurofibrosarcomas and malignant gliomas, which are characterized by infiltrative tumor cells throughout the brain. Although intracranial tumor masses can be debulked surgically, treated with palliative radiation therapy and chemotherapy, the survival associated with a diagnosis of glioma, especially glioblastoma, is typically measured in months.
Oldfield et al. introduced viral vectors carrying the herpes simplex virus (HSV)-1 thymidine kinase (HS-tk) gene into brain tumor cells in human patients. (Oldfield et al.,
Human Gene Therapy
4: 39 [1993]). In this study, there was some evidence of anti-tumor effect in five of the eight patients in the clinical trial. However, none of the patients was cured of brain cancer. Some of the limitations of current viral based therapies, described by Oldfield, include: (1) the low titer of virus produced; (2) virus spread limited to the region surrounding the producer cell implant; (3) possible immune response to the producer cell line; (4) possible insertional mutagenesis and transformation of virally infected cells; (5) a single treatment regimen of the drug, gancyclovir, because the “suicide” product kills virally infected cells and producer cells; and (6) the bystander effect of killing being limited to cells in direct contact with the virally transformed cells. (Bi, W. L. et al.,
Human Gene Therapy
4: 725 [1993]).
During the early 1990's, the use of genetically engineered replication-competent HSV-1 viral vectors was first explored in the context of finding an antitumor viral therapy. Replication-competent mutants of herpes simplex virus type I (HSV-1) with single mutations demonstrated therapeutic potential against experimental malignant brain tumors, while being attenuated for neurovirulence. It was thought that a replication-competent virus would have the advantage of being able to enter one tumor cell, make multiple copies of its genome, lyse the cell and spread to other tumor cells. A thymidine kinase-deficient (TK
−
) mutant, dlsptk, was able to destroy human malignant glioma cells implanted into the brain of an animal. (Martuza et al., Science 252: 854 [1991]). The major disadvantage to this system was that these TK
−
mutants were only moderately attentuated for neurovirulence, i.e., the ability to replicate in brain cells causing inflammation of the brain, and they produced encephalitis at the doses required to kill the tumor cells adequately. (J. M. Markert et al., Neurosurgery 32: 597 [1993]). Roizman described a HSV-based T
−
vector system capable of expressing foreign genes inserted into the TK gene. (Roizman, Herpes Simplex Virus as a Vector, U.S. Pat. Nos. 5,599,691 and 5,288,641). Residual neurovirulence of TK
−
limits the usefulness of such vectors for tumor therapy.
Other single mutants of HSV-1 included hrR3, containing an insertion of the
Escherichia coli
lacZ gene into the viral ICP6 gene, which encodes the ribonucleotide reductase large subunit (T. Mineta et al., Gene Therapy 1:S78 [1994]; T. Mineta et al., J. Neurosurg. 80:381 [1994]) and R3613 containing deletions in both copies of the &ggr;34.5 gene, a neurovirulence gene. (Markert et al., Neurosurgery 32:597 [1993]). Roizman described a recombinant, purportedly avirulent HSV lacking the ability to express a functional &ggr;34.5 gene product, a neurovirulence factor. (Roizman, Recombinant Herpes Simplex Viruses vaccines and methods, U.S. Pat. No. 5,328,688). Spontaneous reactivation rates of these mutants was only relatively attenuated, not entirely eliminated. (E.g., G.-C. Perng et al, J. Virol. 70(5):2883-93 [1996]; G.-C. Perng et al., J. Virol. 69(5):3033-411 [1995]).
Multi-mutated HSV-1 mutants have been described having augmented safety. Multiple mutations engineered into HSV-1 made the possibility of reversions of wild type unlikely and confirmed multiple and potentially synergistic safety features by attenuating of multiple mechanisms of virulence. Kramm et al. reported a HSV-1 mutant vector, MGH-1, defective for both ribonucleotide reductase and &ggr;34.5, which had higher therapeutic safety than hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. (C. M. Kramm et al., Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy, Hum. Gene Ther. 8(17):2057-68 [1997]). Martuza et al. taught a replication competent HSV-1 vector having deletions in both of its &ggr;34.5 genes, as well as in the ICP6 gene which encodes for the large sub unit of the HSV ribonucleotide reductase. (Martuza et al., Replication-competent Herpes Simplex Virus mediate
Black Keith L.
Nesburn Anthony B.
Perng Guey-Chuen
Wechsler Steven L.
Yu John S.
Cedars-Sinai Medical Center
Sidley Austin Brown & Wood LLP
Wehbe Anne M.
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