Antibodies with immune effector activity and that internalize in folate receptor alpha-positive cells

Abstract

This invention relates to the use of monoclonal and polyclonal antibodies that specifically bind to and have the ability in the alternative to become internalized by cells expressing folate receptor alpha (FRA) and to induce an immune effector activity such as antibody-dependent cellular cytotoxicity. The antibodies are useful in specific delivery of pharmacologic agents to FRA-expressing cells as well as in eliciting an immune-effector activity particularly on tumor cells and precursors. The invention is also related to nucleotides encoding the antibodies of the invention, cells expressing the antibodies; methods of detecting cancer cells; and methods of treating cancer using the antibodies.

1 . An in-out anti-folate receptor alpha antibody that (a) specifically binds to folate receptor alpha (FRA) and (b) alternatively elicits an immune effector activity or internalizes within FRA-bearing cells.  
     
     
         2 . The antibody of  claim 1  wherein said antibody binds FRA with an affinity of at least about 1×10 −7  M.  
     
     
         3 . The antibody of  claim 1  wherein said antibody binds FRA with an affinity of at least about 1×10 −8  M.  
     
     
         4 . The antibody of  claim 1  wherein said antibody binds FRA with an affinity of at least about 1×10 −9  M.  
     
     
         5 . The antibody of  claim 1  wherein said antibody binds FRA with an affinity of at least about 1×10 −10  M.  
     
     
         6 . The antibody of  claim 1  wherein said antibody is a chimeric antibody.  
     
     
         7 . The antibody of  claim 6  wherein said chimeric antibody is a human-mouse chimeric antibody.  
     
     
         8 . The antibody of  claim 1  wherein said antibody is a humanized antibody.  
     
     
         9 . The antibody of  claim 1  wherein said antibody is a fully human antibody.  
     
     
         10 . The antibody of  claim 1  wherein antibody is conjugated to a chemotherapeutic agent.  
     
     
         11 . The antibody of  claim 10  wherein said chemotherapeutic agent is a radionuclide.  
     
     
         12 . The antibody of  claim 1  wherein FRA comprises an amino acid sequence of SEQ ID NO:2.  
     
     
         13 . The antibody of  claim 1  wherein FRA is encoded by the nucleotide sequence of SEQ ID NO:1.  
     
     
         14 . The antibody of  claim 1 , wherein the immune effector activity is antibody-dependent cellular cytotoxicity.  
     
     
         15 . A polynucleotide encoding a heavy chain of the antibody of  claim 1 .  
     
     
         16 . A polynucleotide encoding a light chain of the antibody of  claim 1 .  
     
     
         17 . A polynucleotide encoding a heavy chain and a light chain of the antibody of  claim 1 .  
     
     
         18 . A pharmaceutical composition comprising the antibody of  claim 1 .  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the antibody is conjugated to a chemotherapeutic agent.  
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the chemotherapeutic agent is a radionuclide.  
     
     
         21 . A vector comprising a polynucleotide encoding a heavy chain of the antibody of  claim 1 .  
     
     
         22 . A vector comprising a polynucleotide encoding a light chain of the antibody of  claim 1 .  
     
     
         23 . A vector comprising a polynucleotide encoding a heavy chain of the antibody of  claim 1  and a light chain of the antibody of  claim 1 .  
     
     
         24 . An expression cell comprising a polynucleotide encoding a heavy chain of the antibody of  claim 1  and a polynucleotide encoding a light chain of the antibody of  claim 1 .  
     
     
         25 . An expression cell comprising the vector of  claim 23 .  
     
     
         26 . The expression cell of  claim 25 , wherein the cell is a mammalian cell.  
     
     
         27 . The expression cell of  claim 24  wherein the cell is a mammalian cell.  
     
     
         28 . A cell that produces the antibody of  claim 1 .  
     
     
         29 . The cell of  claim 28 , wherein the cell is a hybridoma.  
     
     
         30 . A method of producing an in-out antibody that specifically binds to FRA comprising the steps of culturing the cell of  claim 28  and recovering the antibody from growth medium.  
     
     
         31 . A method of inhibiting the growth of FRA-positive cells comprising administering to a subject having said cells an in-out anti-FRA antibody.  
     
     
         32 . The method of  claim 31  wherein said in-out anti-FRA antibody is conjugated to a biomolecule.  
     
     
         33 . The method of  claim 31  wherein the FRA-positive cells are dysplastic cells.  
     
     
         34 . The method of  claim 31  wherein the subject is a human.  
     
     
         35 . The method of  claim 31  wherein said antibody is conjugated to a chemotherapeutic agent.  
     
     
         36 . The method of  claim 35  wherein said chemotherapeutic agent is a radionuclide.  
     
     
         37 . The method of  claim 31  further comprising administering to said subject a cytotoxic agent.  
     
     
         38 . The method of  claim 31  further comprising administering to said subject a cytostatic agent.  
     
     
         39 . The method of  claim 31  further comprising administering to said subject a chemotherapeutic agent.  
     
     
         40 . The method of  claim 31  wherein the antibody is administered as an unconjugated antibody.  
     
     
         41 . The method of  claim 31  wherein the antibody is administered as a mixture of unconjugated antibody and antibody conjugated to a chemotherapeutic agent.  
     
     
         42 . A kit comprising an antibody that specifically binds to FRA, wherein the antibody alternatively elicits an immune effector activity or internalizes within FRA-bearing cells, and instructions for using the kit in a method for inhibiting the growth of FRA-bearing cells in a subject.  
     
     
         43 . The kit of  claim 42  further comprising at least one chemotherapeutic agent.  
     
     
         44 . The kit of  claim 42  further comprising at least one diagnostic agent.  
     
     
         45 . The kit of  claim 42  further comprising means and instructions for administering the antibody to the subject.  
     
     
         46 . A kit comprising an in-out anti-FRA antibody and instructions for using the kit in a method for identifying the presence of FRA-bearing cells in vitro or in vivo.  
     
     
         47 . The kit of  claim 46  further comprising at least one diagnostic agent.