Monoclonal antibodies to growth and differentiation factor 15 (gdf-15), and uses thereof for treating cancer cachexia and cancer

Abstract

The present invention relates to monoclonal anti-human-GDF-15 antibodies. The antibodies include chimeric antibodies and humanized antibodies. The invention also relates to monoclonal anti-human-GDF-15 antibodies including murine antibodies, chimeric antibodies and humanized antibodies for use in methods for the treatment of cancer cachexia and also for the treatment of cancer. The invention also provides pharmaceutical compositions, kits, methods and uses and cell lines capable of producing the monoclonal antibodies of the invention.

1 .- 60 . (canceled) 
     
     
         61 . A monoclonal antibody capable of binding to human GDF-15, or an antigen-binding portion thereof, wherein the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence at least 90% identical thereto, and wherein the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence at least 85% identical thereto, wherein the constant domain of the heavy chain comprises the amino acid sequence of SEQ ID No: 29, or an amino acid sequence at least 85% identical thereto, and wherein the constant domain of the light chain comprises the amino acid sequence of SEQ ID No: 32, or an amino acid sequence at least 85% identical thereto. 
     
     
         62 . A monoclonal antibody capable of binding to human GDF-15, or an antigen-binding portion thereof, wherein the binding is binding to a conformational or discontinuous epitope on human GDF-15 comprised by the amino acid sequences of SEQ ID No: 25 and SEQ ID No: 26, wherein the constant domain of the heavy chain comprises the amino acid sequence of SEQ ID No: 29, or an amino acid sequence at least 85% identical thereto, and wherein the constant domain of the light chain comprises the amino acid sequence of SEQ ID No: 32, or an amino acid sequence at least 85% identical thereto. 
     
     
         63 . The antibody or antigen-binding portion thereof of any one of  claims 61 - 62 , wherein the antibody is a humanized antibody. 
     
     
         64 . The antibody or antigen-binding portion thereof according to any one of  claims 61 - 63  for use in medicine. 
     
     
         65 . An antibody or antigen-binding portion thereof according to any one of  claims 61 - 63 , for use in a method for treating cancer cachexia in a mammal. 
     
     
         66 . An antibody or antigen-binding portion thereof according to any one of  claims 61 - 63 , for use in a method for treating cancer in a mammal. 
     
     
         67 . A kit comprising the antibody or antigen-binding portion thereof of any of  claims 61 - 63 . 
     
     
         68 . An expression vector comprising a nucleotide sequence encoding the antibody or antigen-binding portion thereof according to any of  claims 61 - 63 . 
     
     
         69 . A cell line capable of producing an antibody or antigen-binding portion thereof according to any one of  claims 61 - 63 . 
     
     
         70 . A monoclonal antibody capable of binding to human GDF-15, or an antigen-binding portion thereof, wherein the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence at least 90% identical thereto, and wherein the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence at least 85% identical thereto, for use in a method for treating cancer cachexia in a mammal. 
     
     
         71 . A monoclonal antibody capable of binding to human GDF-15, or an antigen-binding portion thereof, wherein the binding is binding to a conformational or discontinuous epitope on human GDF-15 comprised by the amino acid sequences of SEQ ID No: 25 and SEQ ID No: 26, for use in a method for treating cancer cachexia in a mammal. 
     
     
         72 . The antibody or antigen-binding portion thereof of any one of  claim 65 - 66  or  70 - 71  for the use according to any one of  claim 65 - 66  or  70 - 71 , wherein the method is a method for both treating cancer and treating cancer cachexia in the same mammal. 
     
     
         73 . The antibody or antigen-binding portion thereof of any one of  claim 65 - 66  or  70 - 72  for the use according to any one of  claim 65 - 66  or  70 - 72 , wherein the cancer cells of the mammal endogenously express GDF-15 and/or the cancer cells of the mammal stimulate endogenous expression of GDF-15 in non-cancerous cells of the mammal. 
     
     
         74 . The antibody or antigen-binding portion thereof of any one of  claim 65 - 66  or  70 - 73  for the use according to any one of  claim 65 - 66  or  70 - 73 , wherein the cancer cells of the mammal endogenously express GDF-15. 
     
     
         75 . The antibody or antigen-binding portion thereof of any one of  claim 65 - 66  or  70 - 74  for the use according to any one of  claim 65 - 66  or  70 - 74 , wherein the mammal is a human patient. 
     
     
         76 . The antibody or antigen-binding portion thereof of any one of  claims 71 - 75  for the use according to any one of  claims 71 - 75 , or the antibody or antigen-binding portion thereof of any one of  claims 62 - 63 , wherein the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence at least 90% identical thereto, and wherein the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence at least 85% identical thereto. 
     
     
         77 . The antibody or antigen-binding portion thereof of any one of  claims 70  and  72 - 75  for the use according to any one of  claims 70  and  72 - 75 , or the antibody or antigen-binding portion thereof of any one of  claims 61  and  63 , wherein the binding is binding to a conformational or discontinuous epitope on human GDF-15 that is comprised by the amino acid sequences of SEQ ID No: 25 and SEQ ID No: 26. 
     
     
         78 . The antibody or antigen-binding portion thereof of any one of  claims 70 - 77  for the use according to any one of  claims 70 - 77 , or the antibody or antigen-binding portion thereof of any one of  claims 61 - 63 , wherein the heavy chain variable domain comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 3 and a CDR2 region comprising the amino acid sequence of SEQ ID NO: 4, and wherein the light chain variable domain comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 6 and a CDR2 region comprising the amino acid sequence ser-ala-ser.