Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds expression product or fragment thereof of...
Reexamination Certificate
2000-08-25
2003-09-30
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds expression product or fragment thereof of...
C424S131100, C424S133100, C424S134100, C424S135100, C424S136100, C424S137100, C424S139100, C424S141100, C424S142100, C424S143100, C424S144100, C424S145100, C424S146100, C424S147100, C424S150100, C424S151100, C424S152100, C424S153100, C424S154100, C424S155100, C424S156100, C424S158100, C424S172100, C424S174100
Reexamination Certificate
active
06627196
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the treatment of disorders characterized by the overexpression of ErbB2 or disorders expressing epidermal growth factor receptor (EGFR), comprising administering to a human or animal presenting the disorders a therapeutically effective amount of an antibody that binds ErbB2. More specifically, the invention concerns the treatment of human patients susceptible to or diagnosed with cancer overexpressing ErbB2 or expressing EGFR, where the treatment is with an anti-ErbB2 antibody administered by front loading the dose of antibody during treatment by intravenous and/or subcutaneous administration. The invention optionally includes treatment of cancer in a human patient with a combination of an anti-ErbB2 antibody and a chemotherapeutic agent, such as, but not limited to, a taxoid. The taxoid may be, but is not limited to paclitaxel or docetaxel. The invention further includes treatment of cancer in a human patient with a combination of anti-ErbB2 antibody and a chemotherapeutic agent, such as, but not limited to, an anthracycline derivative. Optionally, treatment with a combination of anti-ErbB2 and an anthracycline derivative includes treatment with an effective amount of a cardioprotectant. The present invention further concerns infrequent dosing of anti-ErbB2 antibodies.
BACKGROUND OF THE INVENTION
Proto-oncogenes that encode growth factors and growth factor receptors have been identified to play important roles in the pathogenesis of various human malignancies, including breast cancer. It has been found that the human ErbB2 gene (erbB2, also known as her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoprotein receptor (p185
HER2
) related to the epidermal growth factor receptor (EGFR), is overexpressed in about 25% to 30% of human breast cancer (Slamon et al.,
Science
235:177-182 [1987]; Slamon et al.,
Science
244:707-712 [1989]).
Several lines of evidence support a direct role for ErbB2 in the pathogenesis and clinical aggressiveness of ErbB2-overexpressing tumors. The introduction of ErbB2 into non-neoplastic cells has been shown to cause their malignant transformation (Hudziak et al.,
Proc. Natl. Acad. Sci. USA
84:7159-7163 [1987]; DiFiore et al.,
Science
237:78-182 [1987]). Transgenic mice that express HER2 were found to develop mammary tumors (Guy et al.,
Proc. Natl. Acad. Sci. USA
89:10578-10582 [1992]).
Antibodies directed against human erbB2 protein products and proteins encoded by the rat equivalent of the erbB2 gene (neu) have been described. Drebin et al.,
Cell
41:695-706 (1985) refer to an IgG2a monoclonal antibody which is directed against the rat neu gene product. This antibody called 7.16.4 causes down-modulation of cell surface p185 expression on B104-1-1 cells (NIH-3T3 cells transfected with the neu proto-oncogene) a inhibits colony formation of these cells. In Drebin et al.
PNAS
(
USA
) 83:9129-9133 (1986), the 7.16.4 antibody was shown to inhibit the tumorigenic growth of neu-transformed NIH-3T3 cells as well as rat neuroblastoma cells (from which the neu oncogene was initially isolated) implanted into nude mice. Drebin et al. in
Oncogene
2:387-394 (1988) discuss the production of a panel of antibodies against the rat neu gene product. All of the antibodies were found to exert a cytostatic effect on the growth of neu-transformed cells suspended in soft agar. Antibodies of the IgM, IgG2a and IgG2b isotypes were able to mediate significant in vitro lysis of neu-transformed cells in the presence of complement, whereas none of the antibodies were able to mediate high levels of antibody-dependent cellular cytotoxicity (ADCC) of the neu-transformed cells. Drebin et al.
Oncogene
2:273-277 (1988) report that mixtures of antibodies reactive with two distinct regions on the p185 molecule result in synergistic anti-tumor effects on neu-transformed NIH-3T3 cells implanted into nude mice. Biological effects of anti-neu antibodies are reviewed in Myers et al.,
Meth. Enzym
. 198:277-290 (1991). See also WO94/22478 published Oct. 13, 1994.
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 SKBR3. Relative cell proliferation of the SKBR3 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,including 7C2 and 7F3, reduced cellular proliferation to a lesser extent in this assay. Hudziak et al. conclude that the effect of the 4D5 antibody on SKBR3 cells was cytostatic rather than cytotoxic, since SKBR3 cells resumed growth at a nearly normal rate following removal of the antibody from the medium. The antibody 4D5 was further found to sensitize p 185 -overexpressing breast tumor cell lines to the cytotoxic effects of TNF-&agr;. See also WO89/06692 published Jul. 27, 1989. 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); and D'souza et al.
Proc. Natl. Acad. Sci
.91:7202-7206 (1994).
Tagliabue et al.
Int. J. Cancer
47:933-937 (1991) describe two antibodies which were selected for their reactivity on the lung adenocarcinoma cell line (Calu-3) which overexpresses ErbB2. One of the antibodies, called MGR3, was found to internalize, induce phosphorylation of ErbB2, and inhibit tumor cell growth in vitro.
McKenzie et al.
Oncogene
4:543-548 (1989) generated a panel of anti-ErbB2 antibodies with varying epitope specificities, including the antibody designated TA1. This TA1 antibody was found to induce accelerated endocytosis of ErbB2 (see Maier et al.
Cancer Res
. 51:5361-5369 [1991]). Bacus et al.
Molecular Carcinogenesis
3:350-362 (1990) reported that the TA1 antibody induced maturation of the breast cancer cell lines AU-565 (which overexpresses the erbB2 gene) and MCF-7 (which does not). Inhibition of growth and acquisition of a mature phenotype in these cells was found to be associated with reduced levels of ErbB2 receptor at the cell surface and transient increased levels in the cytoplasm.
Stancovski et al.
PNAS
(
USA
) 88:8691-8695 (1991) generated a panel of anti-ErbB2 antibodies, injected them i.p. into nude mice and evaluated their effect on tumor growth of murine fibroblasts transformed by overexpression of the erbB2 gene. Various levels of tumor inhibition were detected for four of the antibodies, but one of the antibodies (N28) consistently stimulated tumor growth. Monoclonal antibody N28 induced significant phosphorylation of the ErbB2 receptor, whereas the other four antibodies generally displayed low or no phosphorylation-inducing activity. The effect of the anti-ErbB2 antibodies on proliferation of SKBR3 cells was also assessed. In this SKBR3 cell proliferation assay, two of the antibodies (N12 and N29) caused a reduction in cell proliferation relative to control. The ability of the various antibodies to induce cell lysis in vitro via complement-dependent cytotoxicity (CDC) and antibody-mediated cell-dependent cytotoxicity (ADCC) was assessed, with the authors of this paper concluding that the inhibitory function of the antibodies was not attributed significantly to CDC or ADCC.
Bacus et al.
Cancer Research
52:2580-2589 (1992) further characterized the antibodies described in Bacus et al. (1990) and Stancovski et al
Baughman Sharon A.
Shak Steven
Caputa Anthony C.
Genentech Inc.
Holleran Anne L.
Lee Wendy M.
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