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
1997-02-03
1999-09-14
Hutzell, Paula K.
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...
5303877, 5303879, 5303911, C07K 1600
Patent
active
059524715
DESCRIPTION:
BRIEF SUMMARY
This invention relates to peptides and derivatives thereof, to binding agents, including antibodies, which bind selectively to the peptides and to the use of the peptides and binding agents in diagnosis and therapy.
Lung cancer is a leading cause of death in many countries. The disease can New Engl. J. Med. (1985) 312, 652-653!. SCLC comprises 25% of all newly diagnosed lung cancer cases and is characterised by a high metastatic capacity, a high proliferation rate and initially a high sensitivity to chemo- or radiotherapy. Despite good initial response to chemo- or radiotherapy, almost all of the responding patients relapse within one to two years with therapy resistant recurrences. As a result, five-year Respir. Dis. (1986), 134, 594-608!. There is therefore a need for improved methods of diagnosis and treatment of SCLC.
Antibody-mediated diagnosis and therapy of SCLC is a potentially attractive solution, and in recent years a large number of monoclonal antibodies have been generated against surface antigens expressed on small cell lung carcinoma cells. Many of these antibodies have been divided into fifteen main clusters of reactivity, five of which define distinct glycoprotein
It has been suggested that one of these glycoprotein antigens, the so-called cluster-w4 antigen, might be a promising target for 52, 5264-5270!. However, this antigen has been shown to have the same biochemical properties as the leukocyte activation molecule CD24, found on the surfaces of human B cells and to have an identical primary sequence, except for a single valine-alanine substitution at position 57 on a antigens have also been shown to be serologically identical using existing CD24 and cluster-w4 monoclonal antibodies, many of which have been demonstrated to recognise the short sequence leucine-alanine-proline (LAP) Clin. Exp. Immunol. (1993), 93, 279-285!.
The inability of existing antibodies to distinguish between the SCLC cluster-w4 antigen and leukocyte CD24 raises the question of whether these antibodies can ever be successfully used in diagnosis and therapy to differentiate between normal and tumour tissue. What is needed is an antibody which can recognise an epitope on the SCLC cluster-w4 antigen, but which does not cross-react with leukocyte CD24 antigen.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a FACScan analysis illustrating the differential binding of antibodies in mice sera (arrowed) to the human small cell lung carcinoma cell line H69 and the human erythroleukemic cell line K562;
FIG. 2 is a Scatchard Plot showing the binding of rat monoclonal antibody 9A6 to the human small cell lung carcinoma cell line H69 and to the human erythroleukemic cell line, Daudi; and
FIG. 3 is a Scatchard Plot showing the binding of rat monoclonal antibody 9A6 to the human small cell lung carcinoma cell line H128.
We have now identified a region on the cluster-w4 antigen against which it is possible to generate antibodies which advantageously have a higher binding affinity for the cluster-w4 antigen than leukocyte CD24 antigen. The site we have identified is that around and including the valine mutation at position 57 of the cluster-w4 polypeptide chain. Until our experiments there has been no suggestion that this mutation is presented on the surface of small cell lung carcinoma cells and that it can be serologically defined.
Thus, according to one aspect of the invention, we provide a human small cell lung carcinoma cell binding agent which selectively binds to the cluster-w4 polypeptide of said carcinoma cell at a binding site located at and around valine-57 of the cluster-w4 polypeptide.
The position of the binding site is defined herein by reference to the numbering of the amino acid sequence obtainable by expression of the cDNA coding for the cluster-w4 polypeptide as described by Jackson, D., et al in Cancer Res. ibid.
The binding site located at and around valine-57 comprises at least the valine-57 amino acid, but apart from this essential element may be of variable size and composition. Thus, for example, the binding
REFERENCES:
Hiskey et al. (1967) J. Am. Chem. Soc. 89:437-41.
Jackson et al. (1992) Cancer Res. 52:5264-70.
Weber et al. (1993) Clin. Exp. Immunol. 92:279-85.
Yamamura (1993) Cancer Res. 53:423-8.
Kimmel et al J. Neurosurg. 66:161-171, 1987.
Jackson et al (Can. Res. 1992, 52: 5264-5270).
Weber et al (Clin. Exp. Immunol, 1993, 93: 279-285.
Celltech Therapeutics Limited
Hutzell Paula K.
Ungar Susan
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