NZ776574B2

NZ776574B2 - Combination therapy using inhibitors of human growth and differentiation factor 15 (GDF-15) and immune checkpoint blockers

Info

Publication number: NZ776574B2
Application number: NZ776574A
Authority: NZ
Inventors: Reinhard Dummer; Markus Haake; Matthias Mehling; Tina Schafer; Martina Selle; Jorg Wischhusen
Original assignee: Julius Maximilians Universität Würzburg
Filing date: 2016-09-30
Publication date: 2025-09-02

Abstract

The present invention relates to uses of inhibitors of human Growth and Differentiation Factor 15 (GDF-15), particularly anti-hGDF-15 antibodies, and to combined uses of such inhibitors with tumour reactive T-cells and optionally immune checkpoint blockers, in the treatment of solid cancers.

Claims

WE CLAIM:

1. Use of an hGDF-15 inhibitor in the manufacture of a medicament for: a) treating a solid cancer in a human patient, wherein the hGDF-15 inhibitor is to be administered with a further ingredient pharmaceutically active against cancer, which is reactive T cells, or b) treating a solid cancer in a human patient, wherein the hGDF-15 inhibitor is to be administered with an immune checkpoint blocker, and wherein the hGDF-15 inhibitor is to be administered with a further ingredient pharmaceutically active t cancer, which is tumor-reactive T cells, wherein the immune oint blocker is selected from one or more of the following group consisting of: i) an inhibitor of human PD-1, the inhibitor being a monoclonal antibody e of binding to human PD-1, or an PDbinding portion thereof; and ii) an inhibitor of human PD-L1, the inhibitor being a monoclonal antibody capable of binding to human PD-L1, or an PD-L1-binding portion thereof, wherein the hGDF-15 inhibitor is an antibody capable of binding to hGDF-15, or an hGDFbinding fragment thereof.

2. The use according to claim 1, wherein in a), the patient is a patient who has a hGDF-15 serum level of at least 1.2 ng/ml prior to the start of administration of the 5 inhibitor, wherein the patient is preferably a t who has a hGDF-15 serum level of at least 1.5 ng/ml prior to the start of administration of the hGDF-15 inhibitor, and wherein the patient is more preferably a patient who has a hGDF-15 serum level of at least 1.8 ng/ml prior to the start of administration of the hGDF-15 inhibitor.

3. The use according to claim 1 or 2, wherein the cancer is selected from the group consisting of melanoma, ctal cancer, prostate cancer, head and neck , urothelial cancer, stomach cancer, pancreatic cancer, liver , testis , ovarian cancer, endometrial cancer, cervical cancer, brain cancer, breast cancer, gastric cancer, renal cell oma, Ewing’s sarcoma, oral squamous cell carcinoma, nonsmall cell lung cancer and small cell lung cancer.

4. The use according to any one of claims 1-3, wherein the inhibitor is a monoclonal antibody capable of g to hGDF-15, or an hGDFbinding n f, wherein the binding to hGDF-15 is preferably binding to a conformational or discontinuous epitope on hGDF-15, and wherein the conformational or discontinuous epitope comprises the amino acid sequences of SEQ ID No: 25 and SEQ ID No: 26, and/or wherein the antibody or hGDFbinding portion thereof ses a heavy chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 region sing the amino acid ce of SEQ ID NO: 4 and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5, and wherein the antibody or hGDFbinding portion thereof comprises a light chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 region comprising the amino acid sequence ser-ala-ser and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7.

5. The use according to any one of claims 1-4, wherein the solid cancer is a cancer metastasis.

6. The use according to any one of claims 1-5, wherein the hGDF-15 inhibitor increases the tage of CD8+T-cells in the cancer by increasing the adhesion of cells to endothelial cells, thereby increasing entry of the CD8+T-cells from the blood stream into the cancer.

7. The use according to any one of claims 1-6, wherein the hGDF-15 inhibitor is to be administered in combination with an immune checkpoint blocker, wherein the immune checkpoint blocker is selected from one or more of the following group consisting of: i) an inhibitor of human PD-1, the inhibitor being a monoclonal antibody capable of binding to human PD-1, or an PDbinding n thereof; and ii) an inhibitor of human PD-L1, the inhibitor being a monoclonal antibody e of g to human PD-L1, or an PD-L1-binding portion thereof.

8. Use of a combination of an hGDF-15 inhibitor and an immune checkpoint blocker in the cture of a medicament for treating a solid cancer in a human patient, wherein the hGDF-15 inhibitor is to be administered with a r ingredient pharmaceutically active t cancer, which is tumor-reactive T cells, wherein the hGDF-15 inhibitor is an antibody capable of binding to hGDF-15, or an hGDFbinding fragment thereof, and wherein the immune checkpoint blocker is as defined in claim 7.

9. The use according to claim 1 or 8, wherein the patient is as defined in claim 2, and/or wherein the cancer is as defined in claim 3, and/or n the hGDF-15 inhibitor is as defined in claim 4 or 6.

10. The use according to claim 1, wherein in b), the 5 inhibitor increases the percentage of CD8+ T- cells in the cancer, and wherein preferably, the 5 inhibitor increases the percentage of CD8+T-cells in the solid cancer by increasing the adhesion of CD8+T-cells to endothelial cells, thereby increasing entry of the CD8+T-cells from the blood stream into the solid cancer, and wherein preferably, said increase in adhesion of CD8+T-cells to endothelial cells increases the rolling of CD8+ T cells on endothelial cells such that said entry of the CD8+T-cells from the blood stream into the solid cancer is increased.

11. Use of a combination of an 5 inhibitor and any one of the following: a) polyinosinic:polycytidylic acid; b) an anti-humanCD40 antibody, preferably a monoclonal anti-humanCD40 antibody; or c) polyinosinic:polycytidylic acid and an anti-humanCD40 antibody, preferably a monoclonal anti-humanCD40 antibody, in the manufacture of a medicament for treating a solid cancer in a human patient, n the hGDF-15 inhibitor is to be administered with a further ingredient ceutically active against cancer, which is tumor-reactive T cells, and wherein the combination optionally comprises an immune checkpoint blocker, wherein the hGDF-15 tor is an antibody capable of binding to hGDF-15, or an hGDFbinding nt thereof, and wherein the immune checkpoint blocker is as defined in claim 7.

12. The use of any one of claims 1-11, n the hGDF-15 inhibitor and the further ingredient pharmaceutically active against cancer are to be administered together.

13. The use of any one of claims 1-11, wherein the hGDF-15 tor and the further ingredient pharmaceutically active against cancer are to be stered separately.