Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Attached to antibody or antibody fragment or immunoglobulin;...
Patent
1996-07-02
1999-03-02
Feisee, Lila
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Attached to antibody or antibody fragment or immunoglobulin;...
5303871, 5303873, 5303877, 5303881, 5303882, 5303888, 53038885, 5303911, 5303913, 5303917, 530413, 5301301, 435 6, 4241781, 4241811, A61K 5100, A61K 39395, C07K 1600, C12Q 168
Patent
active
058766910
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to antibodies against carcinoembryonic antigen (CEA) and their use in diagnosis and therapy.
CEA is an antigen which is expressed on tumours such as colorectal tumours and is therefore a marker for tumour cells. Various tumour cell markers are known in the art and it has been proposed that therapy against these tumours can be achieved by targeting agents against these markers. Usually, the agent is an antibody or fragment thereof which has been linked to a cytotoxic agent or to an enzyme capable of converting a pro-drug into an active cytotoxic agent.
Alternatively, the antibodies can be linked to imaging agents. This is useful in the diagnosis and prognosis of conditions which involve the expression of a tumour cell marker.
The use of cell surface markers as target agents has been reviewed by Begent, 1990 (see ref 1 below).
There are two main criteria to consider when selecting an antibody suitable for use in targeted anti-tumour therapies. It is desirable that the antibody has a good affinity for its target antigen. This is required so that once the antibody has reached its target, it remains bound to that target for long enough to achieve the desired result, for example cytotoxicity.
In addition, the antibody should have good specificity for the target antigen so that binding to non-target antigens does not occur to any significant extent.
Many antibodies are produced on a commercial scale by recombinant means. This usually involves expression of the antibody in a host cell such as E.coli or yeast. It is therefore desirable that the antibody is encoded by a s nucleic acid sequence which is capable of high levels of expression in a host cell. For reasons that are still not well understood some recombinant nucleic acid sequences can be expressed less well than others by particular types of cells.
CEA has been used as a marker antigen for cancer imaging (ref 8) and therapy (refs 9-13). A large number of CEA antibodies with different specificities and affinities are known (ref 7). One antibody which is widely used in the art against CEA is A5B7. This antibody is useful in imaging and therapy, and has been used in human trials (refs 9, 12, 13). Although many antibodies to CEA exist, the A5B7 antibody has to date been considered the most promising.
We have now found that it is possible to obtain antibody of good specificity and considerably greater affinity to CEA that A5B7 (about 10 times greater affinity). The antibody has proved superior in tumour localisation in vivo to A5B7, and a higher proportion and amount of the antibody is localised to tumour rather than to other body tissues. A clinical trial of tumour imaging with the antibody has begun with successful tumour localisation in 8 patients with colorectal carcinoma. No non-specific antibody localisation was seen.
The antibody was initially obtained from a bacteriophage library. Antibody genes were inserted into bacteriophage and the resulting library of 10.sup.7 phage was screened for expression of antibody against CEA. Genes encoding the desired antibody were selected and the genes were expressed in bacteria.
In a first embodiment, the invention provides an antibody specific for CEA which has a dissociation constant (Kd) of less than 5.0 nM. The antibody generally has a dissociation constant of from 0.5 to 5.0 nM, for example a dissociation constant of 2.5+/-1.3 nM. Preferably the antibody will bind competitively for the epitope on CEA recognised by the MFE-23 antibody described below.
The specificity of the antibody is preferably such that it binds to human colorectal adenocarcinoma but does not bind to some or all of the following normal tissues: liver, kidney, large intestine, tonsil, lung, brain, testis, ovary, cervix, breast, blood films, placenta, spleen, thyroid, oesophagus, stomach, pancreas, lymph node and skeletal muscle. This is in contrast to many CEA antibodies which commonly show cross reaction with a variety of normal tissues (see ref 7).
The term "antibody" is used herein to include complete antibodies (i
REFERENCES:
Burgess et al. (J. Cell Bio. 111:2129-2138), 1990.
Lazar et al., (Mol. & Cell Biol. 8:1247-1252), 1988.
Tao et al., ( J. Immunol. 143:2595-2601), 1989.
Bowie et al., (Science, 247:1306-1310), 1990.
Osband, M. E. et al., 1990. Immunol. Today 11: 193-195.
Drewomlp. B. et al. 1986, Cancer Res. 46(10);5137-5143.
Bagshawe, K. D. 1991, Antibody Immunoconjugates and Radiopharmaceuticals 4(4):915-922.
Milenic, D. E. et al., 1991. Cancer Res. 51(23): 6363-6371.
Bosslet, K. et al., 1991. Br. J. Cancer, 63: 681-686.
Clackson et al Letters to Nature vol. 352 Aug. 1991 624-628 Making antibody fragments using phage display libraries.
Nap et al Cancer Research 52, 2329-2339, Apr. 1992 Specificity and Affinity of Monoclonal Antibodies against Carcinoembryonic Antigen.
Chester et al J. Cellular Biochem 1994 S18D 198 Production of a High Affinity Anti-Cea etc.
Chester et al The Lancet vol. 343 No. 8895 pp. 455-456 Feb. 1994 Phage libraries for generation of clinically useful antibodies. Date Considered.
Milstein et al Nature vol. 349 Jan. 1991 pp. 293-299 Man-made antibodies.
Goldenberg International J. of Biological Markers vol. 7 No. 3, pp. 183-188 Cancer imaging with CEA antibodies:historical and current perspectives, (1992).
Pedley et al (1993) Br. J. Cancer 68 pp. 69-73 Comparative radioimmunotherapy using intact or F(ab').sub.2 fragments of .sup.131 l anti-CEA antibody in a colonic xenograft model.
Pedley et al Int. J. Cancer 43, 713-718 (1989) The Effect of Second Antibody Clearance on the Distribution and Dosimetry of Radiolabelled Anti-CEA Antibody in a Human Colonic tumor Xenograft Model.
Ledermann et al 1988 Br. J. Cancer 58 654-659 Repeated Antitumour antibody therapy in man with suppression of the host response by Cyclosporin A.
Lederman et al Int. J. Cancer 47, 659-664 (1991) A Phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or contnuous administration of cyclosporin A etc.
Boxer et al Br. J. Cancer (1992), 65, 825-831 Factors influencing variability of localisation of antibodies etc.
Begent Richard Henry John
Chester Kerry Anne
Hawkins Robert Edward
Cancer Research Campaign - Technology Limited
Feisee Lila
Ungar Susan
LandOfFree
Antibody against carcionembryonic antigen (CEA) does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antibody against carcionembryonic antigen (CEA), we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antibody against carcionembryonic antigen (CEA) will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-419538