Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Patent
1992-11-06
1996-09-24
Adams, Donald E.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
5303873, 53038822, 530867, 4241301, 4241431, 436501, 536 2353, A61K 3516
Patent
active
055588646
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
The invention relates to new humanized monoclonal antibodies comprising an artificial modified consensus sequence at least of the FRs in the variable region of the heavy chain of human immunoglobulins.
The invention relates, furthermore, to humanized and chimeric monoclonal antibodies which are binding to epitopes of the Epidermal Growth Factor. The invention discloses the amino acid sequences of the responding antigen-binding site for this receptor.
The invention relates to pharmaceutical compositions comprising the said antibodies for the purposes of treating tumors like melanoma, glioma or carcinoma. The said antibodies can be used also for diagnostic applications regarding locating and assessing the said tumors in vitro or in vivo.
The specification relates to several technical terms which are here defined as follows:
"Humanized" antibodies mean antibodies comprising FRs of the variable regions and constant regions of amino acids located in the light and heavy chain which derive from human sources whereas the hypervariable regions derive from non-human sources.
"Chimeric" antibodies mean antibodies comprising variable and hypervariable regions which derive from non-human sources whereas the constant regions derive from human origin.
"FRs" mean the framework regions of an antibody and are found within the variable regions. In these regions a certain alteration of amino acids occurs.
"CDRs" mean the complementarity determining or "hypervariable" regions of an antibody and are found within the variable regions. These regions represent the specific antigen-binding site and show an immense exchange of amino acids. CDRs are primarily responsible for the binding affinity of the antigen.
"Consensus sequence" means a non-naturally occurring amino acid sequence as light or heavy chain variable regions and is used as substitute for the originally present non-human heavy or light chain variable regions. The consensus sequences is synthetic and therefore an artificial sequence of the most common amino acids of a distinct class or subclass or subgroup of heavy or light chains of human immunoglobluins.
"EGF" and "EGFR" mean the Epidermal Growth Factor and its receptor.
"V.sub.L " regions mean light chain variable regions.
"V.sub.H " regions mean heavy chain variable regions.
BACKGROUND OF THE INVENTION
The murine monoclonal antibody 425 (MAb 425) was raised against the human A431 carcinoma cell line and found to bind to a polypeptide epitope on the external domain of the human epidermal growth factor receptor (EGFR). It was found to inhibit the binding of epidermal growth factor (EGF) at both low and high affinity EGFR sites (Murthy et al., 1987), Enhanced expression of EGFR is found to occur on malignant tissue from a variety of sources thus making MAb 425 a possible agent for the diagnosis and therapeutic treatment of human tumors. Indeed, MAb 425 was found to mediate tumor cytotoxicity in vitro and to suppress tumor cell growth of epidermoid and colorectal carcinoma-derived cell lines in vitro (Rodeck et al., 1987). Radiolabelled MAb 425 has also been shown to bind to xenografts of human malignant gliomas in mice (Takahashi et al., 1987).
EGF is a polypeptide hormone which is mitogenic for epidermal and epithelial cells. When EGF interacts with sensitive cells, it binds to membrane receptors; the receptor EGF complexes cluster and then are internalized in endocytotic vesicles. This is responsible for the phenomenon of "down-regulation". EGF binding induces a tyrosine kinase activity of the receptor molecule and induces synthesis of DNA.
The EGF-receptor is a transmembrane glycoprotein of about 170,000 Daltons (Cohen, 1982). It is the gene product of the c-erb-B proto-oncogene (Downward et al., Nature, Vol. 307, pp. 521-527, 1984). The receptor exists in two kinetic forms: so-called low affinity and high-affinity receptors.
The A431 carcinoma cell line expresses abundant EGF-receptors on its cell surfaces, and thus has been used in many studies to generate anti-EGF-receptor anti
REFERENCES:
Harris et al TibTech 11:42-46 1993.
Kabat Sequences of Proteins of Immunological Intent 4th Ed p. 106 1987.
Rechavi et al PNAS 80:8555-859 1983.
Rodeck et al Cancer Research 47:3692-3696 1987.
Cunningham et al TibTech 10 1992.
Tramontano et al., J. of Mol. Biol., vol. 215, No. 1, pp. 175-182 (Sep. 5, 1990).
Murthy et al., Arch Biochem. Biophys., vol. 252, No. 2, pp. 549-560 (Feb. 1, 1987).
Verhoeyen et al., Science, vol. 239, pp. 1534-1536 (Mar. 25, 1988).
Rodeck et al., J. Cell. Biochem., vol. 44, No. 2, pp. 69-79 (Oct. 1990).
Queen et al., Proc. Nat'l Acad. Sci. USA, vol. 86, pp. 10029-10033 (Dec. 1989).
Kettleborough et al., Protein Eng., vol. 4, No. 7, pp. 773-783 (Oct. 1991).
Bendig Mary M.
Kettleborough Catherine A.
Saldanha Jose
Adams Donald E.
Merck Patent Gesellschaft mit beschrankter Haftung
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