Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1998-02-18
2002-07-09
Huff, Sheela (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S338000, C530S387100, C530S387300, C530S391300, C530S391700, C435S188000, C435S326000
Reexamination Certificate
active
06417337
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to humanized monoclonal antibodies and fragments or derivatives thereof which specifically bind carcinoembryonic antigen (CEA), which is an antigen expressed by various human carcinomas including breast, lung, and gastrointestinal carcinomas such as stomach and colon cancers. More specifically, the present invention relates to humanized monoclonal antibodies and humanized antibody fragments and derivatives thereof which are derived from murine monoclonal antibody COL-1, a high affinity anti-CEA antibody. The present invention further relates to methods for producing such humanized monoclonal antibodies specific to CEA, pharmaceutical and diagnostic compositions containing such humanized monoclonal antibodies, and methods of use thereof for the treatment or diagnosis of cancer.
BACKGROUND OF THE INVENTION
The identification of antigens expressed by tumor cells and the preparation of monoclonal antibodies which specifically bind such antigens is well known in the art. Anti-tumor monoclonal antibodies exhibit potential application as both therapeutic and diagnostic agents. Such monoclonal antibodies have potential application as diagnostic agents because they specifically bind tumor antigens and thereby can detect the presence of tumor cells or tumor antigen in an analyte. For example, use of monoclonal antibodies which bind tumor antigens for in vitro and in vivo imaging of tumor cells or tumors using a labeled form of such a monoclonal antibody is conventional in the art.
Moreover, monoclonal antibodies which bind tumor antigens have well known application as therapeutic agents. The usage of monoclonal antibodies themselves as therapeutic agents, or as conjugates wherein the monoclonal antibody is directly or indirectly attached to an effector moiety, e.g., a drug, cytokine, cytotoxin, etc., is well known.
Essentially, if the monoclonal antibody is attached to an effector moiety, then the monoclonal antibody functions as a targeting moiety, i.e. it directs the effector moiety (which typically possesses therapeutic activity) to the antibody's target, e.g., a tumor which expresses the antigen bound by the monoclonal antibody. In contrast, when the monoclonal antibody itself operates as a therapeutic agent, the antibody functions both as a targeting moiety—i.e. it will specifically bind a cell which expresses the antigen—and as an effector which mediates therapeutic activity, typically tumor cell lysis. A monoclonal antibody may possess one or more of such effector functions, which include, e.g., antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), among others; these functions are effected by the portion of the antibody molecule generally referred to in the literature as the Fc portion.
One specific tumor antigen to which various monoclonal antibodies have been produced is the carcinoembryonic antigen (CEA). CEA is an antigen complex having a molecular weight of about 180,000 D, which is expressed by numerous carcinomas including gastrointestinal carcinomas, colorectal carcinomas, breast carcinomas, ovarian carcinomas, and lung carcinomas. See, e.g., Robbins et al.,
Int'l J. Cancer,
53(6):892-897 (1993); Greiner et al.,
J. Clin. Oncol.,
10(5):735-746 (1992); Ohuchi et al.,
Cancer Res.,
47(13):3565-3571 (1987); Muraro et al.,
Cancer Res.,
45(11 Pt. 2):5769-5780 (1985).
The use of monoclonal antibodies to detect various, specific CEA epitopes differentially expressed on human carcinomas has been reported in the literature. See, e.g., Ohuchi et al.,
Cancer Res.,
47(13):3565-3571 (1987); Muraro et al.,
Cancer Res.,
45(11 Pt. 2):5769-5780 (1985).
In particular, Muraro et al. (id.) report generation of monoclonal antibodies designated COL-1 through COL-15, which exhibit a strong, selective reactivity for human colon carcinomas versus normal adult tissues. These antibodies react with distinct, restricted epitopes on CEA. Of these antibodies, the COL-1 antibody has been the focus of considerable attention because of its high affinity for CEA (1.4×10
9
M
−1
) and also because it comprises no detectable reactivity for CEA-related antigens such as the nonspecific cross-treating antigen (NCA) and the normal fecal antigen (NFA). Robbins et al.,
Int'l J. Canc.,
53(6):892-897 (1993).
Because of its binding properties, COL-1 is currently being evaluated for use as a therapeutic agent. For example, Siler et al. (
Biotech. Ther.,
4(3-4):163-181 (1993)) report the administration of
131
I-labeled COL-1 to LS-M4T human colon carcinoma xenograft-containing athymic mice. They report that this treatment resulted in reduction of the rate of tumor growth, within little or no toxicity, and that their results demonstrate the potential therapeutic efficacy of radiolabeled COL-1 in clinical trials. Also, Yu et al. (
J. Clin. Oncol.,
14(6):1798-1809 (1996)) report that
131
I-labeled COL-1 is now in phase 1 clinical trials in patients having gastrointestinal malignancies. They further indicate that the antibody conjugate is well tolerated, except for some hematologic toxicity. In addition, the use of conjugates of COL-1 and &bgr;-galactosidase has been shown to specifically kill in vitro tumor cells from a variety of tumor cell lines. Abraham et al.,
Cell Biophys.,
24-25:127-133 (1994).
However, while murine antibodies, such as COL-1 and other anti-CEA murine antibodies, have applicability as therapeutic agents in humans, they are disadvantageous in some respects. Specifically, because murine antibodies are of foreign species origin, they may be immunogenic in humans. This may result in a neutralizing antibody response—a human anti-murine antibody (HAMA) response—which is particularly problematic if the antibodies are desired to be administered repeatedly, e.g., for treatment of a chronic or recurrent disease condition. This is a significant drawback, as some cancer treatments are effected over a prolonged time period, e.g., over several years or longer. Also, because these antibody molecules contain murine constant domains they may not exhibit human effector functions.
In an effort to eliminate or reduce such problems, chimeric antibodies have been disclosed. Chimeric antibodies contain portions of two different antibodies, typically of two different species. Generally, such antibodies contain human constant regions attached to variable regions from another species, typically murine variable regions. For example, some mouse/human chimeric antibodies have been reported which exhibit binding characteristics of the parental mouse antibody and effector functions associated with the human constant region. See, e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.; U.S. Pat. No. 4,978,745 to Schoemaker et al.; U.S. Pat. No. 4,975,369 to Beavers et al.; and U.S. Pat. No. 4,816,397 to Boss et al. Generally, these chimeric antibodies are constructed by preparing a genomic gene library from DNA extracted from pre-existing murine hybridomas. Nishimura et al.,
Cancer Res.,
47:999 (1987). The library is then screened for variable region genes from both heavy and light chains exhibiting the correct antibody fragment rearrangement patterns. Alternatively, cDNA libraries are prepared from RNA extracted from the hybridomas and then screened, or the variable regions are obtained by polymerase chain reaction. The cloned variable region genes are then ligated into an expression vector containing cloned cassettes of the appropriate heavy or light chain human constant region gene. The chimeric genes are then expressed in a cell line of choice, usually a murine myeloma line. Such chimeric antibodies have been used in human therapy.
Moreover, the production of a chimeric mouse anti-human antibody derived from COL-1, which specifically binds CEA, has been reported. See e.g., U.S. Pat. No. 5,472,693 to Gourlie et al. (owned by The Dow Chemical Company).
Also, Morrison et al. report the preparation of several anti-tumor chimeric monoclonal antibodies, in
Important Advances in Oncology, Recombinant Chi
Anderson W. H. Kerr
Armour Kathryn
Carr Frank J.
Harris William J.
Tempest Philip R.
Helms Larry R.
Huff Sheela
Kimble Karen L.
Scott Mark S.
The Dow Chemical Company
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