DNA encoding a novel RG1 polypeptide

Abstract

The present invention relates to novel human extracellular matrix polypeptides, designated RG1, polynucleotides encoding the polypeptides, methods for producing the polypeptides, expression vectors and genetically engineered host cells for expression of the polypeptides. The invention further relates to antibodies directed against the polypeptides and to methods for using the polynucleotides, and polypeptides, and antibodies in research, diagnosis, and therapeutic applications.

What is claimed is:  
     
         1 . An isolated human antibody, or antigen-binding antibody fragment thereof, or a variant thereof, that specifically binds to an epitope present in an RG1 polypeptide.  
     
     
         2 . The antibody, or antigen-binding antibody fragment, of  claim 1 , wherein the RG1 polypeptide to which it binds has the amino acid sequence of SEQ ID NO: 2.  
     
     
         3 . The antibody, or antigen-binding antibody fragment, of  claim 1 , wherein binding to the RG1 polypeptide occurs with a K D  equal to or less than 1 μM.  
     
     
         4 . The antibody, or antigen binding antibody fragment, of  claim 3 , wherein binding to the RG1 polypeptide occurs with a K D  equal to or less than 10 nM.  
     
     
         5 . The antibody of  claim 1 , wherein the antibody comprises a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 26 or SEQ ID NO: 29.  
     
     
         6 . The antibody of  claim 1 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, or SEQ ID NO: 31.  
     
     
         7 . The antibody of  claim 1 , wherein the antibody comprises a light chain variable region encoded by a nucleotide sequence comprising SEQ ID NO: 20 or SEQ ID NO: 23.  
     
     
         8 . The antibody of  claim 1 , wherein the antibody comprises a heavy chain variable region encoded by a nucleotide sequence comprising SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, or SEQ ID NO: 25.  
     
     
         9 . The antibody of  claim 1 , wherein the antibody comprises a light chain variable region having the amino acid sequence SEQ ID NO: 26 and a heavy chain variable region having the amino acid sequence SEQ ID NO: 27 or SEQ ID NO: 28.  
     
     
         10 . The antibody of  claim 1 , wherein the antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 29 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 31.  
     
     
         11 . The antibody of  claim 9 , wherein the heavy chain variable region has the amino acid sequence SEQ ID NO: 27.  
     
     
         12 . The antibody of  claim 9 , wherein the heavy chain variable region has the amino acid sequence SEQ ID NO: 28.  
     
     
         13 . The antibody of  claim 10 , wherein the heavy chain variable region has the amino acid sequence SEQ ID NO: 30.  
     
     
         14 . The antibody of  claim 10 , wherein the heavy chain variable region has the amino acid sequence SEQ ID NO: 31.  
     
     
         15 . An antibody which recognizes and binds the same epitope as the epitope bound by the antibody of  claim 9 .  
     
     
         16 . An antibody which recognizes and binds the same epitope as the epitope bound by the antibody of  claim 10 .  
     
     
         17 . The antibody fragment of  claim 1 , wherein the antibody fragment is selected from a group of fragments consisting of Fv, F(ab′), F(ab′)2, and scFv fragments.  
     
     
         18 . An immunoconjugate comprising the human monoclonal antibody or antibody fragment of  claim 1 , wherein the antibody or antibody fragment is conjugated to a molecule which is a therapeutic agent or a detectable marker.  
     
     
         19 . The immunoconjugate of  claim 18 , wherein the therapeutic agent is a cytotoxic agent.  
     
     
         20 . The immunoconjugate of  claim 19 , wherein the cytotoxic agent is selected from a group consisting of ricin, doxorubicin, daunorubicin, Taxol™ (paclitaxel), ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, actinomycin D, diphteria toxin, Pseudomonas exotoxin (PE) A, PE40, ricin, abrin, glucocorticoid and radioisotopes.  
     
     
         21 . The immunoconjugate of  claim 20 , wherein the cytotoxic agent is a radioisotope and is selected from a group consisting of  46 Sc,  47 Sc,  48 Sc,  72 Ga,  73 Ga,  90 Y,  67 Cu,  109 Pd,  11 Ag,  149 Pm,  153 Sm,  166 Ho,  177 Lu,  186 Re,  188 Re,  211 At,  211 Bi,  212 Bi,  213 Bi and  214 Bi.  
     
     
         22 . The immunoconjugate of  claim 18 , wherein the detectable marker is a radiolabel, an enzyme, a chromophore, or a fluorescer.  
     
     
         23 . The immunoconjugate of  claim 22 , wherein the detectable marker is a radiolabel and is selected from a group consisting of is  43 Sc,  44 Sc,  52 Fe,  55 Co,  68 Ga,  64 Cu,  86 Y,  94m Tc,  111 In, and  99m Tc.  
     
     
         24 . The immunoconjugate of  claim 18 , wherein conjugation of the antibody or antibody fragment, with the therapeutic agent or detectable marker utilizes a chelator selected from a group consisting of p-SCN-Benzyl-DPTA and derivatives thereof, 1,4,7,10-tetraazacyclododecane-N, N′, N″, N′″-tetracetic acid (DOTA) and derivatives thereof, and 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA) and derivatives thereof.  
     
     
         25 . The immunoconjugate of  claim 24 , wherein the chelator used is cyclohexyl-DPTA (CHX-DPTA) or MX-DPTA (1B4M-DPTA).  
     
     
         26 . A method for selectively destroying a cell expressing a human RG1 polypeptide having the amino acid sequence of SEQ ID NO: 2, comprising reacting the immunoconjugate of  claim 20  with the cell such that the cell is destroyed.  
     
     
         27 . A method for treating a disease-state in a human patient, wherein the disease-state is associated with expression of an RG1 polypeptide having the amino acid sequence of SEQ ID NO: 2, and wherein the method comprises administering to the patient a therapeutically effective amount of the immunoconjugate of  claim 19 .  
     
     
         28 . The method of  claim 27 , wherein the therapeutic agent of the immunoconjugate is  90 Y or  177 Lu.  
     
     
         29 . The method of  claim 27 , wherein the disease-state is prostate cancer.  
     
     
         30 . A method of detecting a disease-state in a subject, wherein the disease-state is associated with expression of an RG1 polypeptide having the amino acid sequence of SEQ ID NO: 2, and wherein the method comprises: 
 (a) administering to the subject the immunoconjugate of  claim 22;     (b ) detecting the binding of the immunoconjugate within the subject.; and    (c) determining if the level of binding of the immunoconjugate in the subject is increased as compared with the level of binding detected in disease-free control subjects.    
     
     
         31 . The method of  claim 30 , wherein the method of detection is immunoscintigrapy.  
     
     
         32 . The method of  claim 31 , wherein the detectable marker of the immunoconjugate is  111 In or  99m Tc.  
     
     
         33 . The method of  claim 32 , wherein the method of detection is positron emitting tomography.  
     
     
         34 . The method of  claim 33 , wherein the detectable marker of the immunoconjugate is selected from a group consisting of  43 Sc,  44 Sc,  52 Fe,  55 Co,  68 Ga,  64 Cu,  86 Y or  94m Tc.  
     
     
         35 . The method of  claim 34 , wherein the disease-state is prostate cancer.