Novel nucleic acid molecules with antitumoral activity

Abstract

The present invention relates to a binding molecule that specifically binds to two different epitopes of an antigen expressed on tumor cells, wherein the binding molecule comprises: (a) a first binding (poly)peptide that specifically binds to a first epitope of said antigen expressed on tumor cells, wherein said first binding (poly)peptide is a Fyn SH3-derived polypeptide; and (b) a second binding (poly)peptide that specifically binds to a second epitope of said antigen expressed on tumor cells. The present invention further relates to a nucleic acid molecule encoding the binding molecule of the invention, a vector comprising said nucleic acid molecule as well as a host cell or a non-human host transformed with said vector. The invention further relates to a method of producing a binding molecule of the invention as well as to pharmaceutical and diagnostic composition. Moreover, the present invention also relates to the binding molecule, the nucleic acid molecule, the vector or the host cell of the invention for use in the treatment of tumors.

1 . A binding molecule that specifically binds to two different epitopes of an antigen expressed on tumor cells said molecule comprising:
 (a) a first binding (poly)peptide that specifically binds to a first epitope of said antigen expressed on tumor cells, wherein said first binding (poly)peptide is a Fyn SH3-derived polypeptide; and   (b) a second binding (poly)peptide that specifically binds to a second epitope of said antigen expressed on tumor cells.   
     
     
         2 . The binding molecule of  claim 1 , wherein the antigen expressed on tumor cells is HER2, HER1, HER3, HER4, receptors of the insulin, PDGF, FGF, VEGF, HGF, Trk, Eph, AXL, LTK, TIE, ROR, RET, KLG, RYK, MuSK families, EpCAM, CD20, CD33, CD52, or CD30. 
     
     
         3 . The binding molecule of  claim 1 , wherein the second binding (poly)peptide is an antibody. 
     
     
         4 . The binding molecule to of  claim 1 , wherein the first and second binding (poly)peptide are linked by a linker. 
     
     
         5 . The binding molecule to of  claim 4 , wherein the linker is a peptide-linker. 
     
     
         6 . The binding molecule of  claim 1 , wherein said binding molecule further comprises at least one additional (poly)peptide. 
     
     
         7 . The binding molecule of  claim 1 , wherein the first binding (poly)peptide comprises or consists of
 (i) an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 152; or   (ii) an amino acid sequence having at least 65% sequence identity to the amino acid sequence of SEQ ID NO: 1.   
     
     
         8 . The binding molecule of  claim 1 , wherein the second binding (poly)peptide is an antibody, wherein
 (a) the heavy chain of the antibody comprises or consists of the amino acid sequence of SEQ ID NO: 154 and the light chain of the antibody comprises or consists of the amino acid sequence of SEQ ID NO: 155;   (b) the heavy chain of the antibody comprises or consists of SEQ ID NO: 160 and the light chain of the antibody comprises or consists of the amino acid sequence of SEQ ID NO: 163;   (c) the heavy chain of the antibody comprises or consists of an amino acid sequence having at least 65% sequence identity to the amino acid sequence of SEQ ID NO: 154 and the light chain of the antibody comprises or consists of an amino acid sequence having at least 65% sequence identity to the amino acid sequence of SEQ ID NO: 155; or   (d) the heavy chain of the antibody comprises or consists of an amino acid sequence having at least 65% sequence identity to the amino acid sequence of SEQ ID NO: 160 and the light chain of the antibody comprises or consists of an amino acid sequence having at least 65% sequence identity to the amino acid sequence of SEQ ID NO: 163.   
     
     
         9 . A nucleic acid molecule encoding the binding molecule of  claim 1 . 
     
     
         10 . A vector comprising the nucleic acid molecule of  claim 9 . 
     
     
         11 . A host cell or a non-human host transformed with the vector of  claim 10 . 
     
     
         12 . A method for the production of a binding molecule that specifically binds to two different epitopes of an antigen expressed on tumor cells comprising culture of the host cell of  claim 11  under suitable conditions and isolation of the binding molecule produced. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A method for treating a tumor comprising administering a composition comprising the binding molecule of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the tumor is a breast cancer, ovarian cancer, bladder cancer, salivary gland cancer, endometrium cancer, pancreatic cancer, thyroid cancer, kidney cancer, lung cancer, cancer concerning the upper gastrointestinal tract, colon cancer, colorectal cancer, prostate cancer, squamous-cell carcinoma of the head and neck, cervical cancer, glioblastoma, malignant ascites, lymphoma, or leukemia tumor. 
     
     
         18 . A method for treating a tumor comprising administering a composition comprising the nucleic acid of  claim 9 . 
     
     
         19 . The method of  claim 18 , wherein the tumor is a breast cancer, ovarian cancer, bladder cancer, salivary gland cancer, endometrium cancer, pancreatic cancer, thyroid cancer, kidney cancer, lung cancer, cancer concerning the upper gastrointestinal tract, colon cancer, colorectal cancer, prostate cancer, squamous-cell carcinoma of the head and neck, cervical cancer, glioblastoma, malignant ascites, lymphoma, or leukemia tumor. 
     
     
         20 . A method for treating a tumor comprising administering a composition comprising the vector of  claim 10 . 
     
     
         21 . The method of  claim 20 , wherein the tumor is a breast cancer, ovarian cancer, bladder cancer, salivary gland cancer, endometrium cancer, pancreatic cancer, thyroid cancer, kidney cancer, lung cancer, cancer concerning the upper gastrointestinal tract, colon cancer, colorectal cancer, prostate cancer, squamous-cell carcinoma of the head and neck, cervical cancer, glioblastoma, malignant ascites, lymphoma, or leukemia tumor. 
     
     
         22 . A method for treating a tumor comprising administering a composition comprising the host cell of  claim 11 . 
     
     
         23 . The method of  claim 22 , wherein the tumor is a breast cancer, ovarian cancer, bladder cancer, salivary gland cancer, endometrium cancer, pancreatic cancer, thyroid cancer, kidney cancer, lung cancer, cancer concerning the upper gastrointestinal tract, colon cancer, colorectal cancer, prostate cancer, squamous-cell carcinoma of the head and neck, cervical cancer, glioblastoma, malignant ascites, lymphoma, or leukemia tumor.