Anti-GDF 15 antibodies for neoadjuvant therapy of cancer

Abstract

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

Description

Technical Field

[0001] The present invention relates to anti-GDF15 antibodies for neoadjuvant treatment of cancer. Background Art

[0002] Research in the field of cancer treatment has provided different treatment strategies such as surgery, chemotherapy, radiotherapy, hormone therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy), or synthetic lethality, the application of which depends in particular on the location and grade of the tumor and the stage of the disease. While complete removal of cancer without damaging other parts of the body (e.g., by surgery) would be the ideal treatment outcome, the effectiveness of surgical intervention is often limited due to the tendency of cancer to invade adjacent tissues or spread to distant sites via microscopic metastases. Neoadjuvant treatments such as chemotherapy or hormone therapy are given in addition to primary or initial treatment to promote reduction in tumor size, thereby facilitating more effective surgery.

[0003] For example, urothelial bladder cancer is the fourth most common cancer in the United States (US), with over 60,000 new cases per year. Approximately 25% of patients with urothelial carcinoma will have muscle-invasive disease (T2-4) and present or subsequently develop metastases (von der Maase et al, 2005). Initially, if a bladder mass is detected in a patient, transurethral resection of the bladder tumor (TURBT) is performed for comprehensive primary tumor staging. When muscle-invasive bladder cancer (MIBC) is determined to be present, radical cystectomy (RC) is performed. Despite aggressive local and systemic treatment strategies, MIBC is generally associated with high recurrence rates and poor overall prognosis. Unfortunately, up to 50% of patients will still have a recurrence of cancer within 12 months, and all patients remain at increased risk of recurrence for the rest of their lives. Even after RC, the 5-year mortality rate for patients with MIBC remains at approximately 50% to 70% (Grossman et al, 2003).

[0004] Due to this high recurrence rate, neoadjuvant chemotherapy administered in this context has been well established and is listed as level 1 evidence in the National Comprehensive Cancer Network guideline (NCCN, 2021), but only achieves relatively small survival improvements (approximately 6% at 5 years) compared to RC alone.

[0005] Given the aggressiveness and poor prognosis of MIBC, as well as the high recurrence rate and mortality after RC, there is a need in the art for improved treatment strategies.

[0006] Although the present invention exemplifies clinical studies on a specific cancer (i.e., MIBC), it should be understood that the results will generally also allow for the adjustment and improvement of the treatment of other types of cancer in human patients. Summary of the Invention

[0007] The present invention aims to overcome the unmet clinical needs to provide a safe and effective treatment for cancer treatment in human patients.

[0008] Based on extensive experimental testing, the inventors of the present application have found that the anti-growth differentiation factor 15 (GDF-15) antibody visugromab (CTL-002) generates tumor-selective immune influx of CD8+ and CD4+ T cells. In addition, visugromab in combination with anti-PD-1 therapy has shown encouraging anti-tumor efficacy in fully anti-PD-1 / PD-L1 recurrent / refractory subjects (see, for example, WO 2022 / 101263).

[0009] Due to the negative correlation between GDF-15 expression and defined clinical outcomes in urothelial tumors, as well as the reduced response to checkpoint inhibitor therapy, bladder cancer has been identified as the indication of interest. In this regard, the present invention sets out to provide clinical data on the neoadjuvant treatment of subjects with MIBC using visugromab.

[0010] Furthermore, in a non-limiting embodiment, the present invention also teaches the mode of action of anti-GDF-15 antibodies as neoadjuvant treatment for cancer treatment. According to this embodiment of the present invention, adding visugromab to neoadjuvant treatment / as neoadjuvant treatment may contribute to reducing the tumor stage and may also achieve a pathologic complete response (pCR) of the primary tumor (pT0) in a greater proportion of subjects compared to current use of immunotherapy or chemotherapy alone.

[0011] Another non-limiting advantage of the neoadjuvant treatment according to the present invention is that it allows for the very effective delivery of immune cells into the tumor because the blood vessels of the tumor remain intact before surgery. Thus, the neoadjuvant treatment according to the present invention allows for an improved immune response to cancer.

[0012] Therefore, neoadjuvant treatment using anti-GDF-15 antibodies generally allows for a reduced risk of recurrence and recurrence-free survival in human cancer patients.

[0013] The present invention provides the following preferred embodiments:

[0014] Item 1. An anti-GDF-15 antibody for neoadjuvant treatment of cancer in a human patient.

[0015] Item 2. The anti-GDF-15 antibody for the use according to Item 1, wherein the cancer is a solid cancer, and wherein the neoadjuvant treatment is used to treat or inhibit tumor growth of the solid cancer.

[0016] Item 3. The anti-GDF-15 antibody for the use according to Item 1 or 2, wherein the anti-GDF-15 antibody will be administered in combination with at least one checkpoint inhibitor, and wherein the checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0017] Item 4. The anti-GDF-15 antibody for the use according to Item 2 or 3, wherein the patient is scheduled for surgery on the primary tumor of the solid cancer.

[0018] Item 5. The anti-GDF-15 antibody for the use according to any one of Items 2 to 4, wherein the surgery is a resection surgery.

[0019] Item 6. The anti-GDF-15 antibody for the use according to any one of Items 2 to 5, wherein the resection surgery is a radical cystectomy including removal of the bladder, adjacent organs, and regional lymph nodes.

[0020] Item 7. The anti-GDF-15 antibody for the use according to any one of Items 2 to 6, wherein the duration of the neoadjuvant treatment before the resection surgery is at most 3, 6, or 12 weeks.

[0021] Item 8. The anti-GDF-15 antibody for the use according to any one of Items 2 to 7, wherein the treatment is aimed at reducing the stage of locally advanced solid cancer to reduce the surgical margin or to perform an organ-preserving surgery.

[0022] Item 9. The anti-GDF-15 antibody for the use according to Item 8, wherein the duration of the neoadjuvant treatment is at most 3, 4, 6, 12, or 24 weeks.

[0023] Item 10. The anti-GDF-15 antibody for the use according to any one of Items 2 to 9, wherein the cancer is selected from: colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostatic adenocarcinoma, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, cancer of unknown primary (CUP), and breast cancer.

[0024] Item 11. The anti-GDF-15 antibody for the use according to Item 10, wherein the cancer is bladder cancer.

[0025] Item 12. The anti-GDF-15 antibody for use according to item 11, wherein the bladder cancer is muscle-invasive bladder cancer.

[0026] Item 13. The anti-GDF-15 antibody for use according to any one of items 1 to 12, wherein the patient is unable or refuses to receive chemotherapy.

[0027] Item 14. The anti-GDF-15 antibody for use according to item 13, wherein the chemotherapy is chemotherapy for neoadjuvant treatment, such as cisplatin-based chemotherapy.

[0028] Item 15. The anti-GDF-15 antibody for use according to any one of items 2 to 14, wherein the programmed death-ligand 1 combined positive score (CPS) of the tissue sample of the tumor is ≥10%.

[0029] Item 16. The anti-GDF-15 antibody for use according to any one of items 2 to 14, wherein the PD-L1 CPS of the tissue sample of the tumor is <10%.

[0030] Item 17. The anti-GDF-15 antibody for use according to any one of items 1 to 16, wherein the cancer is classified as a stage T2 tumor.

[0031] Item 18. The anti-GDF-15 antibody for use according to any one of items 1 to 17, wherein the cancer is classified as a stage T3 / T4 tumor.

[0032] Item 19. The anti-GDF-15 antibody for use according to any one of items 1 to 18, wherein the cancer tissue covers non-basal / squamous tissue.

[0033] Item 20. The anti-GDF-15 antibody for use according to any one of items 1 to 18, wherein the cancer tissue covers basal / squamous tissue.

[0034] Item 21. The anti-GDF-15 antibody for use according to any one of items 1 to 20, wherein the anti-GDF-15 antibody will be administered to the human patient, preferably i) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a two-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, ii) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a three-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, or iii) The dosage is 3 to 20 mg / kg, preferably 20 mg / kg, and the dosage regimen is at least one administration cycle, where the cycle is a four-week period, and where the dosage will be administered at least once in each cycle of at least one cycle.

[0035] Item 22. The anti-GDF-15 antibody for the application according to Item 21, wherein the anti-GDF-15 antibody will be administered at a dosage of 20 mg / kg and a dosage regimen of at least one administration cycle, where the cycle is a four-week period, and where the dosage will be administered at least once in each cycle of at least one cycle.

[0036] Item 23. The anti-GDF-15 antibody for the application according to Item 21 or 22, wherein the cycle is a four-week period, where the dosage will be administered at least once in each cycle of at least one cycle, and where the dosage will be administered for at least one, two, three, or four cycles.

[0037] Item 24. The anti-GDF-15 antibody for the application according to any one of Items 21 to 23, wherein the anti-GDF-15 antibody will be administered to the human patient at a dosage of 20 mg / kg and a dosage regimen of three administration cycles, where the cycle is a four-week period, and where the dosage will be administered at least once in each cycle.

[0038] Item 25. The anti-GDF-15 antibody for the application according to any one of Items 3 to 24, wherein the checkpoint inhibitor will be administered according to the same dosage regimen as the anti-GDF-15 antibody.

[0039] Item 26. The anti-GDF-15 antibody for the application according to Item 25, wherein the checkpoint inhibitor will be administered before the anti-GDF-15 antibody, preferably within 120 minutes before the anti-GDF-15 antibody is administered, more preferably within 30 minutes before the anti-GDF-15 antibody is administered.

[0040] Item 27. The anti-GDF-15 antibody for the application according to Item 25 or 26, wherein the dosage of the anti-GDF-15 antibody will be administered intravenously.

[0041] Item 28. The anti-GDF-15 antibody for the application according to any one of Items 1 to 27, wherein the anti-GDF-15 antibody comprises a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprises 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 the light chain variable domain comprises 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.

[0042] Item 29. The anti-GDF-15 antibody for the application according to Item 28, wherein the anti-GDF-15 antibody has a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO:6, and the light chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO:7.

[0043] Item 30. The anti-GDF-15 antibody for the application according to Item 28 or 29, wherein the anti-GDF-15 antibody has a heavy chain and a light chain, the heavy chain comprises 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 with the amino acid sequence shown in SEQ ID NO:8, and the light chain comprises 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 with the amino acid sequence shown in SEQ ID NO:9.

[0044] Item 31. The anti-GDF-15 antibody for the application according to any one of Items 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.

[0045] Item 32. The anti-GDF-15 antibody for the application according to any one of Items 1 to 31, wherein the anti-GDF-15 antibody can be obtained by expression in CHO cells.

[0046] Item 33. An anti-GDF-15 antibody for use according to any one of Items 1 to 32, wherein the anti-GDF-15 antibody is visugromab.

[0047] Item 34. An anti-GDF-15 antibody for use according to any one of Items 1 to 33, wherein the neoadjuvant treatment further comprises at least one treatment modality selected from the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiotherapy.

[0048] Item 35. A combination product for neoadjuvant treatment of cancer in a human patient, comprising an anti-GDF-15 antibody according to any one of Items 1 to 34 and at least one active substance used in the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiotherapy.

[0049] Item 36. A pharmaceutical composition for neoadjuvant treatment of cancer in a human patient, comprising a combination of an anti-GDF-15 antibody according to any one of Items 1 to 34 and at least one active substance used in the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiotherapy.

[0050] Item 37. The combination product according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a checkpoint inhibitor; wherein the checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0051] Item 38. The combination product according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a bispecific T cell engager.

[0052] Item 39. The combination product according to Item 35 or the pharmaceutical composition according to Item 36, wherein the active substance is a cell-based active substance used in cell therapy.

[0053] Item 40. The combination product or pharmaceutical composition according to any one of Items 35 to 39, wherein the cancer is a solid cancer, and wherein the neoadjuvant treatment is used to treat or inhibit tumor growth of the solid cancer.

[0054] Item 41. The combination product or pharmaceutical composition according to Item 40, wherein the patient is scheduled for surgery of the primary tumor of the solid cancer.

[0055] Item 42. The combination product or pharmaceutical composition according to any one of Items 35 to 41, wherein the surgery is resection surgery.

[0056] Item 43. The combination product or pharmaceutical composition according to any one of Items 35 to 42, wherein the resection surgery is a radical cystectomy including removal of the bladder, adjacent organs, and regional lymph nodes.

[0057] Item 44. The combination product or pharmaceutical composition according to any one of Items 35 to 43, wherein the duration of the neoadjuvant therapy before the resection surgery is at most 3, 6, or 12 weeks.

[0058] Item 45. The combination product or pharmaceutical composition according to any one of Items 35 to 44, wherein the treatment is intended to reduce the stage of locally advanced solid cancer to reduce the surgical scope or perform organ-preserving surgery.

[0059] Item 46. The combination product or pharmaceutical composition according to Item 45, wherein the duration of the neoadjuvant therapy is at most 3, 4, 6, 12, or 24 weeks.

[0060] Item 47. The combination product or pharmaceutical composition according to any one of Items 35 to 46, wherein the cancer is selected from: colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate adenocarcinoma, pancreatic cancer, uterine cancer, cervical cancer, thyroid cancer, cutaneous squamous cell carcinoma, mesothelioma, carcinoma of unknown primary (CUP), and breast cancer.

[0061] Item 48. The combination product or pharmaceutical composition according to Item 47, wherein the cancer is bladder cancer.

[0062] Item 49. The combination product or pharmaceutical composition according to Item 48, wherein the bladder cancer is muscle-invasive bladder cancer.

[0063] Item 50. The combination product or pharmaceutical composition according to any one of Items 35 to 49, wherein the patient is unable to receive or refuses to receive chemotherapy.

[0064] Item 51. The combination product or pharmaceutical composition according to Item 50, wherein the chemotherapy is chemotherapy for neoadjuvant therapy, for example, cisplatin-based chemotherapy.

[0065] Item 52. The combination product or pharmaceutical composition according to any one of Items 35 to 51, wherein the PD-L1 combined positive score (CPS) of the tissue sample of the tumor is ≥ 10%.

[0066] Item 53. The combination product or pharmaceutical composition according to any one of Items 35 to 51, wherein the PD-L1 CPS of the tissue sample of the tumor is < 10%.

[0067] Item 54. The combination product or pharmaceutical composition according to any one of Items 35 to 53, wherein the cancer is classified as a T2-stage tumor.

[0068] Item 55. The combination product or pharmaceutical composition according to any one of Items 35 to 53, wherein the cancer is classified as a T3 / T4-stage tumor.

[0069] Item 56. The combination product or pharmaceutical composition according to any one of Items 35 to 55, wherein the cancer tissue covers non-basal / squamous tissue.

[0070] Item 57. The combination product or pharmaceutical composition according to any one of Items 35 to 55, wherein the cancer tissue covers basal / squamous tissue.

[0071] Item 58. The combination product or pharmaceutical composition according to any one of Items 35 to 57, wherein the anti-GDF-15 antibody will be administered to the human patient, preferably i) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a two-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, ii) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a three-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, or iii) at a dose of 3 to 20 mg / kg, preferably at a dose of 20 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a four-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle.

[0072] Item 59. The combination product or pharmaceutical composition according to Item 57, wherein the anti-GDF-15 antibody will be administered at a dose of 20 mg / kg and a dosing regimen of at least one administration cycle, wherein the cycle is a four-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle.

[0073] Item 60. The combination product or pharmaceutical composition according to any one of Items 57 or 58, wherein the cycle is a four-week period, wherein the dose will be administered at least once in each cycle of at least one cycle, and wherein the dose will be administered for at least one, two, three, or four cycles.

[0074] Item 61. The combination product or pharmaceutical composition according to any one of Items 57 to 60, wherein the anti-GDF-15 antibody will be administered to the human patient at a dose of 20 mg / kg and a dosing regimen of three administration cycles, wherein each cycle is a four-week time period, and wherein the dose will be administered at least once in each cycle.

[0075] Item 62. The combination product or pharmaceutical composition according to any one of Items 35 to 61, wherein the checkpoint inhibitor will be administered according to the same dosing regimen as the anti-GDF-15 antibody.

[0076] Item 63. The combination product or pharmaceutical composition according to Item 62, wherein the checkpoint inhibitor will be administered before the anti-GDF-15 antibody, preferably within 120 minutes before the anti-GDF-15 antibody is administered, more preferably within 30 minutes before the anti-GDF-15 antibody is administered.

[0077] Item 64. The combination product or pharmaceutical composition according to Item 62 or 63, wherein the dose of the anti-GDF-15 antibody will be administered intravenously.

[0078] Item 65. The combination product or pharmaceutical composition according to any one of Items 35 to 64, wherein the anti-GDF-15 antibody comprises a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprises 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, the light chain variable domain comprises 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.

[0079] Item 66. The combination product or pharmaceutical composition according to Item 65, wherein the anti-GDF-15 antibody has a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO:6, the light chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO:7.

[0080] Item 67. The combination product or pharmaceutical composition according to item 65 or 66, wherein the anti-GDF-15 antibody has a heavy chain and a light chain, the 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 with the amino acid sequence shown in SEQ ID NO:8, and the 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 with the amino acid sequence shown in SEQ ID NO:9.

[0081] Item 68. The combination product or pharmaceutical composition according to any one of items 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.

[0082] Item 69. The combination product or pharmaceutical composition according to any one of items 35 to 68, wherein the anti-GDF-15 antibody can be obtained by expression in CHO cells.

[0083] Item 70. The combination product or pharmaceutical composition according to any one of items 35 to 69, wherein the anti-GDF-15 antibody is visugromab. Brief Description of the Drawings Figure 1 : Antitumor Activity in Urothelial Carcinoma Ph2a: Deep and Durable Responses

[0084] Antitumor activity of combination therapy with the GDF-15 blocking antibody visugromab and nivolumab in advanced anti-PD1 / PD-L1 refractory / relapsed patients with urothelial carcinoma. Patient responses and treatment courses are shown for 27 patients in the urothelial carcinoma Ph2a cohort. The objective response rate (ORR) for urothelial carcinoma was 14.7% (4 / 27). The durability of response (DoR) was 10+ months and is still maturing.

[0085] Lane diagrams ( Figure 1 A) and spaghetti diagrams ( Figure 1 B) show patient responses and treatment courses. Detailed Description of the Invention

[0086] In a non-limiting embodiment, the neoadjuvant treatment of the present invention using an anti-GDF-15 antibody is not particularly limited and may further comprise at least one treatment modality selected from the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination, or radiotherapy.

[0087] In this regard, the neoadjuvant treatment using an anti-GDF-15 antibody further comprises using at least one active substance selected from the following: checkpoint inhibitors, oncolytic viruses, bispecific conjugates, or antibody-drug conjugates, such as enhertu.

[0088] It should be understood that according to the present invention, the mention of "at least one checkpoint inhibitor" means that the specified checkpoint inhibitor is required, and additional checkpoint inhibitors may or may not be included, i.e., they are optionally included. For example, it should be understood that in the case where the present invention relates to at least one checkpoint inhibitor, where the checkpoint inhibitor is selected from an anti-PD-1 antibody or its PD-1 binding fragment and an anti-PD-L1 antibody or its PD-L1 binding fragment, this means that a checkpoint inhibitor selected from an anti-PD-1 antibody or its PD-1 binding fragment and an anti-PD-L1 antibody or its PD-L1 binding fragment is required, and additional checkpoint inhibitors (e.g., anti-CD40 antibody or its CD40 binding fragment, anti-LAG-3 antibody or its LAG-3 binding fragment, anti-TIM-3 antibody or its TIM-3 binding fragment, anti-TIGIT antibody or its TIGIT binding fragment, and anti-CTLA4 antibody or its CTLA4 binding fragment) may or may not be included, i.e., they are optionally included.

[0089] In a non-limiting embodiment of the present invention, the checkpoint inhibitor can be any one selected from the following: anti-PD-1 antibody, anti-PD-L1 antibody, anti-CD40 antibody, anti-LAG-3 antibody, anti-TIM-3 antibody, anti-TIGIT antibody, and anti-CTLA4 antibody, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0090] In a preferred embodiment, the anti-PD-1 antibody is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, 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 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.

[0091] The form of administration of at least one checkpoint inhibitor is not particularly limited and may include, for example, intravenous administration and / or subcutaneous administration. Detailed implementation

[0092] 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.

[0093] All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, and suitable methods and materials are described herein.

[0094] For all purposes, all references mentioned herein are incorporated by reference in their entirety. Patent applications are cited herein by using their application numbers and / or publication numbers. Non-patent literature mentioned herein can be cited as a complete reference or in abbreviated form (e.g., Danaher et al., 2018), and then fully cited in the "References" section.

[0095] Each occurrence of terms such as "comprising / including" and its variants mentioned herein can optionally be replaced with "consisting of" or its variants.

[0096] As used herein, the term "neoadjuvant therapy" refers to treatment that is conducted prior to surgical resection of a tumor, preferably a primary tumor. Thus, neoadjuvant therapy encompasses treatments that are intended to downstage locally advanced solid cancers to enable a reduction in the extent of surgery or to perform organ-preserving surgery. In this regard, neoadjuvant therapy may permit a tumor to become resectable or reduce the extent of surgery, for example due to shrinkage of the tumor size. For example, neoadjuvant therapy may be conducted as tumor treatment to enable surgical resection of the tumor.

[0097] As used herein, it is known that some patients are unable to receive or decline chemotherapy, and the criteria for identifying such patients are known in the art. Preferably, a patient who is "unable to receive or declines chemotherapy" refers to a patient who is ineligible for cisplatin as defined by the Galsky criteria shown in Table 1 below: Table 1:

[0098] As used herein, the term "Combined Positive Score (CPS)" refers to a score that reflects PD-L1 expression on tumor cells and tumor-infiltrating immune cells, and can be determined by a validated IHC test. For example, the Combined Positive Score (CPS) of PD-L1 is the sum percentage of cancer cells and cancer-infiltrating cells (e.g., cancer-infiltrating immune cells) that show staining for PD-L1 present on the cell surface. The sum percentage of these 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 show staining for PD-L1 present on the cell surface, dividing said number by the sum of cancer cells and cancer-infiltrating cells in the sample, and multiplying the resulting quotient by 100.

[0099] As used herein, the tumor classification score refers to the globally recognized standard (TNM) for classifying the extent of cancer spread. For example, TNM classification describes the primary tumor (T), lymph node involvement (N), and evidence of metastasis (M0 or M1). The T value describes the size and level of infiltration of the primary tumor.

[0100] Cancer patients to be treated according to the present invention can be selected based on at least one characteristic selected from CPS, tumor classification score, and histological cancer type.

[0101] In one aspect, the cancer tissue of a patient to be treated according to the present invention may have a PD-L1 Combined Positive Score (CPS) of ≥10%. The patient may also have a cancer classified as a T2 or T3 / T4 stage tumor.

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

[0103] In one aspect, a patient to be treated according to the present invention may be selected based on the histological classification of the cancer type. Those skilled in the art are aware of histological techniques for classifying cancer types based on the cellular context of the cancer. For example, carcinomas originating from the skin or tissues lining or covering internal organs may be further classified into different cancer subtypes according to the cell layers within the affected epithelial cells (such as squamous cells, adenocarcinoma cells, transitional cells, and / or basal cells).

[0104] In one aspect, the cancer to be treated according to the present invention may be classified as having a basal / squamous histology.

[0105] In another aspect, the cancer to be treated according to the present invention may be classified as having a non-basal / squamous histology.

[0106] As used herein, the terms "CTL-002" and visugromab are used synonymously. They refer to an antibody having the heavy chain amino acid sequence of SEQ ID NO: 8 and the light chain amino acid sequence of SEQ ID NO: 9. It should be understood that any reference to the amino acid sequence of the antibody of the present invention is intended to cover 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.

[0107] It should be understood that the antibody according to the present invention can be administered in the form of a pharmaceutical composition. Such a pharmaceutical composition is prepared in a manner suitable for storage and administration, for example, by using pharmaceutically acceptable components such as carriers, excipients, or stabilizers.

[0108] When the pharmaceutical composition is administered to a human patient, such pharmaceutically acceptable components are non-toxic at the amounts used. The pharmaceutically acceptable components added to the pharmaceutical composition may depend on the route of administration.

[0109] Generally, pharmaceutically acceptable components used in conjunction with the present invention are used according to knowledge available in the art, such as from Remington’s Pharmaceutical Sciences, Ed. A R Gennaro, 20th Edition, 2000, Williams & Wilkins, PA, USA.

[0110] The present invention is further illustrated by the following non-limiting examples. Examples Example 1: Neoadjuvant immunotherapy Overall study design

[0111] This is a multicenter, stratified, and single-blind phase 2 study of the combination of neoadjuvant immunotherapy with the anti-GDF-15 antibody visugromab (CTL-002) for the treatment of subjects with MIBC who have undergone RC and are ineligible or have refused cisplatin-based chemotherapy.

[0112] This exploratory study will evaluate and explore the clinical efficacy and safety of multiple immuno-oncology agents as neoadjuvant therapy for individuals with MIBC who are ineligible for or have refused cisplatin, as well as the potential for clinical benefit, such as, for example, anti-PD-1 inhibitors and at doses that have shown an increased risk of minimal / acceptable AEs. Translational endpoints should inform which treatments are viable candidates for further study in MIBC.

[0113] The study design is presented in Table 2 below: Table 2:

[0114] The treatment of this study will be allocated and planned as follows: - Eligible subjects will be assigned and stratified 1:1 to one of the treatment groups based on tumor tissue PD-L1 CPS > 10% or PD-L1 CPS < 10% and their tumor size (T2 or T3 / T4) - Subjects will receive the following study treatment: ○ Treatment group A (nivolumab + placebo) ○ Treatment group B (nivolumab + visugromab [CTL-002]) - A total of 3 cycles are planned before surgery - RC + pelvic lymph node dissection for curative intent will be planned at the time of study enrollment to be performed within 4 to 8 weeks after the planned last dose of study drug infusion

[0115] Efficacy assessment will be performed pathologically by evaluating the pathologic response of RC samples and radiologically according to RECIST v1.1. Subjects will be carefully monitored for the occurrence of AEs, and clinical and / or radiologic evidence of disease progression will be monitored according to the conventional standards of clinical practice. Adverse experiences will be evaluated according to the criteria outlined in NCI-CTCAE version 5.0. Immunotherapy treatment period

[0116] The immunotherapy treatment period lasts for 12 weeks (3 cycles of 4 weeks).

[0117] As described above, subjects are assigned and stratified 1:1 into 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 Group B (nivolumab + vesugromab [CTL-002])

[0118] For the combination, vesugromab and nivolumab will be administered simultaneously on the same day, with vesugromab always being administered first. There will be a 30-minute observation period after the administration of vesugromab (CTL-002) to assess safety, and then nivolumab will be infused subsequently (Group B), which is administered according to the SmPC and local guidelines. Radical cystectomy (RC)

[0119] RC requires removal of the bladder, adjacent organs, and local lymph nodes. In men, this includes removal of the prostate and seminal vesicles, while in women, the reproductive organs (ovaries, fallopian tubes, uterus, and anterior vagina) may also be removed to achieve optimal oncological outcomes. The surgery is performed according to the hospital's standard practice (standard of care).

[0120] RC will be planned at the time of study inclusion and ideally performed at the end of the immunotherapy treatment period (4 to 8 weeks [28 to 56 days] after the last study drug infusion). Tumor material will be studied at two time points; the first at baseline, using transurethral resection material, and the second at 4 to 8 weeks [28 to 56 days] after the last study drug infusion) with cystectomy. Tumor tissue studies are mandatory to assess immune cell infiltration in the tumor. If a biopsy cannot be performed for safety reasons, it should be discussed with the medical monitor and the sponsor's medical representative. Subjects who refuse or are unfit for RC at the end of the neoadjuvant period will be managed according to the European Association for Urology guidelines and will primarily be offered chemoradiation as a bladder-sparing option. These subjects will continue to be monitored and included in the long-term safety and efficacy analysis. Example 2: Antitumor activity of the combination therapy of the GDF-15 blocking antibody vesugromab and nivolumab in bladder cancer

[0121] The target population of patients with advanced metastatic solid tumors that are recurrent / refractory to prior anti-PD1 / PD-L1 therapy was selected according to the following criteria: (i) for the indications approved for anti-PD1 / PD-L1 antibodies, prior continuous anti-PD1 / PD-L1 exposure for at least 12 weeks, and (2) progressive disease directly against that anti-PD1 / PD-L1 therapy or (3) if initially responsive, continuous anti-PD1 / PD-L1 therapy without interruption until recurrence / progression, and treated with the combination of the GDF-15 blocking antibody visugromab and nivolumab.

[0122] Clinical results based on the urothelial cancer ph2a cohort support the anti-tumor activity of the combination therapy of the GDF-15 blocking antibody visugromab and nivolumab in advanced anti-PD1 / PD-L1 recurrent / refractory patients, and the combination therapy achieved deep and durable responses, reaching complete responses with durations of up to over 1 year (see Figure 1 ).

[0123] In Figure 1 A (swimmer plot), the clinical results over time of 27 patients with urothelial cancer are shown, showing an objective response rate (ORR) of 14.7% [4 / 27]. The DoR was 10+ months and is still maturing.

[0124] For example, patient [1-01-15] showed tumor shrinkage (TS) starting from week 8 to 16, then showed a partial response (PR) from week 16 to 30, and showed a complete response (CR) as of week 32. Patient [1-01-019] showed tumor shrinkage (TS) as of week 8. Patient [1-06-005] showed a partial response (PR) as of week 10. Patient [1-02-036] showed a partial response (PR) as of week 6. Patient [1-02-037] showed tumor shrinkage (TS) starting from week 6 to 20, and showed a partial response (PR) as of week 20.

[0125] In Figure 1 B (spaghetti plot), the responses over time of multiple patients are shown, i.e., the % change relative to baseline in the target lesions. As illustrated by the curves of patients [1-01-015], [1-02-035], [1-06-005], [1-02-037], the response curves of patients with complete response (CR) or partial response (PR) are in the negative range of the vertical axis.

[0126] In summary, in the urothelial cancer cohort, a response rate of 14.8% was shown, and there were no grade 4 / 5 AEs (thus having a favorable safety profile). Additionally, the data also support an excellent response durability (DoR) of more than 10 months, and patients remaining in PR / CR had further extended DoR.

[0127] According to the present invention, it is expected that the anti-GDF-15 antibody (e.g., in particular, visugromab) will have antitumor activity and its ability to reinvigorate the immune response against cancer (especially bladder cancer), which will allow for effective neoadjuvant therapy. For example, administration of the anti-GDF-15 antibody will help stimulate the immune response against the tumor prior to resection, which will allow for the destruction of residual tissue and micrometastases after surgery, subsequently reducing the risk of recurrence after surgery. This is also particularly applicable in cases where immune checkpoint inhibitors (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) are present to maintain the existing antitumor immune response. Furthermore, according to the present invention, the favorable safety profile of the anti-GDF-15 antibody (e.g., in particular, visugromab) makes the anti-GDF-15 antibody suitable for the neoadjuvant therapy setting. Sequence:

[0128] SEQ ID No:1 (peptide sequence of the heavy chain CDR1 region of a monoclonal anti-human GDF-15 antibody): GFSLSTSGMG

[0129] SEQ ID No:2 (peptide sequence of the heavy chain CDR2 region of a monoclonal anti-human GDF-15 antibody): IYWDDDK

[0130] SEQ ID No:3 (peptide sequence of the heavy chain CDR3 region of a monoclonal anti-human GDF-15 antibody): ARSSYGAMDY

[0131] SEQ ID No:4 (peptide sequence of the light chain CDR1 region of a monoclonal anti-human GDF-15 antibody): QNVGTN

[0132] Peptide sequence of the light chain CDR2 region of a monoclonal anti-human GDF-15 antibody: SAS

[0133] SEQ ID No:5 (peptide sequence of the light chain CDR3 region of a monoclonal anti-human GDF-15 antibody): QQYNNFPYT

[0134] SEQ ID No:6 (heavy chain variable domain of a monoclonal anti-human GDF-15 antibody):

[0135] SEQ ID No: 7 (Light chain variable domain of monoclonal anti - human GDF - 15 antibody):

[0136] SEQ ID No: 8 (Heavy chain of monoclonal anti - human GDF - 15 antibody CTL - 002 without leader peptide sequence):

[0137] SEQ ID No: 9 (Light chain of monoclonal anti - human GDF - 15 antibody CTL - 002 without leader peptide sequence):

[0138] SEQ ID NO: 10 (Heavy chain variable domain of anti - human GDF - 15 antibody H1L5):

[0139] SEQ ID NO: 11 (Light chain variable domain of anti - human GDF - 15 antibody H1L5): 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. Barton, 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

[0140] Anti-GDF-15 antibodies for use in neoadjuvant treatment of cancer in human patients can be industrially prepared and sold as products for the listed methods and uses according to known pharmaceutical product preparation standards. Thus, the present invention is industrially applicable.

Claims

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

2. The anti-GDF-15 antibody for the use according to claim 1, wherein the cancer is a solid cancer, and wherein the neoadjuvant treatment is used to treat or inhibit tumor growth of the solid cancer.

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

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

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

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

7. The anti-GDF-15 antibody for the use according to any one of claims 2 to 6, wherein the duration of the neoadjuvant treatment before the resection surgery is at most 3, 6, or 12 weeks.

8. The anti-GDF-15 antibody for the use according to any one of claims 2 to 7, wherein the treatment is intended to downstage locally advanced solid cancer to reduce the surgical scope or perform an organ-preserving surgery.

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

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

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

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

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

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

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

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

17. An 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. An 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. An anti-GDF-15 antibody for use according to any one of claims 1 to 18, wherein the cancer tissue encompasses non-basal / squamous tissue.

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

21. An anti-GDF-15 antibody for use according to any one of claims 1 to 20, wherein the anti-GDF-15 antibody will be administered to the human patient, preferably iv) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a two-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, v) at a dose of 3 to 20 mg / kg, preferably at a dose of 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a three-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, or vi) at a dose of 3 to 20 mg / kg, preferably at a dose of 20 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a four-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle.

22. An anti-GDF-15 antibody for use according to claim 21, wherein the anti-GDF-15 antibody will be administered at a dose of 20 mg / kg and a dosing regimen of at least one administration cycle, wherein the cycle is a four-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle.

23. An anti-GDF-15 antibody for use according to claim 21 or 22, wherein the cycle is a four-week period, wherein the dose will be administered at least once in each cycle of at least one cycle, and wherein the dose will be administered for at least one, two, three or four cycles.

24. An anti-GDF-15 antibody for use according to any one of claims 21 to 23, wherein the anti-GDF-15 antibody will be administered to the human patient at a dose of 20 mg / kg and a dosing regimen of three administration cycles, wherein the cycle is a four-week period, and wherein the dose will be administered at least once in each cycle.

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

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

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

28. The 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 and a light chain variable domain, the 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, the 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. The anti-GDF-15 antibody for use according to claim 28, wherein the anti-GDF-15 antibody has a heavy chain variable domain and a light chain variable domain, the 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 with the amino acid sequence shown in SEQ ID NO:6, the 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 with the amino acid sequence shown in SEQ ID NO:

7.

30. The anti-GDF-15 antibody for use according to claim 28 or 29, wherein the anti-GDF-15 antibody has a heavy chain and a light chain, the 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 with the amino acid sequence shown in SEQ ID NO:8, the 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 with the amino acid sequence shown in SEQ ID NO:

9.

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

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

34. An anti-GDF-15 antibody for the use according to any one of claims 1 to 33, wherein the neoadjuvant treatment further comprises at least one treatment modality selected from the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination or radiotherapy.

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

36. A pharmaceutical composition for neoadjuvant treatment of cancer in a human patient, comprising a combination of an anti-GDF-15 antibody according to any one of claims 1 to 34 and at least one active substance used in the following: cell therapy, chemotherapy, targeted therapy, immunotherapy, therapeutic vaccination or radiotherapy.

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

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

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

40. The combination product or pharmaceutical composition according to any one of claims 35 to 39, wherein the cancer is a solid cancer, and wherein the neoadjuvant treatment is used to treat or inhibit the tumor growth of the solid cancer.

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

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

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

44. The combination product or pharmaceutical composition according to any one of claims 35 to 43, wherein the duration of the neoadjuvant treatment before the resection surgery is at most 3, 6 or 12 weeks.

45. The combination product or pharmaceutical composition according to any one of claims 35 to 44, wherein the treatment is intended to reduce the stage of locally advanced solid cancer to reduce the surgical scope or perform an organ-preserving surgery.

46. The combination product or pharmaceutical composition according to claim 45, wherein the duration of the neoadjuvant treatment is at most 3, 4, 6, 12 or 24 weeks.

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

48. The combination product or pharmaceutical composition according to claim 47, wherein the cancer is bladder cancer.

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

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

51. The combination product or pharmaceutical composition according to claim 50, wherein the chemotherapy is chemotherapy for neoadjuvant treatment, such as cisplatin-based chemotherapy.

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

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

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

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

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

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

58. The combination product or pharmaceutical composition according to any one of claims 35 to 57, wherein the anti-GDF-15 antibody will be administered to the human patient, preferably iv) the dose is 3 to 20 mg / kg, preferably the dose is 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a two-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, v) the dose is 3 to 20 mg / kg, preferably the dose is 10 mg / kg, and the dosing regimen is at least one administration cycle, wherein the cycle is a three-week period, and wherein the dose will be administered at least once in each cycle of at least one cycle, or vi) The dosage is 3 to 20 mg / kg, preferably 20 mg / kg, and the dosage regimen is at least one administration cycle, wherein the cycle is a four-week time period, and wherein the dosage will be administered at least once in each cycle of at least one cycle.

59. The combination product or pharmaceutical composition according to claim 57, wherein the anti-GDF-15 antibody will be administered at a dosage of 20 mg / kg and a dosage regimen of at least one administration cycle, wherein the cycle is a four-week time period, and wherein the dosage will be administered at least once in each cycle of at least one cycle.

60. The combination product or pharmaceutical composition according to any one of claims 57 or 58, wherein the cycle is a four-week time period, wherein the dosage will be administered at least once in each cycle of at least one cycle, and wherein the dosage will be administered for at least one, two, three, or four cycles.

61. The combination product or pharmaceutical composition according to any one of claims 57 to 60, wherein the anti-GDF-15 antibody will be administered to the human patient at a dosage of 20 mg / kg and a dosage regimen of three administration cycles, wherein the cycle is a four-week time period, and wherein the dosage will be administered at least once in each cycle.

62. The combination product or pharmaceutical composition according to any one of claims 35 to 61, wherein the checkpoint inhibitor will be administered according to the same dosage regimen as the anti-GDF-15 antibody.

63. The combination product or pharmaceutical composition according to claim 62, wherein the checkpoint inhibitor will be administered before the anti-GDF-15 antibody, preferably within 120 minutes before the anti-GDF-15 antibody, more preferably within 30 minutes before the anti-GDF-15 antibody.

64. The combination product or pharmaceutical composition according to claim 62 or 63, wherein the dosage of the anti-GDF-15 antibody will be administered intravenously.

65. The combination product or pharmaceutical composition according to any one of claims 35 to 64, wherein the anti-GDF-15 antibody comprises a heavy chain variable domain and a light chain variable domain, the 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, the 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. The combination product or pharmaceutical composition according to claim 65, wherein the anti-GDF-15 antibody has a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO: 6, and the light chain variable domain comprises 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 with the amino acid sequence shown in SEQ ID NO:

7.

67. The combination product or pharmaceutical composition according to claim 65 or 66, wherein the anti-GDF-15 antibody has a heavy chain and a light chain, the heavy chain comprises 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 with the amino acid sequence shown in SEQ ID NO: 8, and the light chain comprises 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 with the amino acid sequence shown in SEQ ID NO:

9.

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

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

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