Rodent HER2 tumor model

Details Rodent HER2 tumor model Rodent HER2 tumor model

2001-03-16

2003-10-14

Crouch, Deborah (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

Transgenic nonhuman animal

C800S008000, C800S009000, C800S010000, C800S003000, C435S455000, C435S463000, C435S325000, C435S320100

Reexamination Certificate

active

06632979

ABSTRACT:

BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention concerns novel HER2-transgenic non-human mammals and their use to develop a tumor model to test HER2-directed cancer therapies. The invention further concerns anticancer agents identified in this model, and their use in the treatment of cancer.
DESCRIPTION OF THE RELATED ART
Members of the ErbB family of receptor tyrosine kinases are important mediators of cell growth, differentiation and survival. The receptor family includes four distinct members, including epidermal growth factor receptor (EGFR or ErbB 1), HER2 (ErbB2 or p185
neu
), HER3 (ErbB3) and HER4 (ErbB4 or tyro2).
p185
neu
, was originally identified as the product of the transforming gene from neuroblastomas of chemically treated rats. The activated form of the neu proto-oncogene results from a point mutation (valine to glutamic acid) in the transmembrane region of the encoded protein. Amplification of the human homolog of neu is observed in breast and ovarian cancers and correlates with a poor prognosis (Slamon et al.,
Science
, 235:177-182 (1987); Slamon et al.,
Science
, 244:707-712 (1989); and U.S. Pat No. 4,968,603). To date, no point mutation analogous to that in the neu proto-oncogene has been reported for human tumors. Overexpression of ErbB2 (frequently but not uniformly due to gene amplification) has also been observed in other carcinomas including carcinomas of the stomach, endometrium, salivary gland, lung, kidney, colon, thyroid, pancreas and bladder. See, among others, King et al.,
Science
, 229:974 (1985); Yokota et al., Lancet, 1:765-767 (1986); Fukushigi et al.,
Mol Cell Biol
., 6:955-958 (1986); Geurin et al.,
Oncogene Res
., 3:21-31 (1988); Cohen et al.,
Oncogene
, 4:81-88 (1989); Yonemura et al.,
Cancer Res
., 51:1034 (1991); Borst et al.,
Gynecol. Oncol
., 38:364 (1990); Weiner et al.,
Cancer Res
., 50:421-425 (1990); Kern et al.,
Cancer Res
., 50:5184 (1990); Park et al.,
Cancer Res
., 49:6605 (1989); Zhau et al.,
Mol. Carcinog
., 3:354-357 (1990); Aasland et al.
Br. J. Cancer
57:358-363 (1988); Williams et al.
Pathobiology
59:46-52 (1991); and McCann et al.,
Cancer
, 65:88-92 (1990). ErbB2 may be overexpressed in prostate cancer (Gu et al.
Cancer Lett
. 99:185-9 (1996); Ross et al.
Hum. Pathol
. 28:827-33 (1997); Ross et al.
Cancer
79:2162-70 (1997); and Sadasivan et al.
J. Urol
. 150:126-31 (1993)).
Antibodies directed against the rat p185
neu
and human ErbB2 protein products have been described. Drebin and colleagues have raised antibodies against the rat neu gene product, p185
neu
. See, for example, Drebin et al.,
Cell
41:695-706 (1985); Myers et al.,
Meth. Enzym
. 198:277-290 (1991); and W094/22478. Drebin et al.
Oncogene
2:273-277 (1988) report that mixtures of antibodies reactive with two distinct regions of p185
neu
result in synergistic anti-tumor effects on neu-transformed NIH-3T3 cells implanted into nude mice. See also U.S. Pat. 5,824,311 issued Oct. 20, 1998.
Other anti-ErbB2 antibodies with various properties have been described in Tagliabue et al. Int.
J. Cancer
47:933-937 (1991); McKenzie et al.
Oncogene
4:543-548 (1989); Maier et al.
Cancer Res
. 51:5361-5369 (1991); Bacus et al.
Molecular Carcinogenesis
3:350-362 (1990); Stancovski et al. PNAS (USA) 88:8691-8695 (1991); Bacus et al.
Cancer Research
52:2580-2589 (1992); Xu et al.
Int. J. Cancer
53:401-408 (1993); W094/00136; Kasprzyk et al.
Cancer Research
52:2771-2776 (1992);Hancock et al.
Cancer Res.
51:4575-4580 (1991); Shawver et al.
Cancer Res
. 54:1367-1373 (1994); Arteaga et al.
Cancer Res
. 54:3758-3765 (1994); Harwerth et al.
J. Biol. Chem
. 267:15160-15167 (1992); U.S. Pat. No. 5,783,186; and Klapper et al.
Oncogene
14:2099-2109 (1997).
Hudziak et al.,
Mol. Cell. Biol
. 9(3): 1165-1172 (1989) describe the generation of a panel of anti-ErbB2 antibodies which were characterized using the human breast tumor cell line SK-BR-3. Relative cell proliferation of the SK-BR-3 cells following exposure to the antibodies was determined by crystal violet staining of the monolayers after 72 hours. Using this assay, maximum inhibition was obtained with the antibody called 4D5 which inhibited cellular proliferation by 56%. Other antibodies in the panel reduced cellular proliferation to a lesser extent in this assay. The antibody 4D5 was further found to sensitize ErbB2-overexpressing breast tumor cell lines to the cytotoxic effects of TNF-&agr;. See also U.S. Pat. No. 5,677,171 issued Oct. 14, 1997. The anti-ErbB2 antibodies discussed in Hudziak et al. are further characterized in Fendly et al.
Cancer Research
50:1550-1558 (1990); Kotts et al.
In Vitro
26(3):59A (1990); Sarup et al.
Growth Regulation
1:72-82 (1991); Shepard et al.
J. Clin. Immunol
. 11(3):117-127 (1991); Kumar et al.
Mol. Cell. Biol
. 11(2):979-986 (1991); Lewis et al.
Cancer Immunol. Immunother
. 37:255-263 (1993); Pietras et al.
Oncogene
9:1829-1838 (1994); Vitetta et al.
Cancer Research
54:5301-5309 (1994); Sliwkowski et al.
J. Biol. Chem
. 269(20):14661-14665 (1994); Scott et al.
J. Biol. Chem
. 266:14300-5 (1991); D'souza et al.
Proc. Natl. Acad. Sci
. 91:7202-7206 (1994); Lewis et al.
Cancer Research
56:1457-1465 (1996); and Schaefer et al.
Oncogene
15:1385-1394 (1997).
The murine monoclonal anti-HER2 antibody inhibits the growth of breast cancer cell lines that overexpress HER2 at the 2+ and 3+ level, but has no activity on cells that express lower levels of HER2 (Lewis et al.,
Cancer Immunol. Immunother
. [1993]). Based on this observation, antibody 4D5 was humanized (Carter et al.,
Proc. Natl. Acad. Sci. USA
89: 4285-4289 [1992]). The humanized version designated HERCEPTIN® (huMAb4D5-8, rhuMAb HER2, U.S. Pat. No. 5,821,337) was tested in breast cancer patients whose tumors overexpress HER2 but who had progressed after conventional chemotherapy (Cobleigh et al.,
J. Clin. Oncol
. 17: 2639-2648 [1999]). Most patients in this trial expressed HER2 at the 3+ level, though a fraction was 2+ tumors. Remarkably, HERCEPTIN® induced clinical responses in 15% of patients (complete responses in 4% of patients, and partial responses in 11%) and the median duration of those responses was 9.1 months. HERCEPTIN® received marketing approval from the Food and Drug Administration Sep. 25, 1998 for the treatment of patients with metastatic breast cancer whose tumors overexpress the ErbB2 protein.
Although HERCEPTIN° is a breakthrough in treating patients with ErbB2-overexpressing breast cancers that have received extensive prior anti-cancer therapy, generally approximately 85% of the patients in this population fail to respond or respond only poorly to HERCEPTIN® treatment, and in the clinical trial preceding market approval, the median time to disease progression in all treated patients was only 3.1 months.
Therefore, there is a significant clinical need for developing further HER2-directed cancer therapies for those patients with HER2-overexpressing tumors or other diseases associated with HER2 expression that do not respond or respond poorly to HERCEPTIN® treatment.
SUMMARY OF THE INVENTION
The present invention is based on the development of a novel HER2-transgenic mouse tumor model that expresses HER2 at high levels, comparable to those in HER2-positive human patients, but that responds poorly to HERCEPTIN®.
In one aspect, the invention concerns a transgenic non-human mammal that produces in its mammary gland cells detectable levels of a native human HER2 protein or a fragment thereof, wherein said transgenic mammal has stably integrated into its genome a nucleic acid sequence encoding a native human HER2 protein or a fragment thereof having the biological activity of native human HER2, operably linked to transcriptional regulatory sequences directing its expression to the mammary gland, and develops a mammary tumor not responding or poorly responding to anti-HER2 antibody treatment. The transcriptional regulatory sequences preferably comprise a mammary gland specific promot

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