| Binding member which binds to both lewis-y and lewis-b haptens, and its use for treating cancer -> Monitor Keywords |
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  Binding member which binds to both lewis-y and lewis-b haptens, and its use for treating cancerUSPTO Application #: 20080085278Title: Binding member which binds to both lewis-y and lewis-b haptens, and its use for treating cancer Abstract: The invention relates to the use of a binding member which binds to Lewisy and Lewisb haptens in the treatment of tumours and leukaemia. The binding member may be an antibody which binds to Lewisy and Lewisb haptens and cancer cells and induces cells death. (end of abstract)
Agent: Bozicevic, Field & Francis LLP - East Palo Alto, CA, US Inventors: Linda Gillian Durrant, Tina Parsons USPTO Applicaton #: 20080085278 - Class: 424138100 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Binds Expression Product Or Fragment Thereof Of Cancer-related Gene (e.g., Oncogene, Proto-oncogene, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20080085278. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the use of binding members which bind to both Lewis.sup.y and Lewis.sup.b haptens in the treatment of tumours and leukaemia. [0002] The Lewis antigens, which include Lewis y, b, x and a antigens, are blood group antigens. The Lewis.sup.y hapten is a difucosylated tetrasaccharide (Fuc 1-2Gal.beta. 1-4(Fuc.alpha.1-3)GlcNAc found on type 2 blood group oligosaccharides. This antigen is a positional isomer of the Lewis.sup.b hapten (Fuc1-2Gal.beta.1-3(Fuc.alpha.1-4)GlNAc and a fucosylated derivative of the Lewis.sup.x hapten. The Lewis.sup.y hapten is a cell surface antigen epitope which is expressed by colorectal tumours (Abe et al., Cancer Research, 46, 2639 (1986); Kim et al., Cancer Research, 46, 5985 (1986)). [0003] The mouse monoclonal antibody C14 was raised to the C14gp200 antigen. The mouse monoclonal antibody C14 recognises Lewis.sup.y hapten (Brown et al, Biosci. Rep. 3, 163 (1983); Brown et al., Int. J. Cancer, 33, 727) and binds to 78% of colorectal cancers (Durrant et al., J. Natl. Cancer Inst., 81, 688 (1989)). [0004] Other antibodies which bind to the Lewis.sup.y hapten are known. For example, EP-B-0285059 discloses an antibody, BR-55, which reacts with both Lewis.sup.y and B-7-2. B-7-2 has also been shown to be associated with tumour cells (EP-B-0285059). EP-B-0285059 states that the advantage of recognising two cancer-associated epitopes is that it increases the chances of recognising more tumour cells relative to normal cells. However, BR-55 relies on effector cells in order to be able to kill cells. [0005] In addition, U.S. Pat. No. 5,869,045 discloses an antibody, BR-96, which binds to both Lewis.sup.y and Lewis.sup.x haptens. Although U.S. Pat. No. 5,869,045 teaches that antibodies which kill cells by themselves are rare, BR-96, has been shown to have the ability to kill cancer cells in unmodified form (U.S. Pat. No. 5,869,045). Since no other Lewis.sup.y antibody has been reported to cause direct cytotoxicity, the activity of BR-96 can be assumed to be related to it's recognition of the Lewis.sup.x hapten. [0006] Antibodies which bind to both Lewis.sup.y and Lewis.sup.b antigens are known. Studies have demonstrated that C14 monoclonal antibody recognises and binds to both Lewis.sup.y and Lewis.sup.b (extended and non-extended forms) antigens (Durrant at al., Hybridoma, 12, 647-660 (1996)). A C14 monoclonal antibody specific for both Lewis.sup.y and Lewis.sup.b antigens was raised against primary colorectal tumour cells using standard fusion protocols. The C14 antibody recognised a range of solid tumours but as it was an IgM, it was not very useful in reproducibly screening large numbers of serum samples. One of the immunological characteristics of carbohydrate antigens is that they usually elicit a T cell independent response, resulting in the production of an IgM antibody. [0007] Subsequently, an anti-idiotyoic approach in mice was used to produce an IgG variant of the C14 (IgM) monoclonal antibody. Rats were immunised with C14 monoclonal antibody and rat anti-C14 monoclonal antibody was purified. Immunisation of mice with the rat anti-C14 antiserum and the C14gp200 antigen and subsequent fusion of the immune splenocytes with a mouse myeloma produced five IgG (two IgG3s and three IgG1s) monoclonal antibodies recognising the Lewis.sup.y and Lewis.sup.b antigens (Durrant at al., Hybridoma, 12, 647-660 (1996)). Each of the five IgGs (referred to as the "692" monoclonal antibodies) demonstrated the same specificity as C14 (Durrant at al., Hybridoma, 12, 647-660 (1996)). These antibodies were shown by thin layer chromatography and ELISA to bind to extended and non-extended Lewis.sup.y and Lewis.sup.b haptens but not to Lewis.sup.x or H blood group hapten. The antibodies bound to breast, lung, colorectal, gastric, and ovarian tumours and myeloid leukaemia. Recognition of normal tissue was minimal and restricted to weak staining of the upper gastrointestinal tract basement membrane, mucin staining of stomach and fallopian tubes and weak staining of liver capillaries. [0008] The present inventors have now, surprisingly, found that antibodies which bind to both Lewis.sup.y and Lewis.sup.b haptens induce cell death. [0009] According to a first aspect, the present invention provides the use of a naked binding member which binds to both Lewis.sup.y and Lewis.sup.b haptens in the preparation of an agent for treating cancer. [0010] The present invention also provides a pharmaceutical composition for the treatment of cancer, the composition which comprises a naked binding member that binds to both Lewis.sup.y and Lewis.sup.b haptens. [0011] The present invention further provides a method of treatment of a patient such as a mammal, such as a method of treatment of cancer in a patient (preferably human) which comprises administering to said patient an effective amount of a naked binding member which binds to both Lewis.sup.y and Lewis b haptens. [0012] As used herein, a "binding member" is a member of a pair of molecules which have binding specificity for one another. The binding member is, therefore, a specific binding member. The members of a binding pair may be naturally derived or wholly or partially synthetically produced. One member of the pair of molecules has an area on its surface, which may be a protrusion or a cavity, which specifically binds to and is therefore complementary to a particular spatial and polar organisation of the other member of the pair of molecules. Thus, the members of the pair have the property of binding specifically to each other. Examples of types of binding pairs are antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, enzyme-substrate. The present invention is concerned with antigen-antibody type reactions, although a binding member of the invention may be any moiety which can bind to both Lewis.sup.y and Lewis.sup.b haptens. [0013] An "antibody" is an immunoglobulin, whether natural or partly or wholly synthetically produced. The term also covers any polypeptide, protein or peptide having a binding domain which is, or is homologous to, an antibody binding domain. These can be derived from natural sources, or they may be partly or wholly synthetically produced. Examples of antibodies are the immunoglobulin isotypes and their isotypic subclasses; fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb, Fd; and diabodies. [0014] As used herein, "naked" means that the binding member of the present invention is not bound to, or associated with, any agent having anti-tumour properties. [0015] The term "hapten" includes epitopes and antigens. Haptens may be attached to a large carrier molecule such as a cell e.g a tumour cell. [0016] The binding member of the first aspect of the invention may be an antibody such as a monoclonal or polyclonal antibody, or a fragment thereof. The constant region of the antibody may be of any class including, but not limited to, human classes IgG, IgA, IgM, IgD and IgE. The antibody may belong to any sub class e.g. IgG1, IgG2, IgG3 and IgG4. IgG1 is preferred. The antibody may be SC101 (corresponds to, and used interchangeably with, "692" as described in Durrant et al., Hybridoma, 12, 647-660 1996) for example, SC101/23, SC101/29, SC101/33, SC101/42, SC101/43 or C14. [0017] A cell line expressing an antibody which binds to both Lewis.sup.y and Lewis.sup.b haptens, specifically SC101/29, is deposited with ECACC under Accession no. 01050118. [0018] Early investigation by the inventors of the characteristics of SC101 demonstrated that the antibody caused the death of tumour cell-lines in suspension. The inventors have now found that the antibody causes the specific onset of apoptosis or programmed cell-death in colorectal tumour and leukaemia cell-lines and cells derived from disaggregated tumour tissue. Several groups including Terada and Nakanuma, Pathol. Int., 46, 764-770 (1996); Terada and Nakanuma, American J. Pathol., 146, 67-74 (1995); Iwata et al., J. Pathol., 179, 403-408 (1996); Yamada et al., Anticancer Research, 16, 735-740 (1996) have previously used anti-Lewis.sup.y antibodies to characterise apoptotic cells; these results suggested that Lewis.sup.y was a marker of apoptosis and predominantly over-expressed on dying cells. These findings do not explain why the majority of viable tumour cells also express this hapten or why a member (e.g an antibody) which binds to Lewis.sup.y and Lewis.sup.b should induce apoptosis. [0019] Recognition of normal tissue by the SC101 antibody is, surprisingly, minimal compared to tumour cells thereby making the antibody an effective anti-cancer agent. Since the Lewis.sup.y and Lewis.sup.b antigens are expressed on tumour cells and also on normal cells, this finding was contrary to expectation of the art. The minimal binding of the SC101 antibody to normal tissues has the advantage in that a higher dose of the antibody can be used in the treatment of patients whilst avoiding any risk of toxicity to non-cancerous cells. [0020] As used herein, reference to "SC101" and "692" includes sequences which show substantial homology with SC101 and/or 692. Preferably the degree of homology between SC101/692 complementary determining regions (CDRs) and the CDRs of other antibodies will be at least 60%, more preferably 70%, further preferably 80%, even more preferably 90% or most preferably 95%. [0021] The percent identity of two amino acid sequences or of two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence for best alignment with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions. The "best alignment" is an alignment of two sequences which results in the highest percent identity. The percent identity is determined by the number of identical amino acid residues or nucleotides in the sequences being compared (i.e., % identity=# of identical positions/total # of positions.times.100). [0022] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm known to those of skill in the art. An example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. The NBLAST and XBLAST programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410 have incorporated such an algorithm. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilised as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilising BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. [0023] Another example of a mathematical algorithm utilised for the comparison of sequences is the algorithm of Myers & Miller, CABIOS (1989). The ALIGN program (version 2.0) which is part of the CGC sequence alignment software package has incorporated such an algorithm. Other algorithms for sequence analysis known in the art include ADVANCE and ADAM as described in Torellis & Robotti (1994) Comput. Appl. Biosci., 10:3-5; and FASTA described in Pearson & Lipman (1988) Proc. Natl. Acad. Sci. 85:2444-8. Within FASTA, ktup is a control option that sets the sensitivity and speed of the search. [0024] Where high degrees of sequence identity are present there will be relatively few differences in amino acid sequence. Thus for example they may be less than 20, less than 10, or even less than 5 differences. Continue reading... Full patent description for Binding member which binds to both lewis-y and lewis-b haptens, and its use for treating cancer Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Binding member which binds to both lewis-y and lewis-b haptens, and its use for treating cancer patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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