Anti-gdf15 antibody and a dosage regimen for the treatment of cancer

Abstract

The present invention relates to an anti-GDF15 antibody and to a dosage regimen for the treatment of cancer in a human patient using the anti-GDF15 antibody. The present inventors identified a mechanism by which GDF-15 blocks adhesion and transgression of predominantly T-lymphocytes into tissues. Hence, a novel treatment approach has been established by the present invention that facilitates effector T cell entry into tumor tissue upon blockage of GDF-15 using the antibody of the present invention thereby allowing the treatment of cancer in human patients.

1 . A method of treating cancer and/or cancer cachexia in a human patient, the method comprising administering to the human patient a composition comprising an anti-GDF-15 antibody. 
     
     
         2 . The method according to  claim 1 , wherein the anti-GDF-15 antibody is administered according to one of the following (i) to (iii):
 (i) at a dose of 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg, and at a dosage regimen of at least one administration cycle, wherein the cycle is a period of two weeks and wherein said dose is administered at least once in each of the at least one cycle;   (ii) at a dose of between 10 and 20 mg/kg, and at a dosage regimen of at least one administration cycle, wherein the cycle is a period of four weeks and wherein said dose is administered at least once in each of the at least one cycle; or   (iii) at a dose of between 10 and 20 mg/kg and at a dosage regimen of at least one administration cycle, wherein the cycle is a period of three weeks and wherein said dose is administered at least once in each of the at least one cycle.   
     
     
         3 . The method according to  claim 1 , wherein said antibody:
 (a) does not induce antibody-dependent cell-mediated cytotoxicity (ADCC);   (b) does not induce Complement Dependent Cytotoxicity (CDC);   (c) is an IgG4 isotype antibody;   (d) comprises a hinge stabilizing mutation; and/or   (e) comprises a S228P mutation.   
     
     
         4 . (canceled) 
     
     
         5 . The method according to  claim 1 , wherein said anti-GDF-15 antibody comprises:
 (a) a heavy chain variable domain comprising a CDR1 region represented by an amino acid sequences shown in SEQ ID NO: 1, a CDR2 region represented by an amino acid sequences shown in SEQ ID NO: 2 and a CDR3 region represented by an amino acid sequences shown in SEQ ID NO: 3, and a light chain variable domain comprising a CDR1 region represented by an amino acid sequences shown in SEQ ID NO: 4, a CDR2 region represented by an amino acid sequence ser-ala-ser and a CDR3 region represented by an amino acid sequences shown in SEQ ID NO: 5;   (b) a heavy chain variable domain comprising the amino acid sequence represented by SEQ ID NO: 6 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable domain comprising the amino acid sequence represented by SEQ ID NO: 7 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 7; and/or,   (c) a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 8, and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 9.   
     
     
         6 . (canceled) 
     
     
         7 . The method according to  claim 1 , wherein the concentration of GDF-15 in the serum/plasma of said patient is below 10 ng/mL at the end of an administration cycle. 
     
     
         8 . The method according to  claim 2 , wherein the cycle is a period of three weeks and wherein said dose is to be administered at least once in each of the at least one cycle, optionally, wherein said dosage regimen consists of up to 34 administration cycles. 
     
     
         9 . The method according to  claim 2 , wherein the cycle is a period of four weeks and wherein said dose is to be administered at least once in each of the at least one cycle, optionally, wherein said dosage regimen consists of up to 24 administration cycles. 
     
     
         10 . The method according to  claim 2 , wherein said dosage regimen consists of multiple cycles and optionally of up to 52 administration cycles. 
     
     
         11 . The method according to  claim 1 , wherein said anti-GDF-15 antibody is administered in combination with a checkpoint inhibitor, optionally, wherein said checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CD40 antibody. 
     
     
         12 . The method according to  claim 11 , wherein said checkpoint inhibitor is administered in the same dosage regimen as the GDF-15 antibody, or wherein said checkpoint inhibitor is administered prior to the administration of GDF-15 antibody, optionally, wherein said checkpoint inhibitor is to be administered within 120 min prior to the administration of GDF-15 antibody. 
     
     
         13 . The method according to  claim 1 , wherein said cancer is selected from the group consisting of brain cancers, cancers of the nervous system, melanoma, lung cancer, head and neck cancer, urothelial cancer, liver cancer, endometrial cancer, cervical cancer, gastric cancer, renal cell carcinoma, Ewing's sarcoma, non-small cell lung cancer and small cell lung cancer, lip and oral cavity cancer, hepatic carcinoma, leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, bladder cancer, cervix uteri cancer, corpus uteri cancer, testis cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharynx cancer, larynx cancer, pharynx cancer, oesophagus cancer, gastrointestinal tumors, pancreatic cancer, prostate cancer, ovarian cancer, breast carcinoma, and carcinoma of unknown primary. 
     
     
         14 . The method according to  claim 1 , wherein the anti-GDF-15 antibody is administered intravenously. 
     
     
         15 . An anti-GDF-15 antibody, wherein said antibody: is an IgG4 isotype antibody having a hinge stabilizing mutation, and wherein said antibody comprises a heavy chain variable domain comprising the amino acid sequence represented by SEQ ID NO: 6 or an amino acid sequence having at least 90% identity to the amino acid sequence represented by SEQ ID NO: 6, and a light chain variable domain comprising the amino acid sequence represented by SEQ ID NO: 7 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 7. 
     
     
         16 . The anti-GDF-15 antibody according to  claim 15 , wherein the antibody comprises a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 8, and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9 or an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 9, optionally wherein said hinge stabilizing mutation is a S228P mutation. 
     
     
         17 . The antibody according to  claim 15 , wherein said antibody does not induce antibody-dependent cell-mediated cytotoxicity (ADCC) and/or does not induce Complement Dependent Cytotoxicity (CDC). 
     
     
         18 . The antibody according to  claim 15 , wherein said antibody is obtainable by expression in CHO cells. 
     
     
         19 . The antibody according to  claim 15 , wherein said anti-GDF-15 antibody comprises a heavy chain variable domain comprising a CDR1 region represented by the amino acid sequence shown in SEQ ID NO: 1, a CDR2 region represented by the amino acid sequence shown in SEQ ID NO: 2, and a CDR3 region represented by the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable domain comprising a CDR1 region represented by the amino acid sequence shown in SEQ ID NO: 4, a CDR2 region represented by the amino acid sequence ser-ala-ser and a CDR3 region represented by the amino acid sequence shown in SEQ ID NO: 5. 
     
     
         20 . A formulation comprising the anti-GDF-15-antibody according to  claim 15 , wherein said formulation comprises 10-50 mg/ml of the anti-GDF-15 antibody. 
     
     
         21 . The formulation according to  claim 20 , wherein said formulation comprises histidine/histidine HCl, sucrose, arginine-HCl, and polysorbate at a pH between 5 and 6, optionally, wherein said formulation comprises 10-50 mg/ml CTL-002, 10-50 mg/ml histidine/histidine HCl, 100-200 mM sucrose, 20-80 mM arginine-HCl, and 0.01 to 0.05% w/v polysorbate 20 or polysorbate 80 at a pH between 5.0 and 6.0. 
     
     
         22 . The formulation according to  claim 20 , wherein said formulation comprises or consists of 25 mg/ml CTL-002, 20 mM histidine/histidine HCl, 150 mM sucrose, 50 mM arginine-HCl, 0.02% w/v polysorbate 20, at pH 5.5.