Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-09-06
2003-02-11
Wortman, Donna C. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007920, C435S007950, C435S040520, C436S518000, C436S527000
Reexamination Certificate
active
06518033
ABSTRACT:
The present invention relates to a method of diagnosing, classifying and grading of tumor growths and to determine whether the use of chimeric polioviruses is a proper course for the treatment of the tumors. More particularly, the method is directed to the use of antibodies to a poliovirus receptor (PVR), CD155, to detect the presence of CD155 on tumor cells in various organs, such as: breast, colon, bronchial passage, epithelial lining of the gastrointestinal, upper respiratory and genito-urinary tracts, liver, prostate and the brain.
BACKGROUND OF THE INVENTION
It has been found by the inventors that malignant tumors can be successfully treated with chimeric polioviruses wherein the internal ribosomal entry site (IRES) is replaced with the IRES of another picornavirus. This finding is the subject of U.S. patent application Ser. No. 09/129,686, incorporated herein by reference.
Poliovirus is a small iscosahedral RNA virus belonging to the picornavirus family. It is best known as the etiologic agent of poliomyelitis, the visible clinical sign of which is flaccid paralysis. The virus when ingested, infects and replicates in the gut, leading to viremia. In a small portion of infected individuals, the virus invades the central nervous system through the circulation. It is the lytic replication in motor neurons of the brain stem and spinal cord that causes destruction of these cells and the characteristic flaccid paralysis of poliomyelitis. Bodian D.,
Science
(1955)12:105-108. It is known that poliovirus invades only a limited number of specific cells in the body, an unknown population of cells lining the gastrointestinal tract and spinal cord anterior horn as well as medullary motor neurons. It is the unusual restricted cell tropism of poliovirus that leads to unique pathognomonic features, characterized by motor neuron loss in the spinal cord and the medulla, giving rise to the hallmark clinical sign of poliomyelitis, flaccid paralysis, Bodian, D., supra. The restricted tropism of poliovirus is poorly understood. In addition to the restricted cell and tissue tropism, poliovirus only infects primates and primate cell cultures. Other mammalian species remain unaffected. Ren, R. et al.,
Cell
(1990) 63:353-362.
The isolation of poliovirus in 1908 led to intensive research efforts to understand the mechanisms of infection. The earlier work required the use of monkeys and chimpanzees as animal models. Such animals with longer life cycles are very costly and difficult to use in research. The discovery of the human poliovirus receptor (PVR), the cellular docking molecule for poliovirus, led to the development of a transgenic mouse expressing the human poliovirus receptor as a new animal model for poliomyelitis. Mice transgenic for PVR, when infected with poliovirus, develop a neurological syndrome histopathologically and clinically identical to primate poliomyelitis. Koike et al.,
Proc. Natl. Acad. Sci. U.S.A.
(1991) 88:951-955. The observation of poliomyelitis in polio-infected transgenic animals suggests that CD155 alone is responsible for directing poliovirus towards spinal cord anterior horn motor neurons mediating their infection and subsequent lytic destruction. Gromeier et al.,
Proc. Natl. Acad. Sci. U.S.A.
(1996) 93:2370-2375. The poliovirus receptor, previously referred to as PVR, has now been classified as CD155. Mendelsohn C. et al.,
Cell
(1989) 56:855-865 and U.S. Pat. Nos. 5,631,407 and 5,753,521.
Up to the present, CD155 has not been associated with malignant tumors. Polypeptide CD155 is a cell-surface protein belonging to the immunoglobulin superfamily. Its gene is the founding member of a new family of primate and rodent genes that encode polypeptides with a common structural arrangement of three extracellular (V-C2-C2) domains. CD155 is expressed in four isoforms: hPVR&agr; and hPVR&dgr; are membrane-bound variants that differ only in the sequence of the cell-internal C-terminal domain, while hPVR&bgr; and hPVR&ggr; are secreted isoforms lacking the transmembrane domain. Koike et al.,
EMBO J.
(1990) 9: 3217-3229; Wimmer et al., In:
Cellular Receptors for Animal Viruses
(1993) Cold Spring Laboratory Press: Plainview. N.Y. hPVR&agr; and hPVR&dgr; are type Ia single-pass transmembrane glycoproteins with apparent M
r
of >80 kDa, whereas the core polypeptides are 42.5 and 40 kDa, respectively. Binding of poliovirus occurs at the V-domain of the polypeptide. Bernhardt et al.,
Virology
(1994) 203: 344-356.
First indications for an association between CD155 and cancer are based on assays making use of polioviruses to infect and destroy tumor cells derived from human malignancies. In co-pending U.S. application Ser. No. 09/129,686, the effectiveness of recombinant chimeric polioviruses for the treatment of various forms of cancer was desribed. Human tumor cells obtained from explant surgical material were susceptible to poliovirus whereas their non-malignant progenitors are known to resist poliovirus infection. It was suspected that the acquisition of susceptibility to poliovirus is based on the overexpression of the cellular receptor for poliovirus on cells upon malignant transformation. A precedent for this assumption is provided by a homolog of CD155 in rodents, the murine Tage4 molecule. Tage4 was isolated from rodent colon- and mammary carcinomas, where it occurs in abundance. Chadeneau et al.,
Int. J. Cancer
(1994) 68:817-821. In contrast, Tage4 could hardly be detected in normal rodent colon- or mammary duct epithelium. Chadeneau et al., supra.
The link of CD155 with cancer is further evident from studies of the expression of CD155 during embryonic development. Like many of its fellow members of the immunoglobulin superfamily, CD155 appears to be expressed during embryonic development. Frequently, immunoglobulin superfamily molecules that are expressed in a developmental manner have been associated with malignancy. It has been determined that CD155 may be expressed in a group of highly specialized structures within the embryonic central nervous system, e.g., floor plate, notochord, and optic nerve. These studies not only provided evidence for the distribution of CD155 in the developing nervous system but also pointed towards a physiological function of CD155 that may encompass a role during morphogenesis of the central nervous system. Molecules related to CD155 in structure or sequence are known to be expressed with an overlapping distribution during central nervous system ontogeny. Walsh et al.,
Annul Rev. Cell Dev. Biol.
(1997) 13:425-456; Colamarino et al.,
Annul Rev. Neurosci.
(1995) 18:497-529.
Molecules of the immunoglobulin superfamily, for example Tage4 (see above), are increasingly recognized for their association with cancer. Sasaki et al.,
Cancer
(1998) 82:1921-1931; Gingras et al., J. Neuroimmunol. (1995) 57: 143-153; Figarella-Branger et al.,
Cancer Res.
(1990) 50:6364-6370. It is believed that molecules belonging to the immunoglobulin superfamily with a function involving the mediation of cell adhesion and axonal guidance are frequently overexpressed in malignant tumors. Their physiological functions may be of relevance for the biology of tumors. Aberrant properties of tumor cells, for example invasiveness, migration and metastatic spread may correlate to the expression of immunoglobulin superfamily molecules with a function in cell adhesion. Izumoto et al.,
Cancer Res.
(1996) 56:1440-1444. Corroborating the findings with other cell adhesion molecules of the immunoglobulin superfamily with a role in embryonic development of the CNS we provided extensive evidence that CD155, indeed, is abundant in a variety of human malignancies (see below).
Antibodies to CD155
Monoclonal antibodies which recognize CD155 have been developed. In particular, a murine monoclonal antibody was developed by immunizing mice with plasma membrane preparations of HeLa cells. The monoclonal antibody D171 was selected for its ability to protect HeLa cells against the cytopathic effect of poliovirus. It was found that the antibody or its Fab fragments boun
Gromeier Matthias
Wimmer Eckard
Scully Scott Murphy & Presser
The Research Foundation of State University of New York
Wortman Donna C.
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