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...
Patent
1996-02-23
1999-10-12
Scheiner, Toni R.
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...
530395, 5303879, 5303873, 435 723, 4351722, 435344, 435330, 4241331, 4241551, C07K 1618, C07K 1630, G01N 33574
Patent
active
059657103
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/01816, filed Aug. 19, 1994.
The present invention relates to antibodies useful in diagnosing and treating colorectal cancer.
Antibodies are known that react with carcino-embryonic antigen (CEA), but they react with both membrane-associated CEA and soluble CEA and so are not especially useful in diagnosing colorectal cancer.
Monoclonal antibody PR1A3 was raised by fusion of NS1 (P3/NS1/I-Ag-4-1) myeloma cells with spleen cells from mice immunised with normal colorectal epithelium (Richman & Bodmer 1987). PR1A3 reacts strongly to both well and poorly differentiated colorectal carcinomas and has advantages over other colorectal epithelium-reactive antibodies since its antigen appears fixed to the tumour and does not appear in the lymphatics or normal lymph nodes draining a tumour (Granowska et al 1989). PR1A3 reacted with 59/60 colorectal tumours (Richman & Bodmer 1987), whereas CEA reactive B72.3 reacted with only 75% (Salvatore et al 1989). Although there is some evidence for weak binding to normal cells of the stomach, ileum, oesophagus, trachea and breast, in vivo studies have shown that the basement membrane prevents access by the antibody to these tissues (Granowska et al 1990).
Sheahan et al (1990) Am. J. Clin. Path. 94, 157-164 discusses two monoclonal antibodies (D14 and B7.1) which appear to be specific for carcino embryonic antigen.
Sakurai et al (1989) J. Surg. Oncol. 42, 39-46 discusses various monoclonal antibodies which appear to be specific for carcino embryonic antigen.
PR1A3 has been distributed publicly, as immunoglobulin, although the hybridoma has not been made available. The precise epitope to which PR1A3 binds has not previously been known.
The present invention seeks to provide further molecules, including monoclonal antibodies with the same or better specificity for colorectal cancer as PR1A3. Such antibodies may be prepared by raising MAbs to the newly discovered PR1A3 epitope which we have now found is part of the carcino-embryonic antigen (CEA), a tumour marker expressed in colorectal carcinomas.
A first aspect of the present invention provides a molecule which (i) binds membrane-bound human carcinoembryonic antigen (CEA), (ii) binds a hybrid polypeptide consisting of residues 1 to 314 of human biliary glycoprotein (BGP) joined (N-C) to residues 490 to C-terminus of intact human CEA, but (iii) does not bind to human BGP, but excluding an intact mouse monoclonal antibody comprising an IgG.sub.1 group IIA heavy chain and a kappa group V light chain wherein the sequence of the V.sub.H chain is VEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARWDFYDYEAMYWGQGTTVTVS S(SEQ ID No 1) but the first amino acid residue of the V.sub.H CDR1 is glutamine and in either case the sequence of the V.sub.L chain is DRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYYTYPLFTFGSGTKLEMKR (SEQ ID No 2)
The sequence of the V.sub.H chain can also be written as:
Gln Val Lys Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr
Phe Thr Val Phe
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly
Leu Lys Trp Met
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr
Val Glu Glu Phe
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala
Thr Thr Ala Tyr
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala
Lys Tyr Phe Cys
Ala Arg Trp Asp Phe Tyr Asp Tyr Val Glu Ala Met
Asp Tyr Trp Gly
Gln Gly Thr Thr Val Thr Val Ser Ser
The sequence of the V.sub.L chain can also be written as:
Gly Asp Ile Val Met Thr Gln Ser Gln Arg Phe Met Ser Thr Ser Val
Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln
Asn Val Gly Thr
Asn Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser
Pro Lys Ala Leu
Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
Asp Arg Phe Thr
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Asn Val Gln
Ser Glu Asp Leu Ala Glu Tyr Phe Cys His Gln Tyr
Tyr Thr Tyr Pro
Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Met
Lys Arg
The first amino acid residue of the V.sub.H CDR1 is a position 31 in the V.sub.H sequence given.
It is preferred if the mol
REFERENCES:
Granowska et al., "Radiolabelled monoclonal antibodies in oncology II. Clinical applications in diagnosis", Nuclear Medicine Communications, 12, 83-98 (1991).
Richman et al. "Monoclonal antibodies to human colorectal . . . " Int. J. Cancer 39, pp. 317-328, 1987.
M. Granowska et al. ".sup.99m Tc radioimmunoscintigraphy of colorectal cancer" B. J. Cancer, 10, pp. 30-33, 1990.
K. Sheahan et al. "Differential Reactivities of carcinoembryonic . . . " Am. J. Clin. Path. 94, pp. 157-164, 1990.
Y. Sakurai et al. "Conformational epitopes specific to carcinoembryonic . . . " J. Surg. Oncol. 42, pp. 39-46, 1989.
H. Durbin et al. "An epitope on carcinoembryonic antigen . . . " Proc. Natl. Acad. Sci. USA 91, pp. 4313-4317, 1994.
M. Granowska et al. "Radioimmunoscintigraphy with technetium-99m . . . " Eur. J. Nucl. Med. 20, pp. 690-698, 1993.
Pignatelli & Bodmer. "Genetics and biochemistry of collagen . . . " Proc. Natl. Aca. Sci USA 85, pp. 5561-5565, 1988.
Richman & Bodmer. "Control of differentiation in human . . . " J. Pathology, 156, pp. 197-211, 1988.
Sturzbecher et al. "p53 interacts with p34.sup.cdc2 in mammalian . . . " Oncogene 5, pp. 795-801, 1990.
M. Granowska et al. "A new monoclonal antibody for . . . " Nuclear Medicine trends & possibilities in nuclear medicine, Schmidt & Buraggi, eds. Schaltaner, Stuttgart & New York, pp. 531-534, 1989.
M. Pignatelli et a. "Carcinoembryonic antigen functions . . . " Proc. Natl Acad. Sci. USA 87, pp. 1541-1545, 1990.
R.J. Paxton et al. "Sequence analysis of carcinoembryonic . . . " Proc. Natl Acad. Sci. USA 84, pp. 920-924, 1987.
M. Pignatelli et al. "Integrin Cell Adhesion Molecules . . . " Journal of Pathology, vol. 162 (1990), pp. 95-97, 1990.
Bates Paul A
Bodmer Walter F
Durbin Helga
Snary David
Stewart Lorna M D
Imperial Cancer Research Technology Limited
Scheiner Toni R.
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