Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2001-02-27
2003-04-15
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S130100, C424S138100, C424S139100
Reexamination Certificate
active
06548062
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of oncology and is directed to a method for treating or preventing cancer, particularly prostate and pancreatic cancers. The present invention also pertains to the area of neurotrophins and the use of anti-neurotrophin agents such as, for example, antibodies, in treating or preventing cancer and/or pain.
BACKGROUND OF THE INVENTION
Neurotrophins (NTs) are a subfamily of specific neurotrophic factors including four well known structurally and functionally related proteins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5). Recently, two additional NTs, neurotrophin-6 (NT-6) and neurotrophin-7 (NT-7), have been discovered. The neurotrophins bind to and activate specific cell surface membrane receptors which have tyrosine kinase activity. These receptors are known as trk receptors and are classified according to the three subtypes trkA, trkB, and trkC. Each trk receptor subtype binds preferentially to one or more NTs (NGF to trkA, BDNF and NT-4/5 to trkB, and NT-3 to trk C). NT cross reactivity, however, is known to occur between receptor subtypes. Activation of trk receptors by NTs results in receptor oligomerization and tyrosine phosphorylation of specific intracellular substrates. In addition to the trk receptors, a second type of cell surface membrane receptor is known to bind NTs. This receptor is the low-affinity nerve growth receptor p75
NTR
(p75) which is believed to be involved in modulation of NT affinity and/or availability for binding to higher affinity trk receptors. A specific physiological role for receptor p75, however, remains in debate.
It is widely recognized that NTs play an essential role in growth, differentiation, and survival of central and peripheral nervous system cells. There is recent evidence, however, that NTs also contribute to tumor biology outside the nervous system. Neurotrophins and their receptor subtypes have been implicated in various cancers including prostate, breast, thyroid, colon, and lung carcinomas, as well as malignant melanomas, pancreatic carcinoids, and glioblastomas. Specifically, aberrant expression of trk receptors A, B, and C have been found in pancreatic ductal adenocarcinoma (PDAC), and NTs can influence the invasiveness of this tumor type (Miknyoczki, et al.,
Int. J. Cancer,
1999, 81, 417). In addition, NGF has been correlated with perineural invasion and pain that is associated with PDAC (Zhu, et al.,
J. Clin. Oncol.,
1999, 17, 2419). TrkA is also known to be expressed in prostatic epithelial tissue, and the corresponding neurotrophin NGF has been implicated in the stimulation of prostate cancer growth. Immunoreactivity for NGF has been demonstrated in human prostatic carcinomas (De Schryver-Kecskemeti et al,
Arch. Pathol.,
1987, 111, 833) and tumor-derived cell lines (MacGrogan et al.,
J. Neurochem.,
1992, 59, 1381) suggesting a possible mitogenic or survival role for NGF in this cancer. Further, prostatic carcinoma cells have been shown to be chemotactic (Djakiew, et al.,
Cancer. Res.,
1993, 53, 1416) and invasive (Geldof, et al.,
J. Cancer Res. Clin. Oncol.,
1997, 123, 107) in response to NGF in vitro.
Trks have been shown to play a role in both prostatic cancer (Delsite et al.,
J. Androl.,
1996, 17, 481, Pflug et al,
Endocrinology,
1995, 136, 262, Pflug et al.,
Cancer Res.,
1992, 52, 5403, Djakiew et al.,
Cancer Res.,
1991, 51, 3304, Passaniti et al.,
Int. J. Cancer,
1992, 51, 318, MacGrogan et al.,
J. Neurochem.,
1992, 59, 1381, Geldof et al.,
J. Cancer Res. Clin. Oncol.
1997, 123, 107, Pflug et al.,
Mol. Carcin.,
1998, 12, 106, and George et al.,
The Prostrate,
1998, 36, 172) and pancreatic cancer (Oikawa, et al.,
Int. J. Pancreat.,
1995, 18, 15, Ohta et al.,
J. Pathol.,
1997, 181, 405, Miralles et al.,
J. Endocrinology,
1998, 156, 431, and Miknyoczki et al.,
Crit. Rev. Oncogenesis,
1996, 7, 89).
Due to the possible role of trk activity in the development and progression of certain cancers, selective disruption of NT-trk axes has been targeted as a possible therapeutic means. Specifically, small molecules have been developed and tested which show ability to inhibit trk receptors (Ruggeri, et al.,
Current Medicinal Chemistry,
1999, 6, 845). The glycosylated indolocarbazole alkaloids K-252a and K-252b are known to inhibit the biological actions of NGF and other neurotrophins. K-252a has been reported to specifically inhibit the autophosphorylation of trkA as well as trkB and trkC and other related neurotrophin receptors at low nanomolar concentrations (Hashimoto,
Cell Biol.,
1988, 107, 1531; Berg, et al.,
J. Biol. Chem.,
1992, 267, 13; Tarpley, et al.,
Oncogene,
1992, 7, 371; Ohmichi, et al,
Biochemistry,
1992, 31, 4034; Muroya, et al.,
Biochim. Biophys. Acta.,
1992, 1135, 353; and Nye, et al.,
Mol. Biol. Cell,
1992, 3, 677.) By modification of the sugar moiety of K-252a, two additional potent trk inhibitors have been developed. Specifically, CEP-751, a hydroxymethyl derivative of K-252a, has been found to be a potent inhibitor of trkA (IC
50
of 3 nM in an ELISA), trkB, and trkC. A dipeptide derivative, CEP-2563, was also synthesized which showed similar activity and improved water solubility. Another related compound, CEP-701, was also found to have good trkA inhibitory activity showing an IC
50
of 4 nM. Both CEP-751 and CEP-701 have been shown to significantly inhibit human and rat prostatic carcinomas in pre-clinical models (Dionne, et al.,
Clin. Cancer Res.,
1998, 4, 1887 and George, et al.,
Cancer Research,
1999, 59, 2395). CEP-751 has also been shown to display anti-tumor activity in neuroblastoma and medulloblastoma xenografts (Evans, et al.,
Clin. Cancer Res.,
1999, 5, 3594), as well as ovarian cancer and melanoma models. Further, significant anti-tumor activity by CEP-701 in preclinical xenograft models of human pancreatic ductal adenocarcinoma has also been shown (Miknyoczki, et al.,
Clin. Cancer Res.,
1999, 5, 2205). CEP-701 is currently undergoing human clinical trials.
Although these small molecule trk inhibitors can be used as tools for treating prostate, pancreatic, and other cancers, it is difficult to develop small molecules with specificity for a particular target molecule. One of the main concerns in general for small molecules is non-specificity for target receptors or receptor pathways, leading to undesirable activation or inactivation of other receptors and possible toxicity. For instance, K-252a has been shown to have multiple biochemical properties including neurotrophic activity in combination with trk and protein kinase C inhibiting activities (Kaneko, et al,
J. Med. Chem.,
1997, 40, 1863). Thus, therapeutic agents with high specificity for biological targets which are involved in trk receptor activity are desirable as potential drug candidates for the treatment of prostate, pancreatic, and other cancers. To this end, antibodies directed to a particular trk receptor have been shown to be less desirable than small molecules (LeSauteur et al.,
Nature Biotech.,
1996, 14, 1120). The present invention provides a method for treating trk receptor-mediated cancers, such as, for example, pancreatic or prostrate cancer, by administering at least one neutralizing neurotrophin antibody to a mammal. The antibody treatment provides much desired specificity that small molecules may indeed not offer.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating or preventing cancer comprising administering to a mammal a therapeutically effective amount of at least one anti-neurotrophin agent. The anti-neurotrophin agent is preferably either an anti-neurotrophin antibody, an antisense molecule directed to a neurotrophin, a small organic molecule which binds a neurotrophin, and a dominant-negative mutation of a trk receptor that binds a neurotrophin. This method is particularly preferred for the treatment of prostate or pancreatic cancer. Anti-neurotrophin agents include those directed to NGF,
Buchkovich Karen J.
Dionne Craig A.
Miknyoczki Sheila J.
Ruggeri Bruce A.
Cephalon Inc.
Huff Sheela
Woodcock & Washburn LLP
LandOfFree
Method of treating cancer with anti-neurotrophin agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of treating cancer with anti-neurotrophin agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of treating cancer with anti-neurotrophin agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3030003