Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1999-07-01
2004-01-06
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S145100, C424S138100
Reexamination Certificate
active
06673341
ABSTRACT:
BACKGROUND OF THE INVENTION
TGF-&bgr;1 is a polypeptide growth factor that belongs to a large family of structurally related growth factors referred to as the TGF-&bgr; superfamily. It is a multifunctional cytokine that plays a major role in morphogenesis, development, tissue repair, and in the pathogenesis of fibrotic diseases (Massague, J. et al.,
Cancer Surv
1992;12:81-103 (1992), Norgaard, P., Hougaard, S., Poulsen, H. S. & Spang-Thomsen, M.,
Cancer Treat Rev
21, 367-403 (1995)). While TGF-&bgr;1 was originally described as an inducer of anchorage independent growth in fibroblasts, it is known to be a potent inhibitor of epithelial cell growth, though it can stimulate the growth of certain tumor cells (Huang, F., Newman, E., Theodorescu, D., Kerbel, R. S. & Friedman, E.,
Cell Growth Differ
6, 1635-1642 (1995), Lu, C. & Kerbel, R. S.,
Curr Opin Oncol
6, 212-220 (1994)). The role of TGF-&bgr; in human malignancies is complex and both paracrine and autocrine actions need to be assessed. TGF-&bgr;1 is elevated in several cancers including clear-cell renal carcinomas (RCCs) (Derynck, R. et al.,
Cancer Res
4 7, 707-712 (1987), Gomella, L. G. et al.,
Cancer Res
49, 6972-6975 (1989), Ramp, U. et al.,
J Urol
157, 2345-2350 (1997)). Some tumor cells are sensitive to TGF-&bgr;'s growth suppressive effects, whereas others are not (Gomella, L. G. et al.,
Cancer Res
49, 6972-6975 (1989), MacKay, S. L. et al.,
Ann Surg
2 2 1, 767-776; discussion 776-767 (1995), Jakowlew, S. B., Mathias, A., Chung, P. & Moody, T. W.,
Cell Growth Differ
6, 465-476 (1995), Jakowlew, S. B., Moody, T. W. & Mariano, J. M.,
Anticancer Res
17, 1849-1860 (1997), and Norgaard, P., Spang-Thomsen, M. & Poulsen, H. S.,
Br J Cancer
73, 1037-1043 (1996)). In a recent paper, 20/20 primary RCCs and 30/30 RCC cell lines expressed TGF-&bgr;1, with the majority of the cell lines resistant to the growth suppressive effect of exogenous TGF-&bgr;1 (Ramp, U. et al,
Lab Invest
76, 739-749 (1997)). Moreover, serum and urine levels of TGF-&bgr;1 and tissue expression of TGF-&bgr;1 mRNA in several cancers correlate inversely with prognosis, suggesting an important paracrine role for TGF-&bgr;1 in promoting tumor progression and possibly metastasis in vivo (Tsai, J. F. et al.,
Medicine
(Baltimore) 76, 213-226 (1997), Knoefel, B. et al.,
J Interferon Cytokine Res
17, 95-102 (1997), Ivanovic, V., Melman, A., Davis-Joseph, B., Valcic, M. & Gellebter, J.,
Nat Med
1, 282-284 (1995), Friess, H. et al.,
Gastroenterology
105, 1846-1856 (1993), and Junker, U. et al.,
Cytokine
8, 794-798 (1996)).
RCC is the most common cancer of the kidney, occurring in over 27,000 individuals in the U.S. each year and is responsible for over 11,000 deaths annually (Linehan, W. M., Lerman, M. I. & Zbar, B.,
JAMA
273, 564-570 (1995)). The treatment of RCC remains frustrating to the oncologist; locally unresectable and metastatic disease has dismal prognosis. There is tremendous need to understand the basic biology of RCC and develop better therapeutic options. Most sporadic and hereditary RCCs (VHL-disease associated) have mutated and/or loss of both copies of the VHL gene (Linehan, W. M., Lerman, M. I. & Zbar, B.,
JAMA
273, 564-570 (1995)). The VHL gene product (pVHL) is lost in early atypical cysts, suggesting that pVHL might play a “gatekeeper” role in RCC development, analogous to the APC gene product in colon cancer (Lubensky, I. A. et al.,
J Pathol
149, 2089-2094 (1996) and Maher, E. R. & Kaelin, W. G., Jr.,
Medicine
(Baltimore) 76, 381-391 (1997)). VHL-disease associated tumors are typically hypervascular and target genes identified to date include VEGF, TGF-&agr; and PDGF-B, all of which have pro-angiogenic effects (Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G., Jr. & Goldberg, M. A.,
Proc Natl Acad Sci USA
93, 10595-10599 (1996), Knebelmann, B., Ananth, S., Cohen, H. T. & Sukhatme, V. P.,
Cancer Res
58, 226-231 (1998), Mukhopadhyay, D., Knebelmann, B., Cohen, H. T., Ananth, S. & Sukhatme, V. P.,
Mol Cell Biol
17, 5629-5639 (1997), and Gnarra, J. R. et al.,
Proc Natl Acad Sci USA
93, 10589-10594 (1996)). TGF-&bgr; is another gene significantly involved in angiogenesis (Pepper, M. S., Mandriota, S. J., Vassalli, J. D., Orci, L. & Montesano, R.,
Curr Top Microbiol Immunol
213, 31-67 (1996)). Although TGF-&bgr;1 has been found to be elevated in RCCs (Derynck, R. et al.,
Cancer Res
47, 707-712 (1987), Gomella, L. G. et al.,
Cancer Res
49, 6972-6975 (1989), Ramp, U. et al.,
J Urol
157, 2345-2350 (1997), Ramp, U. et al.,
Lab Invest
76, 739-749 (1997), and Knoefel, B. et al.,
J Interferon Cytokine Res
17, 95-102 (1997)) there has been no link to date with the VHL tumor suppressor and no functional role has been ascribed to TGF-&bgr;1 for RCC growth in vivo.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that TGF-&bgr;1 is a novel target gene for pVHL (von Hippel-Lindau) and that pVHL regulates the TGF-&bgr;1 gene at the post-transcriptional level. Furthermore, as described herein, evidence is presented that antagonizing the effects of TGF-&bgr;1 suppresses tumor growth in vivo through an anti-angiogenic mechanism.
In particular, the present invention relates to methods of inhibiting proliferative diseases in a vertebrate. The proliferative disease is characterized as having increased production of TGF-&bgr; and is further characterized by having angiogenic activity. The increased TGF-&bgr; production can be global, or be very localized, and the TGF-&bgr; can be secreted either by proliferating cells, or by stromal cells, such as fibroblasts, macrophages, platelets, endothelial calls, granular neutrophils, and other cells. Because TGF-&bgr; can autoregulate itself, and induce production of more TGF-&bgr;, the cells surrounding those producing TGF-&bgr; can in turn produce TGF-&bgr;. More particularly, the angiogenic activity is TGF-&bgr;-mediated angiogenic activity and the inhibition of the proliferative disease results from the inhibition of TGF-&bgr;-mediated angiogenesis, specifically the “resolution” phase of TGF-&bgr;-mediated angiogenesis. As defined herein, the “resolution” phase of angiogenesis is the phase of angiogenesis where endothelial cells stop proliferating and migrating, in which basement membrane reforms and in which pericytes, the differentiation of which is known to be TGF-&bgr; dependent, attach to the basement membrane.
Although any proliferative disease characterized as above is encompassed by the present invention, in one embodiment of the present invention, the proliferative disease is cancer, or tumor growth, and the inhibition of the disease results in inhibiting the growth of a tumor, or in the regression of an already established tumor. In particular, the cancer is clear-cell renal carcinoma, or RCC.
As described herein, TGF-&bgr;-mediated angiogenesis can be inhibited by contacting the proliferating cells with a molecule that inhibits (or neutralizes or antagonizes) angiogenic activity mediated by TGF-&bgr;, including TGF-&bgr;1, TGF-&bgr;2, and TGF-&bgr;3. For example, the molecule can be an anti-TGF-&bgr; antibody, a TGF-&bgr; antagonist such as decorin or LAP, a soluble form of a TGF-&bgr; receptor or an anti-sense oligonucleotide that binds to (hybridizes with) DNA or RNA encoding TGF-&bgr;, or molecules that block TGF-&bgr;'s interaction with receptor(s), molecules working intracellularly, i.e., downstream, of TGF-&bgr; receptor(s).
In another embodiment of the present invention, the proliferative disease is inhibited by contacting the proliferating cells with a molecule that inhibits TGF-&bgr; activity as described above in combination with one, or more additional anti-angiogenic molecules, e.g., angiostatin or endostatin or restin, or biologically active fragments thereof. In yet another embodiment of the present invention, the proliferating cells are contacted with a chemotherapeutic, immunotherapeutic or radiologic agent in combination with the molecule that inhibits TGF-&bgr; angiogenic activity. Additionally enc
Beth Israel Deaconness Medical Center
Caputa Anthony C.
Gyure Barbara A.
Nickol Gary B
Palmer & Dodge LLP
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