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
1997-05-05
2001-05-22
Spector, Lorraine (Department: 1646)
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...
C530S387300, C530S388100, C530S388150, C530S387700, C424S133100, C424S138100, C424S139100, C424S142100
Reexamination Certificate
active
06235883
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Summary of the Invention
In accordance with the present invention, there are provided fully human contiguous heavy and light chain sequences spanning the complementarity determining regions monoclonal antibodies against human epidermal growth factor receptor (EGF-r). Nucelotide sequences encoding and amino acid sequences comprising heavy and light chain immunoglobulin molecules, particularly sequences corresponding to (CDR's), specifically from CDR1 through CDR3, are provided. Hybridomas expressing such immunoglobulin molecules and monoclonal antibodies are also provided.
2. Background of the Technology
EGF-r has been demonstrated to be overexpressed on many types of human solid tumors. Mendelsohn
Cancer Cells
7:359 (1989), Mendelsohn
Cancer Biology
1:339-344 (1990), Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994). For example, EGF-r overexpression has been observed in certain lung, breast, colon, gastric, brain, bladder, head and neck, ovarian, and prostate carcinomas. Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994). Both epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-&agr;) have been demonstrated to bind to EGF-r and to lead to cellular proliferation and tumor growth.
Thus, certain groups have proposed that antibodies against EGF, TGF-&agr;, and EGF-r may be useful in the therapy of tumors expressing or overexpressing EGF-r. Mendelsohn
Cancer Cells
7:359 (1989), Mendelsohn
Cancer Biology
1:339-344 (1990), Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994), Tosi et al.
Int'l J. Cancer
62:643-650 (1995). Indeed, it has been demonstrated that anti-EGF-r antibodies while blocking EGF and TGF-&agr; binding to the receptor appear to inhibit tumor cell proliferation. At the same time, however, anti-EGF-r antibodies have not appeared to inhibit EGF and TGF-&agr; independent cell growth. Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994).
In view of these findings, a number of murine and rat monoclonal antibodies against EGF-r have been developed and tested for their ability inhibit the growth of tumor cells in vitro and in vivo. Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994). The antibody that has apparently advanced the farthest in the clinic is a chimeric antibody, designated C225, which has a murine variable region and a human IgG1 constant region. Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994). The murine antibody, designated 225, upon which the C225 antibody is based, was developed by University of California and Rorer. See U.S. Pat. No. 4,943,533 and European Patent No. 359,282, the disclosures of which are hereby incorporated by reference. The C225 antibody was demonstrated to inhibit EGF-mediated tumor cell growth in vitro and inhibit human tumor formation in vivo in nude mice. The antibody, moreover, appeared to act in synergy with certain chemotherapeutic agents to eradicate human tumors in vivo in xenograft mouse models. Modjtahedi and Dean
Int'l J. Oncology
4:277-296 (1994).
ImClone has been conducting human clinical trials using the anti-EGF-r antibody designated C225. Phase I and Phase I/II clinical trials in patients with head and neck, prostate, and lung carcinomas apparently have been, or are currently being, conducted with C225. In Phase I clinical trials, no toxicity was detected with multiple injections and with doses of up to perhaps 400 mg/m
2
, even in cases involving immuno compromised patients. Such studies were conducted as dose escalation studies comprising 5 doses of from about 5 to about 200 mg/m
2
and were performed in combination with chemotherapy (i.e., doxorubicin, adriamycin, taxol, and cisplatin). In addition to the apparent safety data that has been generated in these studies, preliminary results from the studies appear to indicate some evidence of tumor shrinkage in 80% of patients having prostate cancer.
Each of these above-mentioned antibodies, however, possess murine or rat variable and/or constant regions. The presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient. In order to avoid the utilization of murine or rat derived antibodies, it has been postulated that one could introduce human antibody function into a rodent so that the rodent would produce fully human antibodies.
The ability to clone and reconstruct megabase-sized human loci in YACs and to introduce them into the mouse germline provides a powerful approach to elucidating the functional components of very large or crudely mapped loci as well as generating useful models of human disease. Furthermore, the utilization of such technology for substitution of mouse loci with their human equivalents could provide unique insights into the expression and regulation of human gene products during development, their communication with other systems, and their involvement in disease induction and progression.
An important practical application of such a strategy is the “humanization” of the mouse humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which the endogenous Ig genes have been inactivated offers the opportunity to study the mechanisms underlying programmed expression and assembly of antibodies as well as their role in B-cell development. Furthermore, such a strategy could provide an ideal source for production of fully human monoclonal antibodies (Mabs)—an important milestone towards fulfilling the promise of antibody therapy in human disease. Fully human antibodies are expected to minimize the immunogenic and allergic responses intrinsic to mouse or mouse-derivatized Mabs and thus to increase the efficacy and safety of the administered antibodies. The use of fully human antibodies can be expected to provide a substantial advantage in the treatment of chronic and recurring human diseases, such as inflammation, autoimmunity, and cancer, which require repeated antibody administrations.
One approach towards this goal was to engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci in anticipation that such mice would produce a large repertoire of human antibodies in the absence of mouse antibodies. Large human Ig fragments would preserve the large variable gene diversity as well as the proper regulation of antibody production and expression. By exploiting the mouse machinery for antibody diversification and selection and the lack of immunological tolerance to human proteins, the reproduced human antibody repertoire in these mouse strains should yield high affinity antibodies against any antigen of interest, including human antigens. Using the hybridoma technology, antigen-specific human Mabs with the desired specificity could be readily produced and selected.
This general strategy was demonstrated in connection with our generation of the first XenoMouse™ strains as published in 1994. See Green et al.
Nature Genetics
7:13-21 (1994). The XenoMouse™ strains were engineered with yeast artificial chromosomes (YACs) containing 245 kb and 190 kb-sized germline configuration fragments of the human heavy chain locus and kappa light chain locus, respectively, which contained core variable and constant region sequences. Id. The human Ig containing YACs proved to be compatible with the mouse system for both rearrangement and expression of antibodies and were capable of substituting for the inactivated mouse Ig genes. This was demonstrated by their ability to induce B-cell development, to produce an adult-like human repertoire of fully human antibodies, and to generate antigen-specific human Mabs. These results also suggested that introduction of larger portions of the human Ig loci containing greater numbers of V genes, additional regulatory elements, and human Ig constant regions might recapitulate substantially the full repertoire that is characteristic of the human humoral response to infection and immunization. The work of Green
Gallo Michael
Jakobovits Aya
Jia Xiao-Chi
Yang Xiao-Dong
Abgenix, Inc.
Hare Christopher A.
Kaufman Claire M.
Spector Lorraine
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