Monoclonal antibodies to growth and differentiation factor 15 (gdf-15), and usesthereof 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 . 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. 
     
     
         2 . 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. 
     
     
         3 . The antibody or an antigen-binding portion thereof of  claim 1  or  2 , 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 90%, more preferably at least 95% 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 90%, more preferably at least 95% identical thereto. 
     
     
         4 . The antibody or an antigen-binding portion thereof of any one of  claims 1  to  3 , 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 98%, preferably at least 99% identical thereto, and wherein the constant domain of the light chain comprises the amino acid sequence of SEQ TD No: 32, or an amino acid sequence at least 98%, preferably at least 99% identical thereto. 
     
     
         5 . The antibody or an antigen-binding portion thereof of any of  claims 1  to  4 , wherein the constant domain of the heavy chain comprises the amino acid sequence of SEQ ID No: 29, and wherein the constant domain of the light chain comprises the amino acid sequence of SEQ ID No: 32. 
     
     
         6 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 5 , wherein the antibody is a humanized antibody. 
     
     
         7 . The antibody or antigen-binding portion thereof of  claim 6 , wherein all of the variable domains of the antibody are humanized variable domains. 
     
     
         8 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 7 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 28, or an amino acid sequence at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 31, or an amino acid sequence at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto. 
     
     
         9 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 8 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 28, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 31. 
     
     
         10 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID No: 27, and wherein the light chain comprises the amino acid sequence of SEQ ID No: 30. 
     
     
         11 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 5 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 34, or an amino acid sequence at least 75%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 37, or an amino acid sequence at least 80%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto. 
     
     
         12 . The antibody or antigen-binding portion thereof of  claim 11 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 34, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 37. 
     
     
         13 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 12 , 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. 
     
     
         14 . The antibody or antigen-binding portion thereof of any one of  claims 2 - 13 , 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. 
     
     
         15 . The antibody or antigen-binding portion thereof of any one of  claims 1  and  3 - 13 , 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. 
     
     
         16 . The antibody or antigen-binding portion thereof of any one of  claims 1 - 15 , wherein the antibody has a size of more than 100 kDa, preferably more than 110 kDa, more preferably more than 120 kDa, still more preferably more than 130 kDa, and most preferably more than 140 kDa. 
     
     
         17 . The antibody or antigen-binding portion thereof of  claim 16 , wherein the antibody is a full-length antibody. 
     
     
         18 . The antibody or antigen-binding portion thereof of  claim 17 , wherein the antibody is a full-length IgG antibody, preferably a full-length IgG1 antibody. 
     
     
         19 . The antibody or antigen-binding portion thereof of any one of  claims 1  to  18 , wherein the antibody has an Fc portion which is capable of binding to the Fc receptor. 
     
     
         20 . The antibody or antigen-binding portion thereof of any one of  claims 1  to  19 , wherein the human GDF-15 is recombinant human GDF-15 having the amino acid sequence represented by SEQ ID No: 8. 
     
     
         21 . The antibody or antigen-binding portion thereof according to any one of claims to 20 for use in medicine. 
     
     
         22 . An antibody or antigen-binding portion thereof according to any one of  claims 1  to  20 , for use in a method for treating cancer cachexia in a mammal. 
     
     
         23 . An antibody or antigen-binding portion thereof according to any one of  claims 1  to  20 , for use in a method for treating cancer in a mammal. 
     
     
         24 . An antibody or antigen-binding portion thereof according to any one of  claims 22  to  23  for use according to any one of  claims 22  to  23 , wherein the method is a method for both treating cancer and treating cancer cachexia in the same mammal. 
     
     
         25 . The antibody or antigen-binding portion thereof of any one of  claims 22  to  24  for the use according to any one of  claims 22  to  24 , wherein the mammal is a human patient. 
     
     
         26 . A kit comprising the antibody or antigen-binding portion thereof of any of  claims 1 - 20 . 
     
     
         27 . An expression vector comprising a nucleotide sequence encoding the antibody or antigen-binding portion thereof according to any of  claims 1 - 20 . 
     
     
         28 . A cell line capable of producing an antibody or antigen-binding portion thereof according to any one of  claims 1  to  20 . 
     
     
         29 . 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. 
     
     
         30 . 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. 
     
     
         31 . The antibody or antigen-binding portion thereof of  claim 29  or  30  for the use according to  claim 29  or  30 , wherein the method for treating cancer cachexia is a method for completely preventing or completely reverting cancer cachexia. 
     
     
         32 . The antibody or antigen-binding portion thereof of  claim 31  for the use according to  claim 31 , wherein the method for treating cancer cachexia is a method for completely preventing cancer cachexia. 
     
     
         33 . The antibody or antigen-binding portion thereof of  claim 31  for the use according to  claim 31 , wherein the method for treating cancer cachexia is a method for completely reverting cancer cachexia. 
     
     
         34 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 33  for the use according to any one of  claims 29 - 33 , wherein in the method, only mammals suffering from both
 i) the cancer, and 
 ii) cancer cachexia 
 
       are treated. 
     
     
         35 . The antibody or antigen-binding portion thereof of any one of  claims 33 - 34  for the use according to any one of  claims 33 - 34 , wherein the method increases body weight of the mammal compared to its body weight before the onset of cancer cachexia. 
     
     
         36 . The antibody or antigen-binding portion thereof of  claim 35  for the use according to  claim 35 , wherein the increase in body weight of the mammal is at least 1.5%, preferably at least 2.5%, more preferably at least 5% compared to its body weight before the onset of cancer cachexia. 
     
     
         37 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 36  for the use according to any one of  claims 29 - 36 , wherein the method is a method for both treating cancer and treating cancer cachexia in the same mammal. 
     
     
         38 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 37  for the use according to any one of  claims 29 - 37 , wherein the antibody has a size of more than 100 kDa, preferably more than 110 kDa, more preferably more than 120 kDa, still more preferably more than 130 kDa, and most preferably more than 140 kDa. 
     
     
         39 . The antibody or antigen-binding portion thereof of  claim 38  for the use according to  claim 38 , wherein the antibody is a full-length antibody. 
     
     
         40 . The antibody or antigen-binding portion thereof of  claim 39  for the use according to  claim 39 , wherein the antibody is a full-length IgG antibody. 
     
     
         41 . The antibody or antigen-binding portion thereof of any one of  claims 29  to  40  for the use according to any one of  claims 29  to  40 , wherein the antibody has an Fc portion which is capable of binding to the Fc receptor. 
     
     
         42 . The antibody or antigen-binding portion thereof of any one of  claims 29  to  41  for the use according to any one of  claims 29  to  41 , 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. 
     
     
         43 . The antibody or antigen-binding portion thereof of any one of  claims 29  to  42  for the use according to any one of  claims 29  to  42 , wherein the cancer cells of the mammal endogenously express GDF-15. 
     
     
         44 . The antibody or antigen-binding portion thereof of any one of  claims 29  to  43  for the use according to any one of  claims 29  to  43 , wherein the mammal is a human patient. 
     
     
         45 . The antibody or antigen-binding portion thereof of any one of  claims 29  to  44  for the use according to any one of  claims 29  to  44 , wherein the human GDF-15 is recombinant human GDF-15 having the amino acid sequence represented by SEQ ID No: 8. 
     
     
         46 . The antibody or antigen-binding portion thereof of any one of  claims 30 - 45  for the use according to any one of  claims 30 - 45 , 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. 
     
     
         47 . The antibody or antigen-binding portion thereof of any one of  claims 29  and  31 - 45  for the use according to any one of  claims 29  and  31 - 45 , 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. 
     
     
         48 . The antibody or antigen-binding portion thereof of any one of  claims 37 - 47  for the use according to any one of  claims 37 - 47 , wherein the method for treating cancer is a method comprising inhibition of cancer growth. 
     
     
         49 . The antibody or antigen-binding portion thereof of any one of  claims 37 - 48  for the use according to any one of  claims 37 - 48 , wherein the method for treating cancer comprises the induction of killing of cancer cells by NK cells and CD8+ T cells in the human patient. 
     
     
         50 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 49  for the use according to any one of  claims 29 - 49 , 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. 
     
     
         51 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 50  for the use according to any one of  claims 29 - 50 , 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%, preferably at least 90%, more preferably at least 95% 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%, preferably at least 90%, more preferably at least 95% identical thereto. 
     
     
         52 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 51  for the use according to any one of  claims 29 - 51 , 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 98%, preferably at least 99% 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 98%, preferably at least 99% identical thereto. 
     
     
         53 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 52  for the use according to any one of  claims 29 - 52 , wherein the constant domain of the heavy chain comprises the amino acid sequence of SEQ ID No: 29, and wherein the constant domain of the light chain comprises the amino acid sequence of SEQ ID No: 32. 
     
     
         54 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 53  for the use according to any one of  claims 29 - 53 , wherein the antibody is a humanized antibody, and wherein all of the variable domains of the antibody are humanized variable domains. 
     
     
         55 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 54  for the use according to any one of  claims 29 - 54 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 28, or an amino acid sequence at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 31, or an amino acid sequence at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto. 
     
     
         56 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 55  for the use according to any one of  claims 29 - 55 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 28, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 31. 
     
     
         57 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 56  for the use according to any one of  claims 29 - 56 , wherein the heavy chain comprises the amino acid sequence of SEQ ID No: 27, and wherein the light chain comprises the amino acid sequence of SEQ ID No: 30. 
     
     
         58 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 53  for the use according to any one of  claims 29 - 53 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 34, or an amino acid sequence at least 75%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 37, or an amino acid sequence at least 80%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, still more preferably at least 99% identical thereto. 
     
     
         59 . The antibody or antigen-binding portion thereof of  claim 58  for the use according to  claim 58 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID No: 34, and wherein the light chain variable domain comprises the amino acid sequence of SEQ ID No: 37. 
     
     
         60 . The antibody or antigen-binding portion thereof of any one of  claims 29 - 50  for the use according to any one of  claims 29 - 50 , wherein the antibody is the antibody to human GDF-15 obtainable from the cell line B1-23 deposited with the Deutsche Sammlung für Mikroorganismen and Zellkulturen GmbH (DMSZ) under the accession No. DSM ACC3142 or an antigen-binding portion thereof.