Anti-GDF15 antibodies for neoadjuvant cancer therapy

Abstract

The present invention relates to anti-GDF15 antibodies for use in neoadjuvant therapy of cancer.

Description

[Technical Field]

[0001] The present invention relates to anti-GDF15 antibodies for use in neoadjuvant therapy of cancer. [Background technology]

[0002] Research in the field of cancer treatment has provided various treatment strategies, such as surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy), or synthetic lethality, which are applied depending on the location and grade of the tumor and the stage of the disease, among others. For example, complete removal of cancer by surgery without damaging the rest of the body is an ideal treatment outcome, but the effectiveness of surgical intervention is often limited due to the tendency of cancer to invade adjacent tissues or spread to distant sites by microscopic metastasis. In addition to primary or initial treatment to promote tumor size reduction, neoadjuvant therapy, such as chemotherapy or hormone therapy, is performed to make surgery more effective.

[0003] For example, urothelial bladder cancer is the fourth most common cancer in the United States (US), with over 60,000 new cases occurring annually. Approximately 25% of urothelial carcinoma patients have muscle-invasive disease (T2–T4) and present or subsequently develop metastases (von der Maase et al., 2005). Once a bladder mass is detected in a patient, transurethral resection of the bladder tumor (TURBT) is performed to adequately stage the primary tumor. Once the presence of muscle-invasive bladder cancer (MIBC) is confirmed, radical cystectomy (RC) is performed. MIBC generally has a high rate of recurrence, and despite aggressive local and systemic treatment strategies, the overall prognosis is poor. Unfortunately, up to 50% of patients still experience cancer recurrence within 12 months, leaving all patients at increased risk for recurrence for the rest of their lives. Even after RC, the 5-year mortality rate for MIBC patients remains approximately 50%–70% (Grossman et al., 2003).

[0004] Due to this high recurrence rate, neoadjuvant chemotherapy administered in this setting is well established and ranked as level 1 evidence in the National Comprehensive Cancer Network guidelines ( NCCN, 2021 ), but has achieved only a relatively small survival benefit over RC alone (approximately 6% at 5 years). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2022 / 101263 [Non-patent literature]

[0006] [Non-Patent Document 1] Remington's Pharmaceutical Sciences, edited by AR Gennaro, 20th edition, 2000, Williams & Wilkins, PA, USA. Summary of the Invention [Problem to be solved by the invention]

[0007] In light of the aggressive nature and poor prognosis of MIBC, and the high recurrence and mortality rates after RC, there is a need in the art for improved treatment strategies.

[0008] Although the present invention illustrates clinical studies relating to a particular cancer (i.e., MIBC), it is understood that the results as a whole may also be adapted and improved for the treatment of other types of cancer in human patients. [Means for solving the problem]

[0009] The present invention aims to overcome the unmet clinical need of providing safe and effective therapeutics for the treatment of cancer in human patients.

[0010] Based on extensive experimental studies, the inventors of the present application have found that the anti-growth differentiation factor 15 (GDF-15) antibody visgromab (CTL-002) induces tumor-selective immune influx of CD8+ T cells and CD4+ T cells. Furthermore, visgromab has been demonstrated to enhance antitumor efficacy in combination with anti-PD-1 therapy in subjects with complete anti-PD-1 / PD-L1 relapse / refractory disease (see, e.g., WO2022 / 101263).

[0011] Bladder cancer has been identified as a target indication due to the negative correlation between GDF-15 expression in urothelial tumors with definitive clinical outcomes and a reduced response to checkpoint inhibitor treatment. In this regard, the present invention aims to provide clinical data using visgromab for the neoadjuvant treatment of MIBC patients.

[0012] Furthermore, in a non-limiting embodiment, the present invention also teaches the mode of action of anti-GDF-15 antibodies as neoadjuvant therapy for the treatment of cancer. According to this embodiment of the invention, the addition of visglobumab to / as neoadjuvant treatment may contribute to tumor downstaging and may also result in a pathological complete response (pCR) in the primary tumor (pT0) in a higher percentage of subjects than with current immunotherapy or chemotherapy alone.

[0013] A further non-limiting advantage of neoadjuvant therapy according to the present invention is that it delivers immune cells to the tumor very efficiently because the tumor's blood vessels are still intact prior to surgery, thus enhancing the immune response against cancer.

[0014] Therefore, neoadjuvant therapy using anti-GDF-15 antibodies overall reduces the risk of recurrence and enables recurrence-free survival in human cancer patients.

[0015] The present invention provides the following preferred embodiments.

[0016] Item 1. An anti-GDF-15 antibody for use in neoadjuvant therapy of cancer in a human patient.

[0017] Item 2. The anti-GDF-15 antibody for use according to Item 1, wherein the cancer is a solid cancer and the neoadjuvant therapy is for treating or inhibiting tumor growth of the solid cancer.

[0018] Item 3. The anti-GDF-15 antibody for use according to Item 1 or 2, wherein the anti-GDF-15 antibody and at least one checkpoint inhibitor are administered in combination, and the checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0019] Item 4: The anti-GDF-15 antibody for use according to Item 2 or 3, wherein the patient is scheduled for surgery of a primary solid cancer tumor.

[0020] Item 5. The anti-GDF-15 antibody for use according to any one of Items 2 to 4, wherein the surgery is excision surgery.

[0021] Clause 6. The anti-GDF-15 antibody for use according to any one of clauses 2 to 5, wherein the resective surgery is a radical cystectomy, including removal of the bladder, adjacent organs, and regional lymph nodes.

[0022] Item 7: The anti-GDF-15 antibody for use according to any one of Items 2 to 6, wherein the duration of the neoadjuvant therapy prior to resective surgery is up to 3, 6, or 12 weeks.

[0023] Item 8. The anti-GDF-15 antibody for use according to any one of Items 2 to 7, wherein the neoadjuvant therapy is intended to downstage locally advanced solid tumors to reduce the extent of surgery or perform organ-sparing surgery.

[0024] Item 9. The anti-GDF-15 antibody for use according to Item 8, wherein the duration of the neoadjuvant therapy is up to 3, 4, 6, 12, or 24 weeks.

[0025] Item 10. The anti-GDF-15 antibody for use according to any one of Items 2 to 9, wherein the cancer is selected from the group consisting of colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, carcinoma of unknown primary (CUP), and breast cancer.

[0026] Item 11. The anti-GDF-15 antibody for use according to Item 10, wherein the cancer is bladder cancer.

[0027] Item 12. The anti-GDF-15 antibody for use according to Item 11, wherein the bladder cancer is muscle-invasive bladder cancer.

[0028] Item 13. The anti-GDF-15 antibody for use according to any one of items 1 to 12, wherein the patient is unable to undergo or refuses to undergo chemotherapy.

[0029] Item 14. An anti-GDF-15 antibody for use according to Item 13, wherein the chemotherapy is a chemotherapy for use in neoadjuvant therapy, such as a cisplatin-based chemotherapy.

[0030] Paragraph 15: The anti-GDF-15 antibody for use according to any one of paragraphs 2 to 14, wherein the PD-L1 combined positive score (CPS) of the tumor tissue sample is ≧10%.

[0031] Paragraph 16: The anti-GDF-15 antibody for use according to any one of paragraphs 2 to 14, wherein the PD-L1 CPS of the tumor tissue sample is <10%.

[0032] Paragraph 17: The anti-GDF-15 antibody for use according to any one of paragraphs 1 to 16, wherein the cancer is classified as a T2 stage tumor.

[0033] Paragraph 18: The anti-GDF-15 antibody for use according to any one of paragraphs 1 to 17, wherein the cancer is classified as a T3 / T4 stage tumor.

[0034] Paragraph 19. The anti-GDF-15 antibody for use according to any one of paragraphs 1 to 18, wherein the cancer tissue comprises non-basal / squamous tissue structures.

[0035] Paragraph 20: The anti-GDF-15 antibody for use according to any one of paragraphs 1 to 18, wherein the cancer tissue comprises basal / squamous tissue architecture.

[0036] Paragraph 21: In a human patient, preferably i) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 2 weeks in duration, and said dose being administered at least once in each of the at least one cycle; ii) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 3 weeks in duration, and said dose being administered at least once in each of the at least one cycle; or iii) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 20 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and said dose being administered at least once in each of the at least one cycle; 21. An anti-GDF-15 antibody for use according to any one of items 1 to 20.

[0037] Item 22. The anti-GDF-15 antibody for use according to Item 21, wherein the anti-GDF-15 antibody is administered at a dose of 20 mg / kg and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and the dose being administered at least once in each of the at least one cycle.

[0038] Clause 23: The anti-GDF-15 antibody for use according to clause 21 or 22, wherein the cycle is four weeks in duration, the dose is administered at least once in each of at least one cycle, and the dose is administered over at least one, two, three, or four cycles.

[0039] Paragraph 24. The anti-GDF-15 antibody for use according to any one of paragraphs 21 to 23, wherein the anti-GDF-15 antibody is administered to a human patient at a dose of 20 mg / kg and in a dosing regimen consisting of three administration cycles, each cycle being 4 weeks in duration, and said dose being administered at least once in each cycle.

[0040] Clause 25. The anti-GDF-15 antibody for use according to any one of clauses 3 to 24, wherein the checkpoint inhibitor is administered in the same dosing regimen as the anti-GDF-15 antibody.

[0041] Item 26. The anti-GDF-15 antibody for use according to Item 25, wherein the checkpoint inhibitor is administered prior to administration of the anti-GDF-15 antibody, preferably within 120 minutes prior to administration of the anti-GDF-15 antibody, more preferably within 30 minutes prior to administration of the anti-GDF-15 antibody.

[0042] Item 27. The anti-GDF-15 antibody for use according to Item 25 or 26, wherein the dose of anti-GDF-15 antibody is administered intravenously.

[0043] Item 28. The anti-GDF-15 antibody for use according to any one of Items 1 to 27, wherein the 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.

[0044] Item 29. The anti-GDF-15 antibody for use according to Item 28, wherein the anti-GDF-15 antibody has 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, preferably at least 95% identity, and more preferably at least 98% 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO: 7.

[0045] Item 30. The anti-GDF-15 antibody for use according to Item 28 or 29, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO: 9.

[0046] Clause 31: The anti-GDF-15 antibody for use according to any one of clauses 28 to 30, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9.

[0047] Clause 32. The anti-GDF-15 antibody for use according to any one of clauses 1 to 31, wherein the anti-GDF-15 antibody is obtained by expression in CHO cells.

[0048] Clause 33: The anti-GDF-15 antibody for use according to any one of clauses 1 to 32, wherein the anti-GDF-15 antibody is visglobumab.

[0049] Clause 34. The anti-GDF-15 antibody for use according to any one of clauses 1 to 33, wherein the neoadjuvant therapy further comprises at least one treatment selected from the group consisting of cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy.

[0050] Clause 35: A combination comprising an anti-GDF-15 antibody according to any one of clauses 1 to 34 and at least one active agent for use in cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy for use in neoadjuvant therapy of cancer in a human patient.

[0051] Clause 36: A pharmaceutical composition comprising a combination of an anti-GDF-15 antibody according to any one of clauses 1 to 34 and at least one active agent for use in cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy for use in neoadjuvant therapy of cancer in a human patient.

[0052] Item 37. The combination according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a checkpoint inhibitor, and the checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0053] Item 38. The combination according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a bispecific T cell engager.

[0054] Item 39. The combination according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a cell-based substance used in cell therapy.

[0055] Item 40. The combination or pharmaceutical composition according to any one of Items 35 to 39, wherein the cancer is a solid cancer and the neoadjuvant therapy is for treating or inhibiting tumor growth of the solid cancer.

[0056] Item 41. The combination or pharmaceutical composition according to Item 40, wherein the patient is scheduled for surgery of a primary solid cancer tumor.

[0057] Item 42. The combination or pharmaceutical composition according to any one of Items 35 to 41, wherein the surgical procedure is an excision surgical procedure.

[0058] Paragraph 43. A combination or pharmaceutical composition according to any one of paragraphs 35 to 42, wherein the resective surgery is a radical cystectomy, including removal of the bladder, adjacent organs, and regional lymph nodes.

[0059] Item 44. The combination or pharmaceutical composition according to any one of Items 35 to 43, wherein the duration of the neoadjuvant therapy before resective surgery is up to 3, 6, or 12 weeks.

[0060] Item 45: The combination or pharmaceutical composition according to any one of Items 35 to 44, wherein the neoadjuvant therapy is intended to downstage locally advanced solid cancer to reduce the scope of surgery or perform organ-preserving surgery.

[0061] Item 46. The combination or pharmaceutical composition according to Item 45, wherein the duration of the neoadjuvant therapy is up to 3, 4, 6, 12, or 24 weeks.

[0062] Item 47. The combination or pharmaceutical composition according to any one of Items 35 to 46, wherein the cancer is selected from the group consisting of colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, carcinoma of unknown primary (CUP), and breast cancer.

[0063] Item 48. The combination or pharmaceutical composition according to Item 47, wherein the cancer is bladder cancer.

[0064] Item 49. The combination or pharmaceutical composition according to Item 48, wherein the bladder cancer is muscle-invasive bladder cancer.

[0065] Item 50. The combination or pharmaceutical composition according to any one of items 35 to 49, wherein the patient is unable to undergo or refuses to undergo chemotherapy.

[0066] Item 51. A combination or pharmaceutical composition according to Item 50, wherein the chemotherapy is a chemotherapy for use in neoadjuvant therapy, such as a cisplatin-based chemotherapy.

[0067] Item 52. The combination or pharmaceutical composition according to any one of items 35 to 51, wherein the PD-L1 combined positive score (CPS) of the tumor tissue sample is ≧10%.

[0068] Clause 53: The combination or pharmaceutical composition according to any one of clauses 35 to 51, wherein the PD-L1 CPS of the tumor tissue sample is <10%.

[0069] Item 54. The combination or pharmaceutical composition according to any one of Items 35 to 53, wherein the cancer is classified as a T2 stage tumor.

[0070] Item 55. The combination or pharmaceutical composition according to any one of Items 35 to 53, wherein the cancer is classified as a T3 / T4 stage tumor.

[0071] Item 56. The combination or pharmaceutical composition according to any one of Items 35 to 55, wherein the cancer tissue comprises non-basal / squamous tissue structures.

[0072] Item 57. A combination or pharmaceutical composition according to any one of Items 35 to 55, wherein the cancer tissue comprises basal / squamous tissue structures.

[0073] 58. The anti-GDF-15 antibody is administered to a human patient, preferably i) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 2 weeks in duration, and said dose being administered at least once in each of the at least one cycle; ii) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 3 weeks in duration, and said dose being administered at least once in each of the at least one cycle; or iii) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 20 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and said dose being administered at least once in each of the at least one cycle; Item 58. A combination or pharmaceutical composition according to any one of items 35 to 57.

[0074] Item 59. The combination or pharmaceutical composition of Item 57, wherein the anti-GDF-15 antibody is administered at a dose of 20 mg / kg and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and the dose being administered at least once in each of the at least one cycle.

[0075] Item 60. The combination or pharmaceutical composition of item 57 or 58, wherein a cycle is 4 weeks in duration, the dose is administered at least once in each of at least one cycle, and the dose is administered over at least one, two, three, or four cycles.

[0076] Paragraph 61. The combination or pharmaceutical composition of any one of paragraphs 57 to 60, wherein the anti-GDF-15 antibody is administered to a human patient at a dose of 20 mg / kg and in a dosing regimen consisting of three administration cycles, each cycle being 4 weeks in duration, and said dose being administered at least once in each cycle.

[0077] Clause 62. The combination or pharmaceutical composition of any one of clauses 35 to 61, wherein the checkpoint inhibitor is administered in the same dosing regimen as the anti-GDF-15 antibody.

[0078] Item 63. The combination or pharmaceutical composition of Item 62, wherein the checkpoint inhibitor is administered prior to administration of the anti-GDF-15 antibody, preferably within 120 minutes prior to administration of the anti-GDF-15 antibody, more preferably within 30 minutes prior to administration of the anti-GDF-15 antibody.

[0079] Item 64. The combination or pharmaceutical composition of Item 62 or 63, wherein the dose of anti-GDF-15 antibody is administered intravenously.

[0080] Item 65: The combination or pharmaceutical composition according to any one of Items 35 to 64, wherein the 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.

[0081] Item 66. The combination or pharmaceutical composition of Item 65, wherein the anti-GDF-15 antibody has 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, preferably at least 95% identity, and more preferably at least 98% 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO: 7.

[0082] Item 67. The combination or pharmaceutical composition of Item 65 or 66, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO: 9.

[0083] Clause 68. The combination or pharmaceutical composition of any one of clauses 65 to 67, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9.

[0084] Clause 69. The combination or pharmaceutical composition of any one of clauses 35 to 68, wherein the anti-GDF-15 antibody is obtained by expression in CHO cells.

[0085] Clause 70. The combination or pharmaceutical composition of any one of clauses 35 to 69, wherein the anti-GDF-15 antibody is visglobumab. [Brief explanation of the drawings]

[0086] [Figure 1A] Figure 1. Urothelial Cancer Ph2a Antitumor Activity: Deep and Durable Responses. Antitumor activity of the GDF-15 blocking antibody visgromab in combination with nivolumab in patients with advanced stage anti-PD1 / PD-L1 relapsed / refractory urothelial cancer. Patient response and treatment course are shown for 27 patients in the urothelial cancer ph2a cohort. The objective response rate (ORR) in urothelial cancer is 14.7% (4 / 27). Duration of response (DoR) is 10+ months and is still maturing. Patient response and treatment course are shown in swimmer plots. [Figure 1B]Figure 1. Urothelial Cancer Ph2a Antitumor Activity: Deep and Durable Responses. Antitumor activity of the GDF-15 blocking antibody visgromab in combination with nivolumab in patients with advanced stage anti-PD1 / PD-L1 relapsed / refractory urothelial cancer. Patient response and treatment course are shown for 27 patients in the urothelial cancer ph2a cohort. The objective response rate (ORR) in urothelial cancer is 14.7% (4 / 27). Duration of response (DoR) is 10+ months and is still maturing. Patient response and treatment course are shown in spaghetti plots. DETAILED DESCRIPTION OF THE INVENTION

[0087] In a non-limiting embodiment, the neoadjuvant therapy of the present invention using an anti-GDF-15 antibody is not particularly limited and may further comprise at least one therapy selected from the group consisting of cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy.

[0088] In this regard, neoadjuvant therapy using an anti-GDF-15 antibody further comprises the use of at least one active agent selected from the group consisting of a checkpoint inhibitor, an oncolytic virus, a bispecific engager, or an antibody-drug conjugate such as Enherz.

[0089] In accordance with the present invention, the phrase "at least one checkpoint inhibitor" is understood to mean that the indicated checkpoint inhibitor is required and that additional checkpoint inhibitors may or may not be included, i.e., additional checkpoint inhibitors are optionally included. For example, when the present invention describes at least one checkpoint inhibitor, and the checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody or a PD-1-binding fragment thereof, and an anti-PD-L1 antibody or a PD-L1-binding fragment thereof, this description is understood to mean that a checkpoint inhibitor selected from the group consisting of an anti-PD-1 antibody or a PD-1-binding fragment thereof, and an anti-PD-L1 antibody or a PD-L1-binding fragment thereof is required, and that additional checkpoint inhibitors (e.g., an anti-CD40 antibody or a CD40-binding fragment thereof, an anti-LAG-3 antibody or a LAG-3-binding fragment thereof, an anti-TIM-3 antibody or a TIM-3-binding fragment thereof, an anti-TIGIT antibody or a TIGIT-binding fragment thereof, and an anti-CTLA4 antibody or a CTLA4-binding fragment thereof) may or may not be included, i.e., additional checkpoint inhibitors are optionally included.

[0090] In a non-limiting embodiment of the present invention, the checkpoint inhibitor may be any one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CD40 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, and an anti-CTLA4 antibody, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0091] In a preferred embodiment, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, dostallimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012 (MGA012), AMP-514 (MEDI0680), and AMP-224. In a preferred embodiment, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-936559, KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, and MEDI4736. In a preferred embodiment, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0092] The mode of administration of the at least one checkpoint inhibitor is not particularly limited and may include, for example, intravenous administration and / or subcutaneous administration.

[0093] Detailed Description of the Invention Unless specifically defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention; suitable methods and materials are described herein.

[0094] All references cited herein are incorporated by reference in their entirety for all purposes. Patent applications are referenced herein using their application number and / or publication number. Non-patent literature referenced herein may be cited as a full reference or in an abbreviated form with the full reference provided below in the "References" section (e.g., Danaher et al., 2018).

[0095] As used herein, each occurrence of a term such as "comprises" may optionally be replaced with "consisting of."

[0096] As used herein, the term "neoadjuvant therapy" refers to treatment administered prior to surgical resection of a tumor, preferably a primary tumor. Neoadjuvant therapy thus encompasses treatments aimed at downstaging locally advanced solid tumors to reduce the extent of surgery or allow organ-sparing surgery to be performed. In this regard, neoadjuvant therapy can make a tumor resectable or reduce the extent of surgery, for example, due to a reduction in tumor size. For example, neoadjuvant therapy can be administered as a treatment for a tumor to allow for surgical resection of the tumor.

[0097] As described herein, it is known that some patients cannot or refuse to receive chemotherapy, and criteria for identifying these patients are known in the art. Preferably, patients who "cannot or refuse to receive chemotherapy" refer to patients who are cisplatin-ineligible as defined by Galski's criteria shown in Table 1 below.

[0098] [Table 1]

[0099] As used herein, the term "combined positive score (CPS)" refers to a score reflecting the expression of PD-L1 on tumor cells and tumor-infiltrating immune cells, and can be determined by a validated IHC test. For example, the PD-L1 combined positive score (CPS) is the sum of the percentage of cancer cells and cancer-infiltrating cells (e.g., cancer-infiltrating immune cells) that stain for the presence of PD-L1 on their cell surface. This sum of the percentage of cancer cells and cancer-infiltrating cells can be determined by counting the total number of all cancer cells and cancer-infiltrating cells in a cancer sample that stain for the presence of PD-L1 on their cell surface, dividing that number by the sum of the total number of cancer cells and cancer-infiltrating cells in the sample, and multiplying the resulting quotient by 100.

[0100] As used herein, tumor classification scores refer to the globally recognized standard (TNM) for classifying the extent of cancer spread. For example, the TNM classification indicates the primary tumor (T), lymph node metastasis (N), and evidence of distant metastasis (M0 or M1). The T value indicates the size and level of invasion of the primary tumor.

[0101] Cancer patients to be treated according to the present invention may be selected based on at least one characteristic selected from the group consisting of CPS, tumor classification score, and histological cancer type.

[0102] In one embodiment, the cancer tissue of a patient treated according to the present invention may have a PD-L1 combined positive score (CPS) of ≧10%. The patient may further have a cancer classified as a T2 or T3 / T4 stage tumor.

[0103] In one embodiment, the cancer tissue of a patient treated according to the present invention may have a PD-L1 combined positive score (CPS) of <10%. The patient may further have a cancer classified as a T2 or T3 / T4 stage tumor.

[0104] In one aspect, patients to be treated according to the present invention can be selected based on the histological classification of cancer type.Those skilled in the art are familiar with histological techniques for classifying cancer types based on the cellular context of cancer.For example, cancers originating from the skin or in tissues lining or covering internal organs can be further classified into different cancer subtypes depending on the cell layer within the affected epithelial cells, such as squamous cells, adenoma cells, transitional cells, and / or basal cells.

[0105] In one aspect, cancers treated according to the present invention can be classified as having basal / squamous histology.

[0106] In a further aspect, cancers treated in accordance with the present invention may be classified as having non-basal / squamous histology.

[0107] As described herein, the terms "CTL-002" and visglobumab are used interchangeably. These terms refer to an antibody having a heavy chain amino acid sequence of SEQ ID NO: 8 and a light chain amino acid sequence of SEQ ID NO: 9. Any reference to the amino acid sequences of the antibodies of the invention is understood to encompass post-translational modifications of these sequences that occur in mammalian cells, such as CHO cells, including, but not limited to, N-glycosylation, O-glycosylation, deamidation, Asp isomerization / fragmentation, pyroglutamate formation, removal of C-terminal lysine, and Met / Trp oxidation.

[0108] It will be appreciated that the antibodies according to the present invention may be administered in the form of a pharmaceutical composition, which is prepared using pharmaceutically acceptable ingredients such as carriers, excipients, or stabilizers so that the pharmaceutical composition can be appropriately stored and administered.

[0109] Such pharmaceutically acceptable ingredients are non-toxic in the amounts used when the pharmaceutical composition is administered to a human patient. The pharmaceutically acceptable ingredients added to a pharmaceutical composition depend on the route of administration.

[0110] Generally, pharmaceutically acceptable ingredients used in connection with the present invention are used in accordance with knowledge available in the art, e.g., from Remington's Pharmaceutical Sciences, edited by A.R. Gennaro, 20th edition, 2000, Williams & Wilkins, PA, USA.

[0111] The present invention is further illustrated by the following non-limiting examples. [Example]

[0112] Example 1 Neoadjuvant immunotherapy Overall study design This is a multicenter, stratified, and single-blind phase 2 study of neoadjuvant immunotherapy in combination with the anti-GDF-15 antibody visgromab (CTL-002) for the treatment of MIBC subjects scheduled to undergo RC who are unable or unwilling to receive cisplatin-based chemotherapy.

[0113] This exploratory study will evaluate and examine the clinical efficacy and safety of various immuno-oncology agents as neoadjuvant treatment for MIBC individuals who are cisplatin-ineligible or refusing cisplatin, as well as the potential for clinical benefit, e.g., with anti-PD-1 inhibitors and at doses shown to impart minimal / acceptable AE risk. Translational endpoints will inform which treatments are viable candidates for further investigation in MIBC.

[0114] The study design is shown in Table 2 below.

[0115] [Table 2]

[0116] Study treatments will be allocated and planned as follows: - Eligible subjects will be assigned 1:1 to one of the treatment arms and stratified based on tumor tissue PD-L1 CPS >10% or PD-L1 CPS <10% and their tumor size (T2 or T3 / T4). - Subject will undergo the following research procedures: - Treatment group A (nivolumab + placebo) - Treatment arm B (nivolumab + visgromab [CTL-002]) - Plan a total of three cycles before surgery - RC + pelvic lymphadenectomy with curative intent planned at the time of study enrollment to occur within 4-8 weeks of the last planned study drug infusion

[0117] Efficacy assessment will be performed pathologically by evaluating RC samples for pathological response and radiologically according to RECIST v1.1. Subjects will be closely monitored for the occurrence of AEs and for clinical and / or radiographic evidence of disease progression according to the usual standards of clinical practice. Adverse experiences will be assessed according to the criteria outlined in NCI-CTCAE, version 5.0.

[0118] Immunotherapy treatment duration The immunotherapy treatment period lasts for 12 weeks (3 cycles of 4 weeks).

[0119] As indicated above, subjects will be assigned and stratified 1:1 to one of the following treatment groups based on tumor tissue PD-L1 CPS>10% or PD-L1 CPS<10% and their tumor size (T2 or T3 / T4): - Treatment group A (nivolumab + placebo) - Treatment arm B (nivolumab + visgromab [CTL-002])

[0120] For the combination, visgromab and nivolumab will be administered consecutively on the same day, with visgromab always administered first, and a 30-minute observation period will be held after the completion of visgromab (CTL-002) administration to assess safety, followed by nivolumab infusion (Group B) according to SmPC and local guidelines.

[0121] Radical cystectomy (RC) RC involves removal of the bladder, adjacent organs, and regional lymph nodes. In men, RC includes removal of the prostate and seminal vesicles, while in women, the reproductive organs (ovaries, fallopian tubes, uterus, and anterior vaginal wall) may also be removed to achieve the best oncologic outcome. Surgery is performed according to the hospital's standard practice (standard of care).

[0122] RC is planned at the time of study enrollment, ideally at the end of the immunotherapy treatment period (4 to 8 weeks [28–56 days] after the last study drug infusion). Tumor material will be examined at two time points: first at baseline using transurethral resection material and second at cystectomy 4 to 8 weeks [28–56 days] after the last study drug infusion. Tumor tissue examination is essential to assess immune cell infiltration into the tumor. If biopsy cannot be obtained for safety reasons, this should be discussed with the medical monitor and sponsor's medical representative. Subjects who decline or are not suitable for RC at the end of the neoadjuvant period will be managed according to European Association for Urology guidelines, and chemoradiation therapy will be offered first as a bladder-preserving option. These subjects will continue to be monitored and enrolled in long-term safety and efficacy analyses.

[0123] Example 2 Antitumor activity of combined treatment with the GDF-15 blocking antibody visgromab and nivolumab in bladder cancer A target population of patients with advanced-stage metastatic solid tumors relapsed / refractory to prior anti-PD1 / PD-L1 treatment was selected according to the following criteria: (i) a minimum of 12 weeks of prior continuous anti-PD1 / PD-L1 exposure with an approved anti-PD1 / PD-L1 antibody for indication, (2) upon direct progression on this anti-PD1 / PD-L1 treatment, or (3) upon initial response with seamless continuation of anti-PD1 / PD-L1 treatment until relapse / progression, to be treated with the GDF-15 blocking antibody bisglobamab in combination with nivolumab.

[0124] Clinical results from the urothelial carcinoma ph2a cohort confirm the antitumor activity of the GDF-15 blocking antibody visgromab in combination with nivolumab in patients with advanced stage anti-PD1 / PD-L1 relapsed / refractory disease, achieving deep and durable responses, even complete responses, over one year (see Figure 1).

[0125] Figure 1A (swimmer plot) shows the clinical outcomes of 27 patients with urothelial carcinoma over time, indicating an objective response rate (ORR) of 14.7% [4 / 27]. The DoR was 10+ months and is still maturing.

[0126] For example, patient [1-01-15] showed tumor shrinkage (TS) from weeks 8 to 16, followed by a partial response (PR) from weeks 16 to 30 and a complete response (CR) at week 32. Patient [1-01-019] showed tumor shrinkage (TS) at week 8. Patient [1-06-005] showed a partial response (PR) at week 10. Patient [1-02-036] showed a partial response (PR) at week 6. Patient [1-02-037] showed tumor shrinkage (TS) from weeks 6 to 20 and a partial response (PR) at week 20.

[0127] In Figure 1B (spaghetti plot), various patient responses, i.e., % change in target lesions from baseline, are shown over time. Response curves for patients with a complete response (CR) or partial response (PR) are located in the negative range of the vertical axis, as exemplified by the curves for patients [1-01-015], [1-02-035], [1-06-005], and [1-02-037].

[0128] In summary, the urothelial cancer cohort demonstrated a 14.8% response rate with no grade 4 / 5 AEs (a very clean safety profile). Furthermore, the data also support an exceptional duration of response (DoR) of 10+ months, with prolonged DoR in patients still in PR / CR.

[0129] According to the present invention, the antitumor activity of anti-GDF-15 antibodies (e.g., particularly visgromab) and their ability to reactivate immune responses against cancer (e.g., bladder cancer) are expected to enable effective neoadjuvant therapy. For example, administration of anti-GDF-15 antibodies prior to resection promotes the stimulation of immune responses against tumors, thereby destroying residual tissue and micrometastases after surgery and subsequently reducing the risk of post-surgical recurrence. This is particularly applicable even in the presence of immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 antibodies, which maintain existing anti-tumor immune responses. Furthermore, according to the present invention, the favorable safety profile of anti-GDF-15 antibodies (e.g., particularly visgromab) makes them suitable for neoadjuvant therapy.

[0130] array: SEQ ID NO: 1 (peptide sequence of the heavy chain CDR1 region of the monoclonal anti-human GDF-15 antibody): GFSLSTSGMG

[0131] SEQ ID NO: 2 (peptide sequence of the heavy chain CDR2 region of the monoclonal anti-human GDF-15 antibody): IYWDDDK

[0132] SEQ ID NO: 3 (peptide sequence of the heavy chain CDR3 region of the monoclonal anti-human GDF-15 antibody): ARSSYGAMDY

[0133] SEQ ID NO: 4 (peptide sequence of the light chain CDR1 region of monoclonal anti-human GDF-15 antibody): QNVGTN

[0134] Peptide sequence of the light chain CDR2 region of the monoclonal anti-human GDF-15 antibody: SAS

[0135] SEQ ID NO: 5 (peptide sequence of the light chain CDR3 region of monoclonal anti-human GDF-15 antibody): QQYNNFPYT

[0136] SEQ ID NO: 6 (heavy chain variable domain of monoclonal anti-human GDF-15 antibody):

[0137] [ka]

[0138] SEQ ID NO: 7 (light chain variable domain of monoclonal anti-human GDF-15 antibody):

[0139] [ka]

[0140] SEQ ID NO: 8 (heavy chain of monoclonal anti-human GDF-15 antibody CTL-002 without leader peptide sequence):

[0141] [ka]

[0142] SEQ ID NO: 9 (light chain of monoclonal anti-human GDF-15 antibody CTL-002 without leader peptide sequence):

[0143] [ka]

[0144] SEQ ID NO: 10 (heavy chain variable domain of anti-human GDF-15 antibody H1L5):

[0145] [ka]

[0146] SEQ ID NO: 11 (light chain variable domain of anti-human GDF-15 antibody H1L5):

[0147] [ka]

[0148] (References) von der Maase, Hans et al., "Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer." Journal of clinical oncology 23.21 (2005): 4602~4608. Grossman, H. Bartonra, et al., “Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.” New England Journal of Medicine 349.9 (2003): 859–866. [Industrial Applicability]

[0149] The anti-GDF-15 antibodies used in the neoadjuvant treatment of cancer in human patients can be industrially manufactured and sold as products for the methods and uses recited, in accordance with known standards for the manufacture of pharmaceuticals. Thus, the present invention is industrially applicable.

Claims

1. An anti-GDF-15 antibody for use in the neoadjuvant therapy of cancer in a human patient.

2. 2. The anti-GDF-15 antibody for use according to claim 1, wherein the cancer is a solid cancer and the neoadjuvant therapy is for treating or inhibiting tumor growth of the solid cancer.

3. 3. The anti-GDF-15 antibody for use according to claim 1 or 2, wherein the anti-GDF-15 antibody and at least one checkpoint inhibitor are administered in combination, and the checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

4. 4. The anti-GDF-15 antibody for use according to claim 2 or 3, wherein the patient is scheduled for surgery of a primary solid cancer tumor.

5. 5. The anti-GDF-15 antibody for use according to any one of claims 2 to 4, wherein the surgery is excision surgery.

6. 6. The anti-GDF-15 antibody for use according to any one of claims 2 to 5, wherein the resective surgery is a radical cystectomy, including removal of the bladder, adjacent organs, and regional lymph nodes.

7. 7. The anti-GDF-15 antibody for use according to any one of claims 2 to 6, wherein the duration of the neoadjuvant therapy prior to resective surgery is up to 3, 6, or 12 weeks.

8. 8. The anti-GDF-15 antibody for use according to any one of claims 2 to 7, wherein the neoadjuvant therapy aims to downstage locally advanced solid tumors to reduce the extent of surgery or to perform organ-sparing surgery.

9. 9. The anti-GDF-15 antibody for use according to claim 8, wherein the duration of the neoadjuvant therapy is up to 3, 4, 6, 12, or 24 weeks.

10. 10. The anti-GDF-15 antibody for use according to any one of claims 2 to 9, wherein the cancer is selected from the group consisting of colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, carcinoma of unknown primary (CUP), and breast cancer.

11. 11. The anti-GDF-15 antibody for use according to claim 10, wherein the cancer is bladder cancer.

12. 12. The anti-GDF-15 antibody for use according to claim 11, wherein the bladder cancer is muscle-invasive bladder cancer.

13. 13. The anti-GDF-15 antibody for use according to any one of claims 1 to 12, wherein the patient is unable or refuses to undergo chemotherapy.

14. 14. The anti-GDF-15 antibody for use according to claim 13, wherein the chemotherapy is a chemotherapy for use in neoadjuvant therapy, such as a cisplatin-based chemotherapy.

15. 15. The anti-GDF-15 antibody for use according to any one of claims 2 to 14, wherein the PD-L1 combined positive score (CPS) of the tumor tissue sample is ≧10%.

16. 15. The anti-GDF-15 antibody for use according to any one of claims 2 to 14, wherein the PD-L1 CPS of the tumor tissue sample is <10%.

17. 17. The anti-GDF-15 antibody for use according to any one of claims 1 to 16, wherein the cancer is classified as a T2 stage tumor.

18. 18. The anti-GDF-15 antibody for use according to any one of claims 1 to 17, wherein the cancer is classified as a T3 / T4 stage tumor.

19. 19. The anti-GDF-15 antibody for use according to any one of claims 1 to 18, wherein the cancer tissue comprises non-basal / squamous tissue architecture.

20. 19. The anti-GDF-15 antibody for use according to any one of claims 1 to 18, wherein the cancer tissue comprises basal / squamous tissue architecture.

21. In a human patient, preferably iv) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 2 weeks in duration, and said dose being administered at least once in each of the at least one cycle; v) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 3 weeks in duration, and said dose being administered at least once in each of the at least one cycle; or vi) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 20 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and said dose being administered at least once in each of the at least one cycle; 21. An anti-GDF-15 antibody for use according to any one of claims 1 to 20.

22. 22. The anti-GDF-15 antibody for use according to claim 21, wherein the anti-GDF-15 antibody is administered at a dose of 20 mg / kg and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and the dose being administered at least once in each of the at least one cycle.

23. 23. The anti-GDF-15 antibody for use according to claim 21 or 22, wherein the cycles are four weeks in duration, the dose is administered at least once in each of at least one cycle, and the dose is administered over at least one, two, three, or four cycles.

24. 24. The anti-GDF-15 antibody for use according to any one of claims 21 to 23, wherein the anti-GDF-15 antibody is administered to a human patient at a dose of 20 mg / kg and in a dosing regimen consisting of three administration cycles, each cycle being 4 weeks in duration, and said dose being administered at least once in each cycle.

25. 25. The anti-GDF-15 antibody for use according to any one of claims 3 to 24, wherein the checkpoint inhibitor is administered in the same dosing regimen as the anti-GDF-15 antibody.

26. 26. The anti-GDF-15 antibody for use according to claim 25, wherein the checkpoint inhibitor is administered prior to administration of the anti-GDF-15 antibody, preferably within 120 minutes prior to administration of the anti-GDF-15 antibody, more preferably within 30 minutes prior to administration of the anti-GDF-15 antibody.

27. 27. The anti-GDF-15 antibody for use according to claim 25 or 26, wherein the dose of anti-GDF-15 antibody is administered intravenously.

28. 28. An anti-GDF-15 antibody for use according to any one of claims 1 to 27, wherein the 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.

29. 29. The anti-GDF-15 antibody for use according to claim 28, wherein the anti-GDF-15 antibody has 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, preferably at least 95% identity, and more preferably at least 98% 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO:

7.

30. 30. The anti-GDF-15 antibody for use according to claim 28 or 29, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO:

9.

31. 31. The anti-GDF-15 antibody for use according to any one of claims 28 to 30, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO:

9.

32. 32. The anti-GDF-15 antibody for use according to any one of claims 1 to 31, wherein the anti-GDF-15 antibody is obtained by expression in CHO cells.

33. 33. The anti-GDF-15 antibody for use according to any one of claims 1 to 32, wherein the anti-GDF-15 antibody is visglobumab.

34. 34. The anti-GDF-15 antibody for use according to any one of claims 1 to 33, wherein the neoadjuvant therapy further comprises at least one therapy selected from the group consisting of cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy.

35. 35. A combination comprising at least one active agent used in cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy and an anti-GDF-15 antibody according to any one of claims 1 to 34 for use in the neoadjuvant therapy of cancer in a human patient.

36. 35. A pharmaceutical composition comprising a combination of at least one active agent used in cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiation therapy with an anti-GDF-15 antibody according to any one of claims 1 to 34 for use in the neoadjuvant therapy of cancer in a human patient.

37. 37. A combination according to claim 35 or a pharmaceutical composition according to claim 36, wherein the active substance is a checkpoint inhibitor, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

38. 37. A combination according to claim 35 or a pharmaceutical composition according to claim 36, wherein the active substance is a bispecific T cell engager.

39. 37. A combination according to claim 35 or a pharmaceutical composition according to claim 36, wherein the active substance is cell-based, for use in cell therapy.

40. 40. The combination or pharmaceutical composition of any one of claims 35 to 39, wherein the cancer is a solid cancer and the neoadjuvant therapy is for treating or inhibiting tumor growth of the solid cancer.

41. 41. The combination or pharmaceutical composition of claim 40, wherein the patient is scheduled for surgery of a primary solid cancer tumor.

42. 42. The combination or pharmaceutical composition according to any one of claims 35 to 41, wherein the surgery is excision surgery.

43. 43. The combination or pharmaceutical composition of any one of claims 35 to 42, wherein the resective surgery is a radical cystectomy, including removal of the bladder, adjacent organs, and regional lymph nodes.

44. 44. The combination or pharmaceutical composition according to any one of claims 35 to 43, wherein the duration of said neoadjuvant therapy before resective surgery is up to 3, 6, or 12 weeks.

45. 45. The combination or pharmaceutical composition according to any one of claims 35 to 44, wherein the neoadjuvant therapy aims to downstage locally advanced solid cancers to reduce the extent of surgery or to perform organ-sparing surgery.

46. 46. ​​The combination or pharmaceutical composition of claim 45, wherein the duration of the neoadjuvant therapy is up to 3, 4, 6, 12, or 24 weeks.

47. 47. The combination or pharmaceutical composition according to any one of claims 35 to 46, wherein the cancer is selected from the group consisting of colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, carcinoma of unknown primary (CUP), and breast cancer.

48. 48. The combination or pharmaceutical composition of claim 47, wherein the cancer is bladder cancer.

49. 49. The combination or pharmaceutical composition of claim 48, wherein the bladder cancer is muscle-invasive bladder cancer.

50. 50. The combination or pharmaceutical composition according to any one of claims 35 to 49, wherein the patient is unable or refuses to undergo chemotherapy.

51. 51. The combination or pharmaceutical composition of claim 50, wherein the chemotherapy is a chemotherapy for use in neoadjuvant therapy, such as a cisplatin-based chemotherapy.

52. 52. The combination or pharmaceutical composition of any one of claims 35 to 51, wherein the PD-L1 combined positive score (CPS) of the tumor tissue sample is ≧10%.

53. 52. The combination or pharmaceutical composition of any one of claims 35 to 51, wherein the PD-L1 CPS in a tumor tissue sample is <10%.

54. 54. The combination or pharmaceutical composition according to any one of claims 35 to 53, wherein the cancer is classified as a T2 stage tumor.

55. 54. The combination or pharmaceutical composition according to any one of claims 35 to 53, wherein the cancer is classified as a T3 / T4 stage tumor.

56. 56. The combination or pharmaceutical composition according to any one of claims 35 to 55, wherein the cancer tissue comprises non-basal / squamous tissue structures.

57. 56. The combination or pharmaceutical composition according to any one of claims 35 to 55, wherein the cancer tissue comprises basal / squamous tissue architecture.

58. The anti-GDF-15 antibody is administered to a human patient, preferably iv) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 2 weeks in duration, and said dose being administered at least once in each of the at least one cycle; v) administered at a dose of between 3 and 20 mg / kg, preferably at a dose of 10 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 3 weeks in duration, and said dose being administered at least once in each of the at least one cycle; or vi) administered at a dose between 3 and 20 mg / kg, preferably at a dose of 20 mg / kg, and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and said dose being administered at least once in each of the at least one cycle; 58. A combination or pharmaceutical composition according to any one of claims 35 to 57.

59. 58. The combination or pharmaceutical composition of claim 57, wherein the anti-GDF-15 antibody is administered at a dose of 20 mg / kg and in a dosing regimen consisting of at least one administration cycle, the cycle being 4 weeks in duration, and the dose being administered at least once in each of the at least one cycle.

60. 59. The combination or pharmaceutical composition of claim 57 or 58, wherein the cycles are four weeks in duration, the dose is administered at least once in each of at least one cycle, and the dose is administered over at least one, two, three, or four cycles.

61. 61. The combination or pharmaceutical composition of any one of claims 57 to 60, wherein the anti-GDF-15 antibody is administered to a human patient at a dose of 20 mg / kg and in a dosing regimen consisting of three administration cycles, each cycle being 4 weeks in duration, and said dose being administered at least once in each cycle.

62. 62. The combination or pharmaceutical composition of any one of claims 35 to 61, wherein the checkpoint inhibitor is administered in the same dosing regimen as the anti-GDF-15 antibody.

63. 63. The combination or pharmaceutical composition of claim 62, wherein the checkpoint inhibitor is administered prior to administration of the anti-GDF-15 antibody, preferably within 120 minutes prior to administration of the anti-GDF-15 antibody, more preferably within 30 minutes prior to administration of the anti-GDF-15 antibody.

64. 64. The combination or pharmaceutical composition of claim 62 or 63, wherein the dose of anti-GDF-15 antibody is administered intravenously.

65. 65. The combination or pharmaceutical composition of any one of claims 35 to 64, wherein the 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.

66. 66. The combination or pharmaceutical composition of claim 65, wherein the anti-GDF-15 antibody has 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, preferably at least 95% identity, and more preferably at least 98% 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO:

7.

67. 67. The combination or pharmaceutical composition of claim 65 or 66, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 or an amino acid sequence having at least 90% identity, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by 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, preferably at least 95% identity, and more preferably at least 98% identity to the amino acid sequence represented by SEQ ID NO:

9.

68. 68. The combination or pharmaceutical composition of any one of claims 65 to 67, wherein the anti-GDF-15 antibody has a heavy chain comprising the amino acid sequence represented by SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO:

9.

69. 69. The combination or pharmaceutical composition according to any one of claims 35 to 68, wherein the anti-GDF-15 antibody is obtained by expression in CHO cells.

70. 70. The combination or pharmaceutical composition of any one of claims 35 to 69, wherein the anti-GDF-15 antibody is visglobumab.

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