Anti-hgdf-15 antibody for use in the treatment of cancer in a patient in combination with a cancer antigen-targeted drug conjugate that induces cancer cell stress

Abstract

The present invention relates to uses of an anti-hGDF-15 antibody for the treatment of cancer in a patient in combination with a cancer antigen-targeted drug conjugate, such as an antibody-drug conjugate, that induces cancer cell stress.

Description

Field of invention The present invention relates to uses of an anti-hGDF-15 antibody for the treatment of cancer in a patient in combination with a cancer antigen-targeted drug conjugate, such as an antibody-drug conjugate, that induces cancer cell stress. Moreover, the invention also relates to a combination therapy for the treatment of cancer further including an immune checkpoint blocker. In addition, the invention provides a combination product, a kit and a pharmaceutical composition comprising an anti-hGDF-15 antibody and an antibody-drug conjugate. Background Antibody-drug conjugates (ADCs) have led to significant advancements in targeted cancer therapy, merging the specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. This therapeutic approach exploits the ability of antibodies to selectively bind to antigens expressed predominantly on the surface of cancer cells, thereby delivering the attached cytotoxic drug directly to the tumor site. The targeted delivery of the cytotoxic drug minimizes the impact on healthy cells thereby reducing the systemic toxicity often associated with traditional chemotherapy. ADCs typically consist of three components: a monoclonal antibody specific to a tumor-associated antigen, a cytotoxic drug (payload), and a linker that stably connects the drug to the antibody. Upon binding to the target antigen, the ADC-antigen complex is internalized by the cancer cell, whereupon the cytotoxic drug is released and induces cell stress or cell death in the cancer cell. In addition to their direct cytotoxic effects, recent observations indicate that ADCs can induce cancer cell stress or cancer cell death thereby stimulating potent anti-cancer immune responses. For example, ADCs have been shown to induce a form of cell death known as immunogenic cell death (ICD) in cancer cells (Cao et al., 2017; Rios-Doria et al., 2017; Bauzon et al., 2019; D'Amico et al., 2019; Boshuizen et al., 2021; Devra Olson et al., 2022). ICD is characterized inter alia by the release of various danger signals and cancer antigens, which can enhance the recruitment and activation of immune cells. The exposure of calreticulin on the cell surface and the release of ATP and HMGB1 are relevant events in this process, serving as 'eat me' signals to dendritic cells and other antigen-presenting cells. These immune cells may then process and present the cancer antigens, effectively triggering a secondary immune response against the cancer (Kroemer et al., 2022). Despite the therapeutic potential of targeted cancer treatment, many patients still die from cancers and there remains a need in the art for improving cancer therapy of ADC-containing regimens. Description of invention The present inventors considered that the unmet clinical need in the field of cancer therapy could be addressed by assessing the role of Growth differentiation factor-15 (GDF-15), a stress-induced cytokine in targeted cancer therapy. Unexpectedly, the inventors have found that cancer antigen-targeted drug conjugates, such as ADCs, induce GDF-15 production in cancer cells. Specifically, the inventors have revealed that that GDF-15 production was induced by increasing concentrations of the ADCs Trastuzumab deruxtecan (anti-HER2) and Sacituzumab govitecan (anti-TR0P2), which was concomitant with induction of cell death as evidenced by a decrease in cell viability. Similarly, the inventors also found that GDF-15 was induced by monomethyl auristatin E (MMAE), a microtubule inhibitor, which inhibits mitotic cell division and ultimately induces apoptosis. GDF-15 is known to inhibit several key processes in anticancer immunity. It impairs the activation and maturation of antigen-presenting cells (APCs), incl. macrophages and dendritic cells, and hinders the effective priming of T cells by DCs and subsequent expansion (Schuberth-Wagner, C., et al., 2023; Zhou, Zhizhong, et al. 2023). Beyond these effects, GDF-15 significantly reduces the adhesion of T cells to endothelial cells, impeding their extravasation and infiltration into tumors, which is essential for direct cancer attack (Haake, Markus, et al. 2023). Moreover, it is also known that overexpression of GDF-15 contributes to an immunosuppressive environment, aiding cancer cells in evading immune surveillance and response. In summary, the experimental evidence provided in the application supports that cancer antigen-targeted drug conjugates, e.g., antibodies conjugated to drugs such as inhibitors of topoisomerase I or microtubule inhibitors induce cancer cell stress and the production of GDF-15. Without being bound by the theory, it is believed that GDF-15 production is a stress response of the cancer cell following ADC treatment. Moreover, it is expected that the presence of GDF-15 in the cancer microenvironment reduces the efficacy of a cancer therapy with antigen-targeted drug conjugates, e.g., ADCs, by counteracting the immune-stimulatory activity of cancer cell stress or cancer cell death. This reduction in efficacy applies particularly also to the synergistic activity of antigen-targeted drug conjugates with immunotherapies, such as immune checkpoint blockade. Thus, based on the findings of the inventors, GDF-15 is considered to reduce therapeutic efficacy of antigen-targeted drug conjugates and the development of treatment resistance. Evidently, the inventors show that neutralizing GDF-15 improves the anti tumor efficacy of an ADC treatment resulting inter alia in tumor regression, enhanced immune infiltration and increased activation of T cells and macrophages. Moreover, the experimental data provided in the application demonstrate that GDF-15 reduces the therapeutic activity of a combination treatment using an ADC and checkpoint blockade / inhibition and that neutralization of GDF-15 results in an enhanced efficacy of the combination treatment using an ADC and immune checkpoint inhibition / blockade. Therefore, neutralization of GDF-15 is expected to improve the ADC activity and the synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting GDF-15-mediated treatment resistance and suppression of ADC-induced immune cell activation. In view of the above, the present invention relates to an anti-hGDF-15 antibody or antigenbinding portion thereof (i.e., hGDF-15-binding portion thereof) for use in the treatment of cancer in a patient in combination with a cancer antigen-targeted drug conjugate that induces cancer cell stress. Anti-hGDF-15 antibodies and antigen-binding portions thereof (i.e., hGDF-15-binding portions thereof) are expected to synergize with cancer antigen-targeted drug conjugate treatment regimens and enhance adaptive anticancer immune responses so as to improve therapeutic efficacy. Thus, the present invention holds potential to establish long-lasting immune surveillance, potentially preventing cancer recurrence and improving patient outcomes in various cancer types. Accordingly, the present invention provides the following preferred embodiments: 1. An anti-hGDF-15 antibody or antigen-binding portion thereof for use in a method for the treatment of cancer in a human patient in combination with a cancer antigen-targeted drug conjugate that induces cancer cell stress. 2. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 1, wherein the cancer cell stress is immunogenic. 3. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 1 or 2, wherein the cancer cell stress is associated with an induction of hGDF-15 expression in the patient. 4. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-3, wherein the cancer antigen-targeted drug conjugate induces cancer cell death. 5. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-4, wherein the cancer cell death is immunogenic cell death (ICD). 6. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-5, wherein the immunogenic cell death (ICD) is associated with an induction of hGDF-15 expression in the patient. 7.     The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-6, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is a neutralizing anti-hGDF-15 antibody or antigen-binding portion thereof. 8. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-7, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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. 9. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-8, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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 shown in SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence represented by SEQ ID NO: 7 or an amino acid sequence having at least 90% identity, preferably at least 95% identity and more preferably at least 98% identity to the amino acid sequence shown in SEQ ID NO: 7. 10. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-9, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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 shown in SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9 or an amino acid sequence having at least 90% identity, preferably at least 95% identity and more preferably at least 98% identity to the amino acid sequence shown in SEQ ID NO: 9. 11. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-10, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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. 12. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-10, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is an anti-hGDF-15 antibody or antigen-binding portion thereof which competes with the antibody defined in item 11 for specific binding to hGDF-15. 13. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-12, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof binds to a conformational or discontinuous epitope on hGDF-15 comprised by the amino acid sequences of SEQ ID No: 12 and SEQ ID No: 13. 14. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-7, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is visugromab, ponsegromab or Rilogrotug. 15. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-14, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is visugromab. 16. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-15, wherein the cancer antigen-targeted drug conjugate comprises a drug that induces cancer cell stress which is linked to a cancer antigen-targeting portion. 17. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 16, wherein the drug is an anticancer drug. 18. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 16 or 17, wherein the drug is a chemotherapeutic drug. 19. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16 -18, wherein the drug is a cytotoxic drug. 20. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 19, wherein the cytotoxic drug is selected from the group consisting of a microtubule inhibitor, a topoisomerase I or II inhibitor, a DNA-damaging agent, an inhibitor of protein synthesis, RNA polymerase III inhibitors, transcription inhibitors, apoptosis inducers, NAMPT inhibitors, proteasome inhibitors, kinase inhibitors, PROTAC, NIR-PIT drug and an immune activating agent. 21. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 19 or 20, wherein the cytotoxic drug is a microtubule inhibitor or a topoisomerase I or II inhibitor. 22. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 19-21, wherein the cytotoxic drug is a microtubule inhibitor. 23. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 20-22, wherein the microtubule inhibitor is selected from the group consisting of monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), mertansine (DM-1), auristatin F-HPA, auristatin-0101, DM21, DM4, maytansinoid, eribulin and SC209. 24. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20 or 21, wherein the topoisomerase I inhibitor is selected from the group consisting of Dxd, SN-38, irinotecan, topotecan, rubitecan, exatecan, belotecan, and MLN576 and camptothecin. 25. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20 or 21, wherein the topoisomerase II inhibitor is selected from the group consisting of etopside, idarubicin, mitoxantrone, PNU-159682, daunorubicine, teniposide, epirubicin and doxorubicin. 26. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the DNA-damaging agent is selected from the group consisting of Calicheamicin, SG3199 / PBD dimer, PBD and Indolinobenzodiazepine (IGN). 27. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the inhibitor of protein synthesis is selected from the group consisting of PE38, geldanamycin, thailanstatin A and a carmaphycin B analogue. 28. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the RNA polymerase III inhibitor is selected from the group consisting of a-amanitin, beta-amanitin, phalloidin, trichothecene T-2, verrucarin A and roridin A. 29. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the transcription inhibitor is selected from the group consisting of triptolide, ST7464AA1, Vorinopstat and dacinostat. 30. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the apoptosis inducer is a BCL-XL inhibitor, such as clezutoclax. 31. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the NAMPT inhibitor is an FK-866 analogue. 32. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the proteasome inhibitor is selected from the group consisting of bortezomib carfilzomib, ixazomib and carmaphycin B analogues. 33. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the kinase inhibitor is selected from the group consisting of genistein, neolymphostin, dasatinib and staurosporine. 34. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the PROTAC is selected from the group consisting of BET / BRD degraders (GNE-987, MZ1 analogues, BRD4 / VHL, BRD4 / CRBN), ERa degraders (ERa / XlAP, ERa / VHL), TGFbR2 degraders (TGFbR2 / VHL), BRM degraders (BRL / VHL), GSTP1 degraders (SMOL006). 35. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the NIR-PIT drug is selected from a water-soluble phthalocyanine derivative, such as the silicon phthalocyanine derivative IR700 (IRDye700DX). 36. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 20, wherein the immune activating agent is selected from the group consisting of a STING agonist, a TLR7 and / or TLR8 agonist and zuvotolimod. 37. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16-19, wherein the drug that induces cancer cell stress is selected from the group consisting of MMAE, MMAF / auristatin-F, Dxd, DM-1, SN-38, camptothecin and DM-4. 38. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 37, wherein the drug that induces cancer cell stress is MMAE. 39. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16-38, wherein the drug is linked to the cancer antigen-targeting portion via a cleavable linker. 40. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16-38, wherein the drug is linked to the cancer antigen-targeting portion via a non-cleavable linker. 41. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16-40, wherein the cancer antigen-targeting portion of the cancer antigen-targeted drug conjugate binds to a cancer cell. 42. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 16-41, wherein the cancer antigen-targeting portion is a ligand, a peptide, or an antibody. 43. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 42, wherein the cancer antigen-targeting portion is an antibody. 44. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 41-43, wherein the cancer antigen-targeting portion binds to a target antigen on a cancer cell. 45. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 44, wherein the target antigen is not hGDF-15. 46. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 44 or 45, wherein the target antigen is selected from a group consisting of Nectin-4, HER2, Trop-2, TF (CD142), CD30, CD22, CD79b, BCMA, CD19, FRa, CD33, LIV-1, HER3, CD25, NaPi2b, B7-H4, c-Met, B7-H3, B7-H4, PTK7, ADAM9, CEACAM5, 5T4, ALK, AXL, GRP20, CDH6, TA-MUC1, KAAG1, DLK1, DLL3, SLAMF7, CA125, C4.4A / LYPD3, CDH3, CDH6, CAIX, CD20, CD26 / DPP4, CD37, CD38, CD138, CD46, ICAM4 / CD54, CD56 / NCAM1, CD70, CD73, CD74, CD205, CD248, C-KIT, CLDN6, CLDN18.2, CLL-1, RET, CRIPTO, DLK-1, DLL3, EGFR, CD105, ENPP3, EPCAM, EPHA2, FAP, FGFR2 / CD332, FLT3, GDNF / GFRA1, GPC2, GPNMB, Guanylyl Cyclase (GCC), IGF-1R, ITGAV, Sialyl-di-Lewis, LGR5, LIV1A, LRRC15, MSLN, STEAP1, PSMA, TMEFF2, NOTCH3, PTK7, SLC44A4, SLC46A3, SLITRK6, TIM-1, LY6E, Cadherin, PD-L1, CD228, FOLRI, CTLA4, GPR20, HGFR, CD123, PSMA, R0R1 and ETBR. 47. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 46, wherein the target antigen is selected from of Nectin-4, HER2, Trop-2, TF (CD142), CD30, CD22, CD79b, BCMA, CD19, FRa and CD33. 48. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-47, wherein the cancer antigen-targeted drug conjugate is an antibodydrug conjugate (ADC). 49. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 48, wherein the ADC is selected from the group consisting of Enfortumab vedotin, Trastuzumab deruxtecan, Trastuzumab emtansine, Sacituzumab govitecan, Tisoumab vedotin, Brentuximab vedotin, Inotuzumab ozogamicin, Moxetumomab pasudotox, Polatuzumab vedotin, Belantamab mafodotin, Loncastuximab tesirine, Mirvetuximab soravtansine-gynx, Gemtuzumab ozagamicin, disitamab vedotin, ladiratuzumab vedotin, datopotamab deruxtecan, patritumab deruxtecan, camidanlumab tesirine, upifitamab rilsodotin, XMT-1592, XMT-1660, XMT-2056, Telisotuzumab vedotin, ABBV-400, mirzotamab clezutoclax, cofetuzumab pelidotin, MORAb-202 (farletuzumab), STR0-OO2, IMGN632, IMGC936, ASP-1929, isacituzumab govitecan, SKB264 and tusamitamab ravtansine. 50. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 49, wherein the ADC is selected from the group consisting of Enfortumab vedotin, Trastuzumab deruxtecan, Trastuzumab emtansine, datopotamab deruxtecan and Sacituzumab govitecan. 51. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-50, wherein the cancer is a solid cancer. 52. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 51, wherein the cancer is selected from the group consisting of urothelial cancer (UC), non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, anal cancer, gastric cancer, liver cancer, bile duct cancer, ovarian cancer, prostate cancer, stomach cancer, esophageal cancer, kidney cancer, thyroid cancer, endometrial cancer, cervical cancer, testicular cancer, melanoma and skin cancer. 53. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 51 or 52, wherein the cancer is urothelial cancer and the drug of the cancer antigen-targeted drug conjugate is a microtubule inhibitor. 54. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 53, wherein the microtubule inhibitor is MMAE. 55. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 53 or 54, wherein the cancer antigen-targeted drug conjugate is enfortumab vedotin. 56. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 51 or 52, wherein the cancer is breast cancer and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor. 57. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 56, wherein the topoisomerase I inhibitor is Dxd. 58. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 56 or 57, wherein the cancer antigen-targeted drug conjugate is trastuzumab deruxtecan. 59. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 51 or 52, wherein the cancer is breast cancer and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor. 60. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 59, wherein the topoisomerase I inhibitor is SN-38. 61. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 59 or 60, wherein the cancer antigen-targeted drug conjugate is sacituzumab govitecan. 62. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 51 or 52, wherein the cancer is NSCLC and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor. 63. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 62, wherein the topoisomerase I inhibitor is Dxd. 64. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 62 or 63, wherein the cancer antigen-targeted drug conjugate is trastuzumab deruxtecan. 65. An anti-hGDF-15 antibody or antigen-binding portion thereof for use in a method of treating cancer in a human patient, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is to be administered in combination with at least one antibody-drug conjugate. 66. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 65, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 67. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 65 or 66, wherein the antibody-drug conjugate is as defined in any one of items 48-50. 68. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 65-67, wherein the antibody-drug conjugate induces cancer cell stress. 69. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 65-68, wherein the cancer is as defined in item 51 or 52. 70. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 65-69, wherein the cancer and the drug are as defined in any one of items 53-64. 71. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 65-70, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof and said antibody-drug conjugate (ADC) are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor. 72. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to item 71, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 73. An antibody-drug conjugate (ADC) for use in a method of treating cancer in a human patient, wherein said antibody-drug conjugate is to be administered in combination with an anti-hGDF-15 antibody or an antigen-binding portion thereof. 74. The antibody-drug conjugate (ADC) for use according to item 73, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 75. The antibody-drug conjugate (ADC) for use according to item 73 or 74, wherein the antibody-drug conjugate is as defined in any one of items 48-50. 76. The antibody-drug conjugate (ADC) for use according to any one of items 73-75, wherein the antibody-drug conjugate induces cancer cell stress. 77. The antibody-drug conjugate (ADC) for use according to any one of items 73-76, wherein the cancer is as defined in item 51 or 52. 78. The antibody-drug conjugate (ADC) for use according to any one of items 73-77, wherein the cancer and the drug are as defined in any one of items 53-64. 79. The antibody-drug conjugate (ADC) for use according to any one of items 73-78, wherein said antibody-drug conjugate (ADC) and said anti-hGDF-15 antibody or antigenbinding portion thereof are to be administered in combination with an immune checkpoint blocker (ICB), wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor. 80. The antibody-drug conjugate (ADC) for use according to item 79, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 81. A combination product of an anti-hGDF-15 antibody or antigen-binding portion thereof and an antibody-drug conjugate for use in a method of treating cancer in a human patient. 82. The combination product for use according to item 81, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 83. The combination product for use according to item 81 or 82, wherein the antibodydrug conjugate is as defined in any one of items 48-50. 84. The combination product for use according to any one of items 81-83, wherein the antibody-drug conjugate induces cancer cell stress. 85. The combination product for use according to any one of items 81-84, wherein the cancer is as defined in item 51 or 52. 86. The combination product for use according to any one of items 81-85, wherein the cancer and the drug are as defined in any one of items 53-64. 87. The combination product for use according to any one of items 81-86, wherein said antibody-drug conjugate (ADC) and said anti-hGDF-15 antibody or antigen-binding portion thereof are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor. 88. The combination product for use according to item 87, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 89. A kit comprising an anti-hGDF-15 antibody or antigen-binding portion thereof and an antibody-drug conjugate. 90. The kit according to item 89, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 91. The kit according to item 89 or 90, wherein the antibody-drug conjugate is as defined in any one of items 48-50. 92. The kit according to any one of items 89-91, wherein the antibody-drug conjugate induces cancer cell stress. 93. The kit according to any one of items 89-92 further comprising an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor. 94. The kit according to item 93, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 95. A pharmaceutical composition comprising a combination of an anti-hGDF-15 antibody and an antibody drug conjugate. 96. The pharmaceutical composition according to item 95, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 97. The pharmaceutical composition according to item 95 or 96, wherein the antibodydrug conjugate is as defined in any one of items 48-50. 98. The pharmaceutical composition according to any one of items 95-97, wherein the antibody-drug conjugate induces cancer cell stress. 99. The pharmaceutical composition according to any one of items 95-98 further comprising an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor. 100. The pharmaceutical composition according to item 99, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 101. Use of an anti-hGDF-15 antibody or antigen-binding portion thereof in combination with a cancer antigen-targeted drug conjugate in the manufacture of a medicament for the treatment of cancer in a human patient, optionally, wherein the cancer antigen-targeted drug conjugate is an antibody-drug conjugate (ADC). 102. Use of an anti-hGDF-15 antibody or antigen-binding portion thereof in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the medicament further comprises a cancer antigen-targeted drug conjugate, optionally, wherein the cancer antigen-targeted drug conjugate is an antibody-drug conjugate (ADC). 103. Use of an antibody-drug conjugate (ADC) in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the medicament further comprises an anti-hGDF-15 antibody or an antigen-binding portion thereof. 104. The use according to any one of items 101-103, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof and said antibody-drug conjugate (ADC) are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor, further optionally, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab. 105. The use according to any one of items 101-104, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of items 7-15. 106. The use according to any one of items 101-105, wherein said antibody-drug conjugate is as defined in any one of items 48-50. 107. The use according to any one of items 101-106, wherein said cancer antigen-targeted drug conjugate or said antibody-drug conjugate induces cancer cell stress. 108. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of items 1-72, the antibody-drug conjugate (ADC) for use according to any one of items 73-80, the combination product for use according to any one of items 81-88, or the use according to any one of items 101-107, wherein the anti-hGDF-15 antibody or antigenbinding portion thereof and the antigen-targeted drug conjugate or the antibody-drug conjugate are administered at the same or at a different time. Brief description of the drawings Figure 1: Induction of cell death by increasing concentrations of Sacituzumab govitecan Quantification of cell viability of MCF-7 or BxPC-3 cancer cell lines was assessed upon treatment with Sacituzumab or Sacituzumab govitecan, as indicated in the Figure. BxPC-3 only and MCF-7 only controls are shown as bars on the left-hand side of the upper part of the Figure. Figure 2: In vitro induction of GDF-15 release by Sacituzumab govitecan Induction of GDF-15 by Sacituzumab or Sacituzumab govitecan was assessed in cancer cell lines (MCF-7 or BxPC-3) using an ELISA assay. An untreated control is shown on the left-hand side of the Figure (concentration="0"). Figure 3: Induction of cell death by increasing concentrations of SN-38 Quantification of cell viability of cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) was assessed upon treatment with SN-38. Figure 4: In vitro induction of GDF-15 release by SN-38 Induction of GDF-15 by SN-38 was assessed in cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) using an ELISA assay. Figure 5: Induction of cell death by increasing concentrations of camptothecin Quantification of cell viability of cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) was assessed upon treatment with camptothecin. MCF-7 only, PC-3 only, BxPC-3 only and SK-MEL-5 only controls are shown as bars on the left-hand side of the upper part of the Figure. Figure 6: In vitro induction of GDF-15 release by camptothecin Induction of GDF-15 by camptothecin was assessed in cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) using an ELISA assay. Figure 7: Induction of cell death by increasing concentrations of Trastuzumab deruxtecan Quantification of cell viability of cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) was assessed upon treatment with Trastuzumab orTrastuzumab deruxtecan. PC-3, BxPC-3, MCF-7 and SK-MEL-5 controls are shown as bars on the left-hand side of the Figure. Figure 8: In vitro induction of GDF-15 release by Trastuzumab deruxtecan Induction of GDF-15 by Trastuzumab or Trastuzumab deruxtecan was assessed in cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) using an ELISA assay. An untreated control is shown on the left-hand side of each panel of the Figure (concentration="0"). Figure 9: Induction of cell death by increasing concentrations of Dxd Quantification of cell viability of cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) was assessed upon treatment with Dxd. MCF-7 only, PC-3 only, BxPC-3 only and SK-MEL-5 only controls are shown as bars on the left-hand side of the upper part of the Figure. Figure 10: In vitro induction of GDF-15 release by Dxd Induction of GDF-15 by Dxd was assessed in cancer cell lines (SK-MEL-5, MCF-7, BxPC-3, PC-3) using an ELISA assay. Figure 11: Induction of cell death by increasing concentrations of MMAE Quantification of cell viability of cancer cell lines (Panc02, MCF-7, BxPC-3, PC-3) was assessed upon treatment with MMAE. Panc02 only, MCF-7 only, PC-3 only and BxPC-3 only controls are shown as bars on the left-hand side of the upper part of the Figure. Figure 12: In vitro induction of GDF-15 release by MMAE Induction of GDF-15 by MMAE was assessed in cancer cell lines (Panc02, MCF-7, BxPC-3, PC-3) using an ELISA assay. Figure 13: Induction of cell death by increasing concentrations of MMAE (Monomethyl auristatin E) & Enfortumab Vedotin Quantification of cell viability of cancer cell lines (RT-4, TUHR4TKB, OS-RC-2, ZR-75-30) was assessed upon treatment with MMAE & Enfortumab Vedotin. The depicted values are calculated as percent (%) cells alive of untreated controls. Calculated IC50 values are indicated in the legends. Figure 14: In vitro induction of GDF-15 release by MMAE (Monomethyl auristatin E) & Enfortumab Vedotin Induction of GDF-15 by MMAE & Enfortumab Vedotin was assessed on cancer cell lines (RT-4, TUHR4TKB, OS-RC-2, ZR-75-30) at the ~IC50 of the respective compounds using an ELISA assay. Figure 15: Induction of cell death by increasing concentrations of DM-1 (Mertansine) & Trastuzumab Emtansine Quantification of cell viability of cancer cell lines (OS-RC-2, ZR-75-30) was assessed upon treatment with DM-1 & Trastuzumab Emtansine. The depicted values are calculated as percent (%) cells alive of Untreated controls. Calculated IC50 values are indicated in the legends. Figure 16: In vitro induction of GDF-15 release by DM-1 (Mertansine) & Trastuzumab Emtansine Induction of GDF-15 by DM-1 & Trastuzumab Emtansine was assessed on cancer cell lines (OS-RC-2, ZR-75-30) at the ~IC50 of the respective compounds using an ELISA assay. Figure 17: Induction of cell death by increasing concentrations of DxD & Trastuzumab Deruxtecan Quantification of cell viability of cancer cell lines (Caov-3, MCF-7, RT-4, SW-780, TUHR4TKB, NCI-N87, SW-837, HepG2, JHH-1, NCI-H2122) was assessed upon treatment with DxD & Trastuzumab Deruxtecan. The depicted values are calculated as percent (%) cells alive of Untreated controls. Calculated IC50 values are indicated in the legends. Figure 18: In vitro induction of GDF-15 release by DxD & Trastuzumab Deruxtecan Induction of GDF-15 by DxD & Trastuzumab Deruxtecan was assessed on cancer cell lines (Caov-3, MCF-7, RT-4, SW-780, TUHR4TKB, NCI-N87, SW-837, HepG2, JHH-1, NCI-H2122) at the ~IC50 of the respective compounds using an ELISA assay. Figure 19: Induction of cell death by increasing concentrations of SN-38 & Sacituzumab Govitecan Quantification of cell viability of cancer cell lines (Caov-3, MCF-7, RT-4, TUHR4TKB, SW-780, OVCAR-3, NCI-N87, SW-837, HT-1376, NCI-H747, NCI-H2122) was assessed upon treatment with SN-38 & Sacituzumab Govitecan. The depicted values are calculated as percent (%) cells alive of Untreated controls. Calculated IC50 values are indicated in the legends. Figure 20: In vitro induction of GDF-15 release by SN-38 & Sacituzumab Govitecan Induction of GDF-15 by SN-38 & Sacituzumab Govitecan was assessed on cancer cell lines (Caov-3, MCF-7, RT-4, TUHR4TKB, SW-780, OVCAR-3, NCI-N87, SW-837, HT-1376, NCI-H747, NCI-H2122) at the ~IC50 of the respective compounds using an ELISA assay. Figure 21: Induction of cell death by increasing concentrations of Calicheamicin & SG3199 Quantification of cell viability of cancer cell lines (AMO-1, JHH-1, OS-RC-2, HT-1376, MCF-7) was assessed upon treatment with Calicheamicin & SG3199. The depicted values are calculated as percent (%) cells alive of Untreated controls. Calculated IC50 values are indicated in the legends. Figure 22: In vitro induction of GDF-15 release by Calicheamicin & SG3199 Induction of GDF-15 by Calicheamicin & SG3199 was assessed on cancer cell lines (AMO-1, JHH-1, OS-RC-2, HT-1376, MCF-7) at the ~IC50 of the respective compounds using an ELISA assay. Figure 23: Induction of cell death on RT-4 cells by increasing concentrations of Sacituzumab, SN-38 & Sacituzumab Govitecan Quantification of cell viability of cancer cell line RT-4 was assessed upon treatment with either Sacituzumab, SN-38 or Sacituzumab Govitecan. The depicted values are calculated as percent (%) cells alive of Untreated controls. Figure 24: Induction of ICD (Immunogenic cell death) on RT-4 cells by Sacituzumab Govitecan Quantification of ICD associated DAMPs (danger associated molecular patterns) represented by eATP as assessed by a bioluminescent assay, HMGB1 as assessed by an ELISA assay and ecto-Calreticulin translocation as assessed by flow cytometry after treatment of cancer cell line RT-4 with Sacituzumab Govitecan. Depicted values are fold changes normalized to the untreated controls for all time-points. Figure 25: Induction of cell death on RT-4 cells by increasing concentrations of Enfortumab, MMAE & Enfortumab Vedotin Quantification of cell viability of cancer cell line RT-4 was assessed upon treatment with either Enfortumab, MMAE or Enfortumab Vedotin. The depicted values are calculated as percent (%) cells alive of Untreated controls. Figure 26: Induction of ICD (Immunogenic cell death) on RT-4 cells by Enfortumab Vedotin Quantification of ICD associated DAMPs represented by eATP as assessed by a bioluminescent assay, HMGB1 as assessed by an ELISA assay and ecto-Calreticulin translocation as assessed by flow cytometry after treatment of cancer cell line RT-4 with Enfortumab Vedotin. Depicted values are fold changes normalized to the untreated controls for all time-points. Figure 27: Induction of cell death on RT-4 cells by increasing concentrations of Trastuzumab, DxD & Trastuzumab Deruxtecan Quantification of cell viability of cancer cell line RT-4 was assessed upon treatment with either Trastuzumab, DxD or Trastuzumab Deruxtecan. The depicted values are calculated as percent (%) cells alive of untreated controls. Figure 28: Induction of ICD (Immunogenic cell death) on RT-4 cells by Trastuzumab Deruxtecan Quantification of ICD associated DAMPs represented by eATP as assessed by a bioluminescent assay, HMGB1 as assessed by an ELISA assay and ecto-Calreticulin translocation as assessed by flow cytometry after treatment of cancer cell line RT-4 with Trastuzumab Deruxtecan. Depicted values are fold changes normalized to the untreated controls for all time-points. Figure 29: Induction of cell death on RT-4 cells by increasing concentrations of Trastuzumab, DM-1 & Trastuzumab Emtansine Quantification of cell viability of cancer cell line RT-4 was assessed upon treatment with either Trastuzumab, DM-1 or Trastuzumab Emtansine. The depicted values are calculated as percent (%) cells alive of untreated controls. Figure 30: Induction of ICD (Immunogenic cell death) on RT-4 cells by Trastuzumab Emtansine Quantification of ICD associated DAMPs represented by eATP as assessed by a bioluminescent assay, HMGB1 as assessed by an ELISA assay and ecto-Calreticulin translocation as assessed by flow cytometry after treatment of cancer cell line RT-4 with Trastuzumab Emtansine. Depicted values are fold changes normalized to the untreated controls for all time-points. Figure 31: Induction of human vs murine GDF-15 protein expression due to Sacituzumab Govitecan in a xenograft tumor model Induction of human vs murine GDF-15 in the serum collected from MCF-7 tumor bearing mice after treatment with Sacituzumab Govitecan as measured by ELISA assay. Tumors from animals treated with vehicle controls are used as controls. Figure 32: Induction of human GDF-15 and IP-10 (ICD marker) gene expression in the tumors due to Enfortumab Vedotin in a xenograft tumor model Induction of human GDF-15 mRNA and IP-10 / CXCL10 (an ICD marker) as assessed by RT-qPCR (calculated with △△ CT method) in tumors collected terminally from HT-1376 tumor bearing mice treated with Enfortumab Vedotin. Tumors from animals treated with vehicle controls are used as controls. Figure 33: Induction of human vs murine GDF-15 protein expression due to Enfortumab Vedotin in a xenograft tumor model Induction of human vs murine GDF-15 in the serum collected from HT-1376 tumor bearing mice after treatment with Enfortumab Vedotin as measured by ELISA assay. Tumors from animals treated with vehicle controls are used as controls. Figure 34: Reduction of tumor volumes due to an anti-GDF-15 antibody (aGDF-15) in combination with Enfortumab Vedotin in a syngeneic tumor model Assessment of tumor volumes of MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin or a combination of aGDF-15 and Enfortumab Vedotin as measured by calliper. Untreated animals are used as controls. Mean tumor volumes are depicted over time. Figure 35: Depiction of tumor volumes of individual animals treated with aGDF-15, Enfortumab Vedotin & aGDF-15 + Enfortumab Vedotin Assessment of tumor volumes of MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin or a combination of aGDF-15 and Enfortumab Vedotin as measured by calliper. Untreated animals are used as controls. Mean tumor volumes are depicted over time of individual animals over time separated by treatment groups. Figure 36: Inhibition of tumor growth due to aGDF-15 in combination with Enfortumab Vedotin in a syngeneic tumor model Assessment of tumor growth inhibition of MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin or a combination of aGDF-15 and Enfortumab Vedotin. Tumor growth inhibition is calculated on day 25 by dividing the tumor volume of an individual mouse with the average control tumor volume on the same day. Figure 37: Induction of immune cell infiltration and activation in the tumors due to aGDF-15 in combination with Enfortumab Vedotin in a syngeneic tumor model Assessment of immune cells from tumors collected terminally from MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin or a combination of aGDF-15 and Enfortumab Vedotin measured by flow cytometry. Changes in immune infiltration and antigen presenting cell (APC) activation due to different treatments is quantified. Figure 38: Induction of CD4 T cell 8i CD8 T activation in the PBMCs due to aGDF-15 in combination with Enfortumab Vedotin in a syngeneic tumor model Assessment of immune cells from PBMCs collected at an interim point (day 8 after treatment start) from MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin or a combination of aGDF-15 and Enfortumab Vedotin measured by flow cytometry. Changes in CD4 T cell & CD8 T cell activation due to different treatments is quantified. Figure 39: Induction of CD4 T cell & CD8 T proliferation in the PBMCs due to aGDF-15 in combination with Enfortumab Vedotin and an anti-PDl antibody (aPDl) in a syngeneic tumor model Assessment of immune cells from PBMCs collected at an interim point (day 8 after treatment start) from MC38 / hNectin4 engrafted animals treated with either aGDF-15, Enfortumab Vedotin, aPDl or a combination of aGDF-15, Enfortumab Vedotin and aPDl measured by flow cytometry. Changes in CD4 T cell & CD8 T cell proliferation due to different treatments are quantified. Statistical significance in the Figures is indicated by asterisks: *P < 0.05, **P < 0.01, ***P < 0.001, and ****p < 0.0001. P-values were calculated using a one-way ANOVA in GraphPad Prism, with significance thresholds determined by the software. Detailed description of invention Definitions and General Techniques Unless specifically defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled artisan in the fields of the invention. All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, with suitable methods and materials being described herein. All literature references referred to herein are incorporated by reference in their entirety for all purposes. Patent applications are referred to herein by using their application and / or publication number. Non-patent literature referred to herein may be cited either as a full reference, or in abbreviated form (e.g., Cao et al., 2017), followed by the full reference in the "References" section and / or after their appearance in the text. The present invention provides an anti-hGDF-15 antibody or antigen-binding portion thereof for use in the treatment of cancer in a patient in combination with a cancer antigen-targeted drug conjugate that induces cancer cell stress. Sequence Alignments of sequences according to the invention are performed by using the BLAST algorithm (see Altschul et al. (1990) "Basic local alignment search tool." Journal of Molecular Biology 215. p. 403-410.; Altschul et al.: (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25:3389-3402.). Preferably, the following parameters are used: Max target sequences 10; Word size 3; BLOSUM 62 matrix; gap costs: existence 11, extension 1; conditional compositional score matrix adjustment. Thus, when used in connection with sequences, terms such as "identity" or "identical" refer to the identity value obtained by using the BLAST algorithm. The term "antibody" as used herein refers to any functional antibody that is capable of specific binding to the antigen of interest, as generally outlined in chapter 7 of Paul, W.E. (Ed.).: Fundamental Immunology 2nd Ed. Raven Press, Ltd., New York 1989, which is incorporated herein by reference. Without particular limitation, the term "antibody" encompasses antibodies from any appropriate source species, including chicken and mammalian such as mouse, goat, non-human primate and human. Preferably, the antibody is a humanized antibody. The antibody is preferably a monoclonal antibody which can be prepared by methods well-known in the art. The term "antibody" encompasses an IgG-l, -2, -3, or -4, IgE, IgA, IgM, or IgD isotype antibody. The term "antibody" encompasses monomeric antibodies (such as IgD, IgE, IgG) or oligomeric antibodies (such as IgA or IgM). The term "antibody" also encompasses - without particular limitations - isolated antibodies and modified antibodies such as genetically engineered antibodies, e.g. chimeric antibodies. The nomenclature of the domains of antibodies follows the terms as known in the art. Each monomer of an antibody comprises two heavy chains and two light chains, as generally known in the art. Of these, each heavy and light chain comprises a variable domain (termed VH for the heavy chain and VL for the light chain) which is important for antigen binding. These heavy and light chain variable domains comprise (in an N-terminal to C-terminal order) the regions FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 (FR, framework region; CDR, complementarity determining region which is also known as hypervariable region). The identification and assignment of the above-mentioned antibody regions within the antibody sequence is generally in accordance with Kabat et al. (Sequences of proteins of immunological interest, U.S. Dept, of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, Md. 1983), or Chothia et al. (Conformations of immunoglobulin hypervariable regions. Nature. 1989 Dec 21-28;342(6252):877-83.), or may be performed by using the IMGT / V-QUEST software described in Giudicelli et al. (IMGT / V-QUEST, an integrated software program for immunoglobulin and T cell receptor V-J and V-D-J rearrangement analysis. Nucleic Acids Res. 2004 Jul l;32(Web Server issue):W435-40.), which is incorporated herein by reference. Preferably, the antibody regions indicated above are identified and assigned by using the IMGT / V-QUEST software. A "monoclonal antibody" is an antibody from an essentially homogenous population of antibodies, wherein the antibodies are substantially identical in sequence (i.e. identical except for minor fraction of antibodies containing naturally occurring sequence modifications such as amino acid modifications at their N- and C-termini). Unlike polyclonal antibodies which contain a mixture of different antibodies directed to numerous epitopes, monoclonal antibodies are directed to the same epitope and are therefore highly specific. The term "monoclonal antibody" includes (but is not limited to) antibodies which are obtained from a monoclonal cell population derived from a single cell clone, as for instance the antibodies generated by the hybridoma method described in Kohler and Milstein (Nature, 1975 Aug 7;256(5517):495-7) or Harlow and Lane ("Antibodies: A Laboratory Manual" Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York 1988), which are incorporated herein by reference. A monoclonal antibody may also be obtained from other suitable methods, including phage display techniques such as those described in Clackson et al. (Nature. 1991 Aug 15;352(6336):624-8) or Marks et al. (J Mol Biol. 1991 Dec 5;222(3):581-97), which are incorporated herein by reference. A monoclonal antibody may be an antibody that has been optimized for antigen-binding properties such as decreased Kd values, optimized association and dissociation kinetics by methods known in the art. For instance, Kd values may be optimized by display methods including phage display, resulting in affinity-matured monoclonal antibodies. The term "monoclonal antibody" is not limited to antibody sequences from particular species of origin or from one single species of origin. Thus, the meaning of the term "monoclonal antibody" encompasses chimeric monoclonal antibodies such as humanized monoclonal antibodies. The anti-hGDF-15 antibody in accordance with the present invention is preferably a monoclonal antibody. "Humanized antibodies" are antibodies which contain human sequences and a minor portion of non-human sequences which confer binding specificity to an antigen of interest (e.g. human GDF-15). Typically, humanized antibodies are generated by replacing hypervariable region sequences from a human acceptor antibody by hypervariable region sequences from a non-human donor antibody (e.g. a mouse, rabbit, rat donor antibody) that binds to an antigen of interest (e.g. human GDF-15, which is also referred to as "hGDF-15"). In some cases, framework region sequences of the acceptor antibody may also be replaced by the corresponding sequences of the donor antibody. In addition to the sequences derived from the donor and acceptor antibodies, a "humanized antibody" may either contain other (additional or substitute) residues or sequences or not. Such other residues or sequences may serve to further improve antibody properties such as binding properties (e.g. to decrease Kd values) and / or immunogenic properties (e.g. to decrease antigenicity in humans). Non-limiting examples for methods to generate humanized antibodies are known in the art, e.g. from Riechmann et al. (Nature. 1988 Mar 24; 332(6162):323-7) or Jones et al. (Nature. 1986 May 29-Jun 4; 321(6069):522-5), which are incorporated herein by reference. The term "human antibody" relates to an antibody containing human variable and constant domain sequences. This definition encompasses antibodies having human sequences bearing single amino acid substitutions or modifications which may serve to further improve antibody properties such as binding properties (e.g. to decrease Kd values) and / or immunogenic properties (e.g. to decrease antigenicity in humans). The term "human antibody" excludes humanized antibodies where a portion of non-human sequences confers binding specificity to an antigen of interest. An "antigen-binding portion" of an antibody as used herein refers to a portion of an antibody that retains the capability of the corresponding antibody to specifically bind to the antigen (e.g. hGDF-15, PD-1 or PD-L1). This capability can, for instance, be determined by determining the capability of the antigen-binding portion to compete with the antibody for specific binding to the antigen by methods known in the art. The antigen-binding portion may contain one or more fragments of the antibody. Without particular limitation, the antigen-binding portion can be produced by any suitable method known in the art, including recombinant DNA methods and preparation by chemical or enzymatic fragmentation of antibodies. Antigen-binding portions may be Fab fragments, F(ab') fragments, F(ab')2 fragments, single chain antibodies (scFv), single-domain antibodies, diabodies or any other portion(s) of the antibody that retain the capability of the antibody to specifically bind to the antigen. As used herein, the terms "binding" or "bind" refer to specific binding to the antigen of interest (e.g. human GDF-15). Preferably, the Kd value is less than 100 nM, more preferably less than 50 nM, still more preferably less than 10 nM, still more preferably less than 5 nM and most preferably less than 2 nM. As used herein, an antibody or antigen-binding portion thereof which "competes" with a second (reference) anti-hGDF-15 antibody (e.g. an anti-hGDF-15 antibody or antigen-binding portion thereof that 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) means that said indicated (first) antibody or antigen-binding portion thereof which "competes" is capable to reduce the binding of a 10 nM reference solution of the second antibody to human or recombinant human GDF-15 by at least 50%. Generally, "competes" means that the concentration of the (first) antibody or antigen-binding portion thereof that is needed in order to reduce the binding of the 10 nM reference solution of the second antibody to human or recombinant human GDF-15 by at least 50% is less than 1000 nM, preferably less than 100 nM and more preferably less than 10 nM. The binding is measured by surface plasmon resonance measurements or by Enzyme-linked Immunosorbent assay (ELISA) measurements. The term "epitope" as used herein refers to a small portion of an antigen that forms the binding site for an antibody. A "single-domain antibody" (which is also referred to as "NanobodyTM") as used herein is an antibody fragment consisting of a single monomeric variable antibody domain. Structures of and methods for producing single-domain antibodies are known from the art, e.g. from Holt U et al. ("Domain antibodies: proteins for therapy." Trends Biotechnol. 2003 Nov;21(ll):484-90.), Saerens D et al. ("Single-domain antibodies as building blocks for novel therapeutics." Curr Opin Pharmacol. 2008 Oct;8(5):600-8. Epub 2008 Aug 22.), and Arbabi Ghahroudi M et al. ("Selection and identification of single domain antibody fragments from camel heavy-chain antibodies." FEBS Lett. 1997 Sep 15;414(3):521-6.), which are incorporated herein by reference. In accordance with the present invention, each occurrence of the terms "comprising", "comprises" and "comprise" may optionally be replaced by the terms "consisting of", "consists of" and "consist of", respectively. Anti-hGDF-15 antibody or antigen-binding portion thereof to be used in accordance with the invention An "anti-hGDF-15 antibody or antigen-binding portion thereof" according to the invention is an antibody or antigen-binding portion thereof which is capable of specifically binding to human GDF-15 (hGDF-15), e.g. recombinant mature hGDF-15. Examples of such antibodies are indicated in the preferred embodiments and in the claims. The anti-hGDF-15 antibody or antigen-binding portion thereof can be a neutralizing antibody or antigen-binding portion thereof. In this regard, it is understood that the term "neutralizing" does not necessarily require complete neutralization but can mean any detectable neutralization, for instance, that at least 50%, at least 80% or at least 90% neutralization is achieved. In order to determine whether an antibody or antigen-binding portion thereof is a neutralizing anti-hGDF-15 antibody or antigen-binding portion thereof, an assay as described e.g. in example 3 of WO2017 / 055613, which is incorporated herein by reference, may be used which is based on a model system for measuring the adhesion of T cells to Human Umbilical Vein Endothelial Cells (HUVEC). In this respect, T-cells are pre-incubated with 100 ng / ml GDF-15 for 1 hour or with 100 ng / ml GDF-15, which was pre-incubated with 10 pg / ml antibody for 1 hour and then tested as briefly described below. T cell flow / adhesion experiment (on HUVEC): Day 1: - p-slides VI 0.4 (ibidi GmbH, Germany) were coated with fibronectin (100 pg / mL): 30pL per loading port. They were incubated for lh at 37°C (or a pre-coated slide was used). - Fibronectin was aspirated, followed by a wash with HUVEC medium. - HUVECs were trypsinized from a 6-well plate (count: 2xl0^ / mL (2mL total)) - They were washed and diluted to 1x10$ cells / mL - 30pL of HUVECs were applied in loading ports of the p-slide VI and checked under a microscope - The p-slide VI was covered with a lid and incubated at 37°C, 5%CO2i Day 2: - HUVECs were activated with TNFa (10 ng / mL) and IFNy (10 ng / mL) in channels 2-5 (see table below): All media were aspirated from the channels and replaced with cytokine-containing pre-warmed media. Day 3: - T cells were isolated (negative isolation of pan T cells). - T cells were pre-incubated in well 1 (1x10$ cells / mL) with or without GDF-15 (100 ng / mL) for lh. - HUVECs were pre-incubated in channels 4 and 5 with GDF-15 (100 ng / mL) for lh: All medium in loading ports was aspirated, and both loading ports were filled with prewarmed medium containing GDF15. - A stage top incubator next to the microscope was pre-warmed, and a gas-mix was connected (5% CO2, 16% O2, 79% N2). - 3x 50mL syringes were prepared: ■ T cells (1x10^ cells / mL): 1mL ■ T cells GDF15 (lxlO6 cells / mL): 1mL ■ Medium - Syringe 1 was connected to channel 1 (see table below) and the flow was started (0.5 dyn / cm2: 0.38 mL / min = 22.8 mL / h). - T cells were flowed for 3 min and in the meantime, 10 fields of view were predefined on the microscope. - Each field of view was video-imaged for 5s. - The remaining channels were assessed in analogy to channel 1 (f-h) with the T cell samples as indicated in the table below. Channel # endothelial cells T cells in flow comments 1 HUVEC unstimulated T cells [negative control] 2 HUVEC stimulated T cells [positive control] 3 HUVEC stimulated T cells GDF-15 4 HUVEC stimulated GDF-15 T cells 5 HUVEC Stimulated GDF-15 T cells GDF-15 Alternative setting (according to Haake et al. 2023, which is incorporated herein by reference): HUVECs (Lonza, Catalog #:CC-2517, used up to a maximum of 5 passages) were cultured in chamber slides over 2-3-days prior to overnight activation with TNF-a (1000 U / ml) and IFN-P (500 U / ml) or IFNg (500 U / ml). Healthy donor PBMCs obtained from buffy coats not older than 24 h on the day of experimentation and MACS® cell separation kits (Miltenyi Biotec) were used to purify panCD8+ T cells (human CD8+TCell Isolation Kit #130-096-495). Purified T-cells were stored at 4 °C in 1% BSA and adapted to 37 °C 1 h prior to experimentation. Alternatively to primary T-cells Jurkat cells are used. Physiological flow (0.5 Dyns / cm2) was generated through mounted HUVEC culture slides on a heated microscope chamber (37 °C) using a calibrated pump. Chemokines (1 pM CXCL12a or 0.5 pM CXCL9 + 0.5 pM CXCL10) and GDF-15 (100 ng / ml) or vehicle control (lOOmM acetic acid) were then perfused over the activated HUVEC monolayer for 5min followed by 15min stasis (step 1). Wash-buffer was then pumped over the HUVECs for lOmin to remove any unbound CXCL chemokines or GDF-15. Leukocyte suspensions were pre-treated for 20min with rhGDF-15 (100 ng / ml), rhGDF-15 (100 ng / ml) + anti-hGDF-15 antibody (20 pg / ml), or blocking anti-LFA-1 antibody TS1 / 18 (20 pg / ml) (# MA1810, ThermoFisher Scientific) (positive control), or vehicle control before centrifugation and resuspension in washing medium. Leukocytes were then perfused over HUVECs for 6min (step 2) before wash-buffer at a pressure of 0.1 Pa was run over the cells for 50min (step-3). Throughout steps 2-3, captured leukocytes were imaged every 30 s by phase-contrast microscopy. The resulting short movie sequences allowed analysis of individual leukocytes over large areas. The total number of adhesion events per unit field (0.19 mm2) was expressed per mm2. T cells adherent to the surface of HUVEC had a phase-white / gray appearance, whereas those that had transmigrated (referred to as recruited) had a phase-black appearance. The number of captured cells at each time point equals the total number of adherent cells on either side of the HUVEC layer. Transmigration events (phase black) were presented as a percentage of total T cells (phase gray + black) captured from flow per unit field. The impact of GDF-15 on T cell adhesion was addressed using either pan T cells or further T cell subsets with the same experimental settings. Depicted time points (30min or 15min) are indicated. Three to four donors were used per condition. Non-limiting examples of anti-hGDF-15 antibodies are described in US 2020 / 0055930 (see e.g. Table 2 and 5), WO2021197171A1, WO2017189724A1, WO2020039321A2, WO2023018803 Al (see e.g. Table 2), WO2022189936A1 and in WO 2014 / 100689 Al, which are incorporated herein by reference. As referred to herein, the terms "CTL-002", "H1L5" 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 is understood that any reference to the amino acid sequences of antibodies of the invention is meant to encompass posttranslational modifications of these sequences occurring in mammalian cells such as CHO cells, including, but not limited to, N-glycosylation, O-glycosylation, deamidation, Asp isomerization / fragmentation, pyro-glutamate formation, removal of C-terminal lysine, and Met / Trp oxidation. Preferred anti-GDF-15 antibodies useful in the present invention may be any one selected form the group consisting of: visugromab, ponsegromab, Rilogrotug (i.e. AV-380) and an antibody having a heavy chain variable region consisting of SEQ ID NO: 19 and a light chain variable region consisting of SEQ ID NO: 20 (e.g., AZD8853), preferably visugromab. The heavy chain of ponsegromab consists of the following amino acids: QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSYNIDWVRQAPGQGLEWMGGINPIFGTAFYNQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCAREAITTVGAMDHWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:15). The light chain of ponsegromab consists of the following amino acids: EIVLTQSPATLSLSPGERATLSCRTSQSVHNYLAWYQQKPGQAPRLLIYDASTRADGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQQFWSWPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C (SEQ ID N0:16). The heavy chain of Rilogrotug consists of the following amino acids: QVQLVQSGAEVKKPGSSVKVSCKASGYTFSDYNMDWVRQAPGQGLEWMGQINPNNGLIFFNQKFKG RVTLTADKSTSTAYMELSSLRSEDTAVYYCAREAITTVGAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID N0:17) The light chain of Rilogrotug consists of the following amino acids: DIQMTQSPSSLSASVGDRVTITCRTSENLHNYLAWYQQKPGKAPKLLIYDAKTLADGVPSRFSGSGSGTD YTLTISSLQPEDFATYYCQHFWSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C (SEQ ID NO: 18) The heavy chain variable region of AZD8853 consists of the following amino acids: QVQLVQSGSELKKPGASVKVSCKASGYTFTDYNMDWIRQSPGKGLEWIGDINPNQGGTFYNQKFKDRA TLTVDKSTSTAYMELRSLRSDDTAVYYCAREEKLYFGLMDYWGQGTTVTVSS (SEQ ID NO: 19) The light chain variable region of AZD8853 consists of the following amino acids: DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLVYNAKTLAEGVPSRFSGSGSGIDF TLTISSLQPEDFATYYCQHQYGSPPTFGQGTKLEIK (SEQ ID NO: 20) Assays to determine whether a first anti-hGDF-15 antibody competes with a second (reference) anti-hGDF-15 antibody for specific binding to hGDF-15 are known in the art. Exemplary assay to determine whether a first anti-hGDF-15 antibody competes with a second anti-hGDF-15 antibody for specific binding to hGDF-15: To determine whether two distinct anti-GDF-15 antibodies are able to bind to one GDF-15 dimer, a Sandwich ELISA is performed. Therefore, an anti-GDF-15 capture antibody (i.e. the second (reference) antibody) is immobilized on the bottom of a 96 well plate (50 pL of 2 pg / mL overnight @ RT). As negative control, isotype control antibody is used for coating. The next day, coating solution is removed and the plate is washed thrice with 150 pL PBS 0.05% Tween. For washing procedure, wells are filled with 150 pL of PBS 0.05% Tween and washes are removed by flicking the plate over a sink and patting the plate on a paper towel. For blocking, the wells are filled with 150 pL PBS 1% BSA and incubated for 1 to 2 hours at room temperature. Then, rhGDF-15 is applied in the indicated concentration (50 pL / well diluted in PBS 1% BSA) for 1.5 to 2 hours @ RT. After removing the GDF-15 solution and washing thrice with 150 pL PBS 0.05% Tween, the indicated detection antibody (i.e. first anti-hGDF-15 antibody or control antibody) is diluted to a final concentration of 1 pg / mL in PBS 1% BSA and 50 pL are applied on each well. After incubation for 1 hour @ RT and washing thrice with PBS 0.05% Tween, a species specific HRP labelled secondary antibody is added for another hour to achieve binding to the Fc part of the detection antibody (here: anti-human HRP / anti-chicken HRP 1:5000 in PBS 1% BSA). Again, plate is washed thrice with PBS 0.05% Tween and then, TMB substrate is prepared (50 pL of TMB 1:100 in Sodium acetate 0.1M pH6, H2O2 1:5000) and 50 pL are pipetted on each well. Following an incubation time of 5 to 15 minutes, when luscious blue color is observed, an equal volume of stopping solution (IM H2SO4) is added and OD 450 nm is determined with Tecan Sunrise. hGDF-15 hGDF-15 can be measured by ELISA which include but are not limited to the R&D systems Quantikine ELISA, an immunoradiometric assay, luminex™ sandwich assay and electrochemiluminescence sandwich assay, as e.g. the ELECSYS® GDF15 assay (Roche Diagnostics), which was summarized by Wollert et al. (Wollert KC, Kempf T, Giannitsis E, et al. An Automated Assay for Growth Differentiation Factor 15. J Appl Lab Med An AACC Publ. 2018;l(5):510-521. doi:10.1373 / jalm. 2016.022376), which is incorporated herein by reference. Alternatively, hGDF-15 serum levels may be determined by known electrochemiluminesence immunoassays using antibodies to GDF-15. For instance, the Roche Elecsys® technology can be used for such electrochemiluminesence immunoassays. All mentioned assays are based on the immunosandwich principle using monoclonal or polyclonal antibodies to capture and to quantify the GDF-15. Dependent on the used reagents and their combination, free GDF-15 or total GDF-15 (free GDF-15 and GDF-15 bound to CTL-002) is measured. hGDF-15 expression in a patient can be, for instance, a serum level of hGDF-15 of the patient. Accordingly, in accordance with the invention, a cancer cell stress or immunogenic cell death (ICD) associated with an induction of hGDF-15 expression in the patient, which is induced by a cancer-antigen-targeted drug conjugate of the invention, is detectable by measuring serum levels of hGDF-15 before and after the start of the treatment with the cancer-antigen-targeted drug conjugate, wherein an increase of the serum levels of hGDF-15 then indicates that there is an induction of hGDF-15 expression in the patient. Cancer antigen-targeted drug conjugate that induces cancer cell stress According to the present invention, the term "cancer antigen-targeted drug conjugate that induces cancer cell stress" is not particularly limited and relates inter alia to a conjugate of a drug and a cancer-antigen targeting portion allowing the specific delivery and internalization of the drug into a cancer cell and the subsequent internal release of the drug which induces cell stress in the cancer cell. The skilled person is aware of methods to assess whether a cancer antigen-targeted drug conjugate induces cancer cell stress (see e.g. Collins, Denis M., et al. 2019, Tiligada, E. 2006, which are incorporated herein by reference). In a non-limiting example, cancer cells stress can be assessed by determining the induction of hGDF-15 as further described herein and as illustrated in the experimental section. Similarly, the skilled person also knows that a cancer antigen-targeted drug conjugate may induce cancer cell death, such as immunogenic cell death (ICD) in cancer cells. In the context of the cancer antigen-targeted drug conjugate used in accordance with the invention, the words "payload", "cargo" and "drug" are used interchangeably and are meant to have the same meaning. Non-limiting examples of drugs used in a cancer antigen-targeted drug conjugate of the invention are selected from the group consisting of microtubule inhibitors, a topoisomerase I or II inhibitors, DNA-damaging agents, inhibitors of protein synthesis and immune activating agents. It is known that targeted cancer therapy using inter alia ADCs induces cancer cells stress or cancer cell death which subsequently stimulates potent anti-cancer immune responses. A well characterized pathway which is induced by ADCs is called immunogenic cell death (ICD) in cancer cells (see e.g. Cao et al., 2017; Rios-Doria et al., 2017; Bauzon et al., 2019; D'Amico et al., 2019; Boshuizen et al., 2021; Devra Olson et al., 2022, which are incorporated herein by reference). ICD is associated with the release of various danger signals and cancer antigens, which can enhance the recruitment and activation of immune cells. Immunogenic cell death (ICD) is a generally known process in the art by which a drug induces apoptosis of cells such as cancer cells in a manner that stimulates the immune system (see e.g. Kroemer et al. 2022, which is incorporated herein by reference). For example, it is known that the exposure of calreticulin on the cell surface and the release of ATP and HMGB1 are linked to ICD. The processed and presented cancer antigens then effectively trigger an immune response against the cancer (Kroemer et al., 2022). It has been surprisingly shown by the present inventors that cancer cell lines produce GDF-15 in response to the exposure with ADCs which contributes to an immunosuppressive environment. Accordingly, the inventors reasoned that a cancer antigen-targeted drug conjugate that induces cancer cell stress will result in suboptimal treatment outcomes due to immune suppression by the cancer cells thereby limiting the immune response against the cancer. According to the present invention, a cancer treatment using the combination of a cancer antigen-targeted drug conjugate and an anti-hGDF-15 antibody or antigen-binding portion thereof allows to reinvirograte, restore, reinforce or strengthen adaptive cancer immune responses. When used for example for medical purposes or for the preparation of a medicament, an antigen-targeted drug conjugate and an anti-hGDF-15 antibody (or antigen-binding portion thereof) may be used at the same time or at different time points. It is clear for a skilled person that two substances such as an anti-hGDF-15 antibody and an antigen-targeted drug conjugate when used "in combination" are not necessarily administered or prepared at the same time but may be administered or prepared at different time points. ADC to be used in accordance with the invention Antibody-drug conjugates (ADCs) are a class of anticancer drugs combining the selectivity of targeted proteins with potent cytotoxic drugs as described herein to allow highly cancer-selective treatments. ADCs are chemoimmunotherapy agents and targeted potent chemotherapy. In the context of the antibody-drug conjugates (ADCs) used in accordance with the invention, the words "payload", "cargo" and "drug" are used interchangeably and are meant to have the same meaning. Cytotoxic drugs used in the context of the present invention are not particularly limited and ideally induce the production of hGDF-15 in cancer cells. Methods for assessing the level of GDF-15 are commonly known in the art and an exemplified ELISA-based method is described above. Moreover, a screening method for assessing whether a given cytotoxic drug induces GDF-15 production in a cancer cell line relates to a routine task in the field. Moreover, the cytotoxic drugs have ideally at least one of the following properties: high potency, high cytotoxic activity (sub nanomolar half maximal inhibitory concentration (IC50) value, in vitro), high stability in the systemic circulation, sufficient solubility in the aqueous environment of antibody and biochemical properties allowing conjugation to an antibody or antigen binding fragment thereof, low immunogenicity, small molecular weight, and a long half-life. When used for example for medical purposes or for the preparation of a medicament, an antibody-drug conjugate and an anti-hGDF-15 antibody (or antigen-binding portion thereof) may be used at the same time or at different time points. It is clear for a skilled person that two substances such as an anti-hGDF-15 antibody and an antibody-drug conjugate when used "in combination" are not necessarily administered or prepared at the same time but may be administered or prepared at different time points. Exemplary classes of cytotoxic drugs used in approved ADCs are microtubule inhibitors or DNA damaging agents as shown below in Table 1. Exemplary ADCs are summarized in Table 1 and 2 below. Table 1: List of approved ADCs: Drug Conjugate name Brand name Payload (Drug) Drug class / Mechanism of Action (MOA) Target antigen Enfortumab vedotin Padcev Monomethyl auristatin E (MMAE) Microtubule inhibitor Nectin-4 Trastuzumab deruxtecan Enhertu Deruxtecan (Dxd) Topoisomerase 1 inhibitor HER2 Trastuzumab emtansine Kadcyla Mertansine (DM-1) Microtubule inhibitor HER2 Sactizumab govitecan Trodelvy SN-38 Topoisomerase 1 inhibitor Trop-2 Tisoumab vedotin Tivdak Monomethyl auristatin E (MMAE) Microtubule inhibitor TF (CD142) Brentuximab vedotin Adcetris Monomethyl auristatin E (MMAE) Microtubule inhibitor CD30 Inotuzumab ozogamicin Besponsa Calicheamicin DNA cleavage CD22 Moxetumomab Lumoxiti PE38 Inhibition        of CD22 pasudotox protein synthesis Polatuzumab vedotin Polivy Monomethyl auristatin E (MMAE) Microtubule inhibitor CD79b Belantamab mafodotin Blenrep Monomethyl auristatin F (MMAF) Microtubule inhibitor BCMA Loncastuximab tesirine Zynlonta SG3199 / PBD dimer DNA cleavage CD19 Mirvetuximab soravtansine-gynx Elahere DM4 Microtubule inhibitor FRa Gemtuzumab ozagamicin Mylotarg Calicheamicin DNA cleavage CD33 Table 2: List of relevant ADCs: Drug Conjugate name Payload (Drug) Drug class / MOA Target antigen disitamab vedotin Monomethyl auristatin E (MMAE) Microtubule inhibitor HER2 ladiratuzumab vedotin Monomethyl auristatin E (MMAE) Microtubule inhibitor LIV-1 datopotamab deruxtecan Dxd Topoisomerase     1 inhibitor Trop-2 patritumab deruxtecan Dxd Topoisomerase     1 inhibitor HER3 camidanlumab tesirine PBD DNA cross-linking CD25 upifitamab rilsodotin Auristatin F-HPA Microtubule inhibitor NaPi2b XMT-1592 Auristatin F-HPA Microtubule inhibitor NaPi2b XMT-1660 Auristatin F-HPA Microtubule inhibitor B7-H4 XMT-2056 Proprietary STING agonist Immune activation HER2 Telisotuzumab vedotin Monomethyl auristatin E (MMAE) Microtubule inhibitor c-Met ABBV-400 Topoisomerase     1 inhibitor c-Met mirzotamab clezutoclax BCL-XL inhibitor B7-H3 cofetuzumab pelidotin Auristatin-0101 Microtubule inhibitor PTK7 MORAb-202 (farletuzumab) Eribulin Microtubule inhibitor FRa STR0-OO2 SC209 Microtubule inhibitor FRa IMGN632 Indolinobenzodiazepine (IGN) DNA alkylation CD123 IMGC936 DM21 Microtubule inhibitor ADAM9 tusamitamab ravtansine Maytansinoid Microtubule inhibitor CEACAM5 Target antigen to be used in accordance with the invention Suitable target antigens (cancer antigens) allowing the selective targeting of a cancer antigen-targeted drug conjugate to cancer cells are known in the art and the skilled person is aware of screening methods for selecting further cancer antigens which are suitable targets for a cancer antigen-targeted drug conjugate, such as an ADC. In accordance with the present invention, the cancer antigen-targeting portion of the conjugate is not limited to an antibody binding a target antigen on a cancer cell but also includes targeting portions which are based on a ligand or a peptide. Irrespective of the exact nature of the cancer antigen-targeting portion, the conjugate of the invention is delivered to a cancer cell via specific interactions between the conjugate and the cancer cell. Exemplary target antigens which are recognized by the cancer antigen-targeted drug conjugate of the invention should be expressed, either exclusively or predominantly, in the cancer cells to reduce or avoid the off-target toxicity. Moreover, the binding to the target antigen should ideally lead to the internalization of the conjugate into the cancer cell. Additionally, the antigen should ideally be located on the surface of the cell rather than intracellular in order to be recognized by the conjugate. Finally, the antigen should also not be secreted or shedded outside the cancer cell, since a soluble antigen in circulation may cause undesirable binding of conjugate outside of the cancer site. Non-limiting examples of target antigens may be selected from any one of the following: Nectin-4, HER2, Trop-2, TF (CD142), CD30, CD22, CD22, CD79b, BCMA, CD19, FRa, CD33, LIV-1, HER3, CD25, NaPi2b, B7-H4, c-Met, B7-H3, PTK7, ADAM9, CEACAM5 , 5T4, ALK, AXL, GRP20, CDH6, TA-MUC1, KAAG1, DLK1, DLL3, SLAMF7, CA125, C4.4A / LYPD3, CDH3, CDH6, CAIX, CD20, CD26 / DPP4, CD37, CD38, CD138, CD46, ICAM4 / CD54, CD56 / NCAM1, CD70, CD73, CD74, CD205, CD248, C-KIT, CLDN6, CLDN18.2, CLL-1, RET, CRIPTO, DLK-1, DLL3, EGFR, CD105, ENPP3, EPCAM, EPHA2, FAP, FGFR2 / CD332, FLT3, GDNF / GFRA1, GPC2, GPNMB, Guanylyl Cyclase (GCC), IGF-1R, ITGAV, Sialyl-di-Lewis, LGR5, LIV1A, LRRC15, MSLN, STEAP1, PSMA, TMEFF2, NOTCH3, PTK7, SLC44A4, SLC46A3, SLITRK6, TIM-1, LY6E, and ETBR. Cancer and cancer antigen-targeted drug conjugate In an embodiment in accordance with all other embodiments of the invention, the cancer is a "solid cancer". A "solid cancer" is a cancer which forms one or more solid tumors. Such solid cancers forming solid tumors are generally known in the art. The term "solid cancer" encompasses both a primary tumor formed by the cancer and possible secondary tumors, which are also known as metastases. "Solid cancers" encompass all non-hematologic cancers and include but are not limited to colorectal cancer, gastric cancer, anal cancer, stomach cancer, esophageal cancer, kidney cancer, thyroid cancer, endometrial cancer, testicular cancer, melanoma, skin cancer, bladder cancer, melanoma, non-small cell lung cancer, head and neck squamous cell cancer, hepatocellular cancer, liver cancer, bile duct cancer, prostate adenocarcinoma, pancreatic cancer, uterine cancer, urothelial cancer, cervical cancer, ovarian cancer, thyroid cancer, cutaneous squamous cell cancer, mesothelioma, cancer of unknown primary (CUP) and breast carcinoma. In an embodiment in accordance with all other embodiments of the invention, the cancer is selected from the group consisting of urothelial cancer (UC), non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, anal cancer, gastric cancer, liver cancer, bile duct cancer, ovarian cancer, prostate cancer, stomach cancer, esophageal cancer, kidney cancer, thyroid cancer, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, cancer of unknown primary, melanoma and skin cancer. Similary, a cancer antigen-targeted drug conjugate in accordance with all other embodiments of the invention is preferably an ADC selected from the group consisting of enfortumab vedotin, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan and sacituzumab govitecan. Immune checkpoint blockers to be used in accordance with the invention Cancer cells harbor genomic mutations which give rise to cancer cell antigens that are specific to the cancer cells and different from the antigens of non-cancerous cells. Therefore, an intact immune system which is not inhibited should recognize these cancer cell antigens, such that an immune response against these antigens is elicited. However, most cancers have developed immune tolerance mechanisms against these antigens. One class of mechanisms by which cancer cells achieve such immune tolerance is the utilization of immune checkpoints. An "immune checkpoint" as used herein generally means an immunological mechanism by which an immune response can be inhibited. More particularly, an immune checkpoint is a mechanism which is characterized in that a molecule of the immune system (or a group of molecules of the immune system) inhibits the immune response by inhibiting the activation of cells of the immune system. Such molecule (or group of molecules) of the immune system which inhibits (inhibit) the immune response by inhibiting the activation of cells of the immune system is (are) also known as checkpoint molecule(s). As used herein, an "immune checkpoint blocker" (ICB) is a molecule which is capable of blocking an immune checkpoint. While it is understood that an hGDF-15 inhibitor as used according to the invention has effects on the immune system including effects on CD8+ T cells, the term "immune checkpoint blocker" as used herein does not refer to an hGDF-15 inhibitor but means a molecule which is different from an hGDF-15 inhibitor. The terms "immune checkpoint blocker" (ICB) and "immune checkpoint inhibitor" (ICI) may be used synonymously. The most common immune checkpoint blockers which are known to date are inhibitors of immune checkpoint molecules such as inhibitors of human PD-1 and inhibitors of human PD-Ll. Further immune checkpoint blockers are anti-LAG-3, anti-B7H3, anti-TIM3, anti-VISTA, anti-TIGIT, anti-KIR, anti-CD27, anti-CD137, anti-CD40, anti-OX40, anti-GITR, anti-ICOS, anti-SIGLEC7, anti-CTLA4, anti-CD276 as well as inhibitors of IDO. Therefore, as used in accordance with the present invention, a preferred form of an immune checkpoint blocker is an inhibitor of an immune checkpoint molecule. Alternatively, an immune checkpoint blocker can be an activator of a co-stimulating signal which overrides the immune checkpoint. Methods to measure the potency of immune checkpoint blockers include in vitro binding assays, primary T cell-based cytokine release assays, and in vivo model systems. Additionally, Promega has now developed a commercially available bioluminescent reporter system for PD-1 / PD-L1, which is, for instance referred to in Mei Cong, Ph.D. et al.: Advertorial: Novel Bioassay to Assess PD-1 / PD-L1 Therapeutic Antibodies in Development for Immunotherapy Bioluminescent Reporter-Based PD-1 / PD-L1 Blockade Bioassay. (http: / / www.genengnews.com / gen-articles / advertorial-novel-bioassay-to-assess-pd-l-pd-ll-therapeutic-antibodies-in-development-for-immun / 5511 / ). Preferred immune checkpoint blockers are inhibitors of human PD-1 and inhibitors of human PD-L1. As used herein, an "inhibitor of human PD-1" can be any molecule which is capable of specifically inhibiting the function of human PD-1. Non-limiting examples of such molecules are antibodies capable of binding to human PD-1 and DARPins (Designed Ankyrin Repeat Proteins) capable of binding to human PD-1. Preferably, the inhibitor of PD-1 to be used in accordance with the invention is an antibody capable of binding to human PD-1, more preferably a monoclonal antibody capable of binding to human PD-1. Most preferably, the monoclonal antibody capable of binding to human PD-1 is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, pidilizumab, AMP-224, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab and spartalizumab, even more preferably nivolumab or pembrolizumab. As used herein, an "inhibitor of human PD-L1" can be any molecule which is capable of specifically inhibiting the function of human PD-L1. Non-limiting examples of such molecules are antibodies capable of binding to human PD-L1 and DARPins (Designed Ankyrin Repeat Proteins) capable of binding to human PD-L1. Preferably, the inhibitor of human PD-L1 to be used in accordance with the invention is an antibody capable of binding to human PD-L1, more preferably a monoclonal antibody capable of binding to human PD-L1. Most preferably, the monoclonal antibody capable of binding to human PD-L1 is selected from the group consisting of atezolizumab, avelumab, durvalumab BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, envafolimab, pacmilimab and cosibelimab. Composition It is understood that the antibodies according to the invention can be administered in the form of pharmaceutical compositions. Such pharmaceutical compositions are prepared in a way that they can be stored and administered appropriately, e.g. by using pharmaceutically acceptable components such as carriers, excipients or stabilizers. Such pharmaceutically acceptable components are not toxic in the amounts used when administering the pharmaceutical composition to a human patient. The pharmaceutical acceptable components added to the pharmaceutical compositions may depend on the route of administration. In general, the pharmaceutically acceptable components used in connection with the present invention are used in accordance with knowledge available in the art, e.g. from Remington's Pharmaceutical Sciences, Ed. AR Gennaro, 20th edition, 2000, Williams & Wilkins, PA, USA. The invention is illustrated by the following non-limiting examples. Examples In vitro cytotoxicity and GDF-15 induction assay: The following exemplary cancer cell lines are tested for hGDF-15 induction: BxPC-3, Panc02 (pancreatic cancer), MCF-7 (breast cancer), PC-3 (prostate cancer) and SK-MEL-5 (skin cancer). Adherent tumor cells were detached from their culture dish with trypsin-EDTA solution, counted and adjusted to a density of 0.3-lxl05 cells / mL in their respective culture medium. 100 pL of this cell suspension was seeded per well in a 96-well flat bottom plate, resulting in 0.3-lxlO4 cells / well. The cells were incubated at 37°C and 5 % CO2 for 24 hours to allow them to attach. The ADCs, unconjugated antibodies or ADC payload drugs were resolved according to the manufacturer's recommendations and a 4-fold concentrated serial dilution series was prepared in the appropriate culture medium of each cancer cell line. 50 pL of the respective drug dilution was added to the seeded tumor cells, and the volume per well was filled to 200 pL with culture medium. The assay plates were then transferred to an incubator and incubated for 3-5 days at 37°C and 5% CO2. At the end of the incubation period, 100 pL of the culture supernatant was harvested and frozen at -80°C in a new 96-well round-bottom plate. The tumor cells remaining in the assay plate were used to perform a CelITiter-Glo viability assay (Promega) according to the manufacturer's instructions. The frozen cell culture supernatants were used to perform a GDF-15 concentration determination using the human (Cat# DY957) or mouse (Cat# DY6385) GDF-15 DuoSet ELISA kit (R&D Systems) according to the manufacturer's protocol. Summary of results The inventors demonstrate that hGDF-15 production was induced by ADCs (see Figure 2 and 8) as well as their unconjugated drugs (payloads) (see Figures 4, 6, 10 and 12) in various cancer cell lines. Specifically, hGDF-15 production was induced by increasing concentrations of the ADCs Trastuzumab deruxtecan (anti-HER2, see Fig. 2) and Sacituzumab govitecan (anti-TROP2, see Fig. 8), as well as their unconjugated toxin drugs (payloads) Dxd (see Fig. 10) and SN-38 (see Fig. 4), respectively, which was concomitant with induction of cell death as evidenced by a decrease in cell viability (see Fig. 1, 3, 7 and 9). Similarly, the inventors also found that hGDF-15 was induced by monomethyl auristatin E (MMAE), a microtubule inhibitor (see Fig. 12) as well as by camptothecin (see Fig. 6) which is an inhibit of topoisomerase I which was also concomitant with induction of cell death as evidenced by a decrease in cell viability (see Fig. 11, 5). Dxd, SN-38 and camptothecin inhibit topoisomerase I which causes DNA damage and subsequent apoptotic cell death whilst MMAE is a microtubule inhibitor which inhibits mitotic cell division and ultimately induces apoptosis. Based on the experimental data, the induction of hGDF-15 production in response to ADC treatment is expected to reduce the therapeutic activity of ADC and their synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting the immune-stimulatory activity of ADC-induced ICD. Accordingly, hGDF-15 is expected to mediate suboptimal anticancer responses and the development of treatment resistance. In summary, an anti-hGDF-15 antibody or antigen-binding portion thereof allowing to neutralize the function of hGDF-15 which is expected to synergize with tumor-targeted treatment regimens and enhance adaptive anticancer immune responses. In vitro cytotoxicity and hGDF-15 induction assay The following exemplary cell lines belonging to different tumor entities are tested for hGDF-15 induction: Lung cancer (NCI-H2122, Bladder cancer (RT-4, HT-1376, SW-780), Breast cancer (MCF-7, ZR-75-30), Ovarian cancer (Caov-3, OVCAR-3), Liver cancer (HepG2, JHH-1), Stomach cancer (NCI-N87), CoIorectum cancer (SW-837, NCI-H747), Kidney cancer (TUHR4TKB, OS-RC-2), Blood cancer (AMO-1). Adherent tumor cells were detached from their culture dish with trypsin-EDTA solution, counted and adjusted to a density of 0.4-lxl05 cells / mL in their respective culture medium. 100 pL of this cell suspension was seeded per well in a 96-well flat bottom plate, resulting in 0.4-lxlO4 cells / well. The cells were incubated at 37°C and 5 % CO2 for 24 hours to allow them to attach. The ADCs, unconjugated antibodies or ADC payloads were dissolved according to the manufacturer's recommendations and a 4-fold concentrated, 9-dose level serial dilution series was prepared in the appropriate culture medium of each cancer cell line. IOuL of the respective drug dilution was added to the seeded tumor cells, and the volume per well was filled to 200pL with culture medium. The assay plates were then transferred to an incubator and incubated for 3-5 days at 37°C and 5% CO2. At the end of the incubation period, lOOpL of the culture supernatant was collected and frozen at -80°C in a new 96-well round-bottom plate. The tumor cells remaining in the assay plate were used to perform a CelITiter-Glo viability assay (Promega #G7572) according to the manufacturer's instructions. The frozen cell culture supernatants were used to perform a hGDF-15 concentration determination at the IC50 of the respective drugs used, using the human (Cat# DY957) DuoSet ELISA kit (R&D Systems) according to the manufacturer's protocol. Summary of results The inventors demonstrate that hGDF-15 production was induced by ADCs as well as their unconjugated drugs (payloads) in cell lines from multiple tumor entities (see Figures 14, 16, 18, 20 and 22). Specifically, hGDF-15 production was induced by Enfortumab Vedotin (see Figure 14), Trastuzumab Emtansine (see Figure 16) and Trastuzumab Deruxtecan (see Figure 18) and Sacituzumab Govitecan (see Figure 20). The induction of cell death as evidenced by a decrease in cell viability was also observed for all tested ADCs (see Figures 13,15,17,19). Similarly, the inventors also found that hGDF-15 was induced by unconjugated payloads of approved ADCs (see e.g. MMAE in Figures 14, DM-1 in Figure 16, DxD in Figures 18 and SN-38 in Figure 20) or of ADCs currently in clinical trials (see e.g. calicheamicin and SG3199 in Figure 22). The induction of cell death as evidenced by a decrease in cell viability was also observed for all tested payloads (see Figure 13,15, 17,19, 21). MMAE and DM-1 are microtubule inhibitors which inhibit mitotic cell division and ultimately lead to cell death due to apoptosis. DxD and SN-38 are topoisomerase 1 inhibiting payloads which cause DNA damage and ultimately apoptotic cell death. Calicheamicin and the PBD dimer S3199 are DNA damage inducing payloads which also result in apoptotic cell death. Based on the experimental data, the induction of hGDF-15 production in response to an ADC treatment is expected to reduce the therapeutic activity of an ADC and the synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting the immune-stimulatory activity of ADCs. Accordingly, hGDF-15 is expected to mediate suboptimal anticancer responses and the development of treatment resistance. The experimental data support that an anti-hGDF-15 antibody or an antigen-binding portion thereof allowing to neutralize the function of hGDF-15 is able to synergize with tumor-targeted treatment regimens thereby enhancing the adaptive anticancer immune responses. ADCs of major subclasses induce hallmarks of immunogenic cell death in vitro: Cell line RT-4 (bladder cancer) was used to show ADC / payload induced killing and induction of ICD hallmarks namely extracellular ATP, HMGB1 and ecto-Calreticulin. Adherent RT-4 cells were detached from their culture dish with trypsin-EDTA solution, counted and adjusted to a density of 1.4 xlO5 cells / mL in their respective culture medium. 500 pL of this cell suspension was seeded per well in a 24-well flat bottom plate, resulting in 7xl04 cells / well. The cells were incubated at 37°C and 5 % CO2 for 24 hours to allow them to attach. The ADC, unconjugated antibody or ADC payload was dissolved according to the manufacturer's recommendations and a 3x concentrated concentration was prepared in the appropriate culture medium and added to the seeded tumor cells. The assay plates were incubated for 24h, 48h or 72hr at 37°C and 5% CO2. After 72h, the tumor cells from one assay plate were used to perform a CellTiter-Glo viability assay (Promega #G7572) according to the manufacturer's instructions. The other plate was used for ICD assessment and supernatant was harvested at different time points for detection of ICD markers. eATP was analysed using the RealTime Gio™ (Promega, #GA5010) luminescent read-out and HMGB1 was analysed using the HMGB1 Express ELISA (IBL, #30164033) according to manufacturer's guidelines. The cells remaining after the supernatant harvest were detached softly and stained for viability (Zombie Violet™ Fixable Viability Kit, Biolegend, # 423113). The same cells were also stained to detect translocation of Calreticulin to the surface using a flow cytometry staining protocol with anti-calreticulin antibody as per the instructions of the manufacturer (aCalr-PE, Abeam, #ab209577). Samples were acquired on the MACSQuantl6 (Miltenyi Biotec) flow cytometry device. Geometric mean of PE of live / dead negative - singlet cells was normalized to untreated control samples. Summary of results Cell line RT-4 (bladder cancer) showed upregulated hGDF-15 following treatment with ADCs having different payloads, i.e. microtubule inhibitors or topoisomerase inhibitors (see Figures 14, 18, 20). The inventors show that concomitant with ADC induced cell death (see Figures 13, 25, T1 & 29), RT-4 cells also upregulated the known ICD hallmarks (see Figures 24, 26, 28 & 30). Specifically, it was shown that a topoisomerase inhibitor as the payload (see Sacituzumab Govitecan in Figure 23 and Trastuzumab Deruxtecan in Figure 27) and a microtubule inhibitor as payload (see Enfortumab Vedotin in Figure 25 and Trastuzumab Emtansine in Figure 29) can induce killing of RT-4 cells and not the backbone antibody. This killing is accompanied by increase in eATP, HMGB1 and ecto-Calreticulin (see Sacituzumab Govitecan in Figure 24, Enfortumab Vedotin in Figure 26, Trastuzumab Deruxtecan in Figure 28, and Trastuzumab Emtansine in Figure 30). eATP, HMGB1 & ecto-Calreticulin are danger associated molecular patterns (DAMPs) that form a signature characteristic of immunogenic cell death. These DAMPs in turn activate the antigen presenting cells to further prime the adaptive immunity against antigens and therefore contributing towards the efficacy of an ADC. Based on the experimental data, the capacity of an ADC to induce ICD hallmarks is expected to contribute to the efficacy and anti tumor activity. However, the simultaneous increase in hGDF-15 might counteract the immune potentiating activity of ADC-induced ICD. ADC-induced GDF-15 release is observed from the tumor and not systemic sources In vivo studies involving tumor xenograft models were used to implant human tumors into immunocompromised mice to detect GDF-15 of human origin as compared to GDF-15 of murine origin. To that end, a total of 45 female 8-week-old NMRI nu / nu mice were inoculated subcutaneously with 1 x 107 MCF-7 human breast cancer cells in matrigel. As soon as tumor volumes reached approximately 200 mm315 days after inoculation, the mice were randomly distributed into study groups with 9 mice each. The day was denoted as day 0 and mice were treated once. Specifically, the mice were either injected intravenously with vehicle control or with 5 mg / kg of the antibody-drug-conjugate, Sacituzumab Govitecan. Blood collection for serum preparation was done 24 hours after treatment and then again after 2 days. To avoid overexertion of the animals, blood was only drawn from three mice per group at each timepoint. Serum GDF-15 levels were then assessed via murine GDF-15 ELISA (R&D systems, Cat# DY6385) and human GDF-15 ELISA (R&D systems, Cat# DY957) to differentiate between hGDF-15 of tumor origin and mGDF-15 of the surrounding tissue. Another xenograft model was used and a total of 54 female 8-9-week-old NOG mice were inoculated subcutaneously with 2 x 106 HT-1376 human bladder cancer cells in matrigel into the right rear flank. As soon as tumor volumes reached approximately 300 mm3 32 days after inoculation, the mice were randomly distributed into study groups with 18 mice each. The day was denoted as day 0 and mice were treated once. They were either injected intravenously with vehicle control or with 5 mg / kg of antibody-drug-conjugate, Enfortumab vedotin. Blood collection for serum preparation was done after 13 days. Serum GDF-15 levels were then assessed via murine GDF-15 ELISA (R&D systems, Cat# DY6385) and human GDF-15 ELISA (R&D systems, Cat# DY957) to differentiate between hGDF-15 of tumor origin and mGDF-15 of the surrounding tissue. In addition to that, tumors were taken of the animals at the end of the study (day 13) for further RNA analysis. RT-PCR assessment of the tumor samples were performed and the snap frozen HT1376 tumors were transferred in RNA-stabilizing solution and dissected. Tissue slices were dissociated using a Rotor-stator device while maintaining a RNAse inhibiting environment. RNA was isolated following the manufacturer's guidelines (RNeasy mini kit, Quiagen, #74104). RNA yield and purities were acquired using a Nanodrop device. RNA concentrations were matched for all samples and genomic DNA digestion and reverse transcription were performed following the manufacturer's guidelines (SS IV VILO Master mix, Thermo Fisher Scientific, #11766050). Using the TaqMan FAST master mix (Thermo Fisher Scientific, #4444557) and the respective probes (Thermo Fisher Scientific; Gapdh: Hs02786624_gl, #4331182; Gdfl5: Hs00171132_ml, # 4331182; CxcIlO: Hs00171042_ml, # 4331182), cycle thresholds were acquired in the Quantstudio 6 flex device. Using the AACT-method, the relative gene expression of Gdfl5 and IP-10 / CXCL10 was compared to that of Gapdh and treated groups were compared to the geometric mean of the vehicle control for the respective gene of interest and reference gene. Summary of results The inventors demonstrate that ADCs are capable of targeted release of hGDF-15 into the serum of mice engrafted with tumors of human origin (see Figures 31-33). Specifically, immunocompromised mice engrafted with human MCF-7 cells and subsequently treated with Sacituzumab Govitecan show significantly elevated levels of human GDF-15 detected in the serum collected from animals 24h and 48h after treatment but no murine GDF-15 is detected (see Figure 31). Similarly, the inventors show that from another xenograft mice model using the HT-1376 human tumors, Enfortumab Vedotin treatment resulted in increased induction of intratumoral GDF-15 as assessed by RT-PCR (see Figure 32). This increase in the gene expression of hGDF-15 could also be translated to detect higher levels of human GDF-15 protein in the serum of these mice at day 13 (see Figure 33). No such increment was seen on murine GDF-15 levels (see Figure 33). The inventors also show that GDF-15 expression is accompanied by increased ICD associated markers. Specifically, following treatment with Enfortumab Vedotin, the increased GDF-15 gene expression is concomitant with increased expression of IP-10 / CXCL10 at the mRNA level (see Figure 32). CXCL10 is a chemokine that is associated with ICD and used as an ICD marker. The experimental data support that an ADC carrying a topoisomerase 1 inhibitor or a microtubule inhibitor as a payload is capable of inducing hGDF-15 release from the targeted tumors in the tested xenograft models. ADCs induced intratumoral GDF-15 and at the same time result in ICD induction. The induction of hGDF-15 production in response to ADC treatment is expected to reduce the therapeutic activity of the ADC treatment and its synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting the immune-stimulatory activity of ADC-induced ICD. Accordingly, hGDF-15 is expected to mediate suboptimal anticancer responses and the development of treatment resistance. Therefore, the experimental evidence supports that an anti-hGDF-15 antibody is expected to synergize with tumor-targeted treatment regimens and enhance adaptive anticancer immune responses. Combination of ADC and GDF-15 blockade enhances antitumor immune responses in vivo In vivo studies involving syngeneic murine models were used to assess the benefit of neutralizing GDF-15 in combination with ADC treatment. To that end, a MC38 a colorectal cancer cell line overexpressing human Nectin-4 was used for engraftment. A total of 32 female 6-8 week old C57BL / 6 mice were inoculated subcutaneously with 1 x 106 MC38 / hNectin4 tumor cells in 0.1 ml PBS into the right rear flank. At day 13 after inoculation, the tumors reached a mean size of approximately 100 mm3. Then, the mice were randomly distributed into four study groups with 8 mice each and the treatment started. The day of treatment start was denoted as day 0. Mice were either left untreated as a control, injected intravenously with 3 mg / kg Enfortumab vedotin once a week or intraperitoneally with 10 mg / kg of an anti-hGDF-15 antibody biweekly. The fourth group received a combination of 3 mg / kg Enfortumab vedotin intravenously once a week and 10 mg / kg of an anti-hGDF-15 antibody intraperitoneally biweekly. After tumor inoculations, mice were monitored regularly and weighed twice per week. The tumor size was assessed twice per week using a calliper and tumor volume in mm3 was calculated. On day 8 after the treatment was started, blood was drawn from the animals to perform flow cytometric analysis of PBMCs. On day 26 after treatment start, the animals were sacrificed, and tumors were analyzed by flow cytometry. For flow cytometric assessment following excision, tumors were cleaned in RPMI1640, and any excess tissue was removed. Then the tumor was weighed to enable absolute cell counting and cut into small pieces. Cells were dissociated from the tumor using a murine tumor dissociation kit (Miltenyi Biotec, Cat#130-096-730) and a gentleMACS tissue dissociator (Miltenyi) according to manufacturers instructions. After achieving single cell suspension, Fc receptors were blocked (Fc block, BD Biosciences, #553142) to prevent nonspecific antibody binding and then surface staining was performed using a cocktail of fluorochrome-conjugated antibodies (aCD45, Biolegend # 103149; aCD80, BioLegend #104726, aCD4 BD #612761; aCD8 eBiosciences #61-0081-82 a41BB, BioLegend #106106; aPDl, BD #744546; aCD39, BD #567295). For blood samples, red blood cell lysis was conducted. Subsequently, cells were fixed and permeabilized to enable flow cytometric staining using a commercially available kit (eBioscience, #00-5523-00). For tumor samples absolute cell counts were determined via the addition of counting beads. Data was then acquired via flow cytometry, and analysis was performed using the Kaluza software. Absolute cell numbers were calculated using a standardized equation incorporating cell and bead counts, volumes, and bead concentration. Summary of results The inventors show that a neutralizing anti-GDF-15 antibody improves the anti-tumor efficacy of an ADC treatment. Specifically, the combination of an anti-GDF-15 antibody with an ADC resulted in tumor regression, enhanced immune infiltration and increased activation of T cells and macrophages (see Figures 34-38). Precisely using the MC38 / hNectin-4 murine model, the combination of Enfortumab Vedotin with an anti-GDF-15 antibody resulted in tumor growth inhibition (see Figure 34 & Figure 36). This tumor regression was accompanied by an increase of intratumoral immune infiltration as seen based on an increased levels of %CD45+ cells in the tumor as a result of a combination of Enforutmab Vedotin and GDF-15 neutralization using an anti-GDF-15 antibody (see Figure 37). Additionally, the combination of ADC and an anti-GDF-15 antibody also resulted in activated APCs in the tumor as supported by an increased levels of CD80 expressing macrophages (see Figure 37). Furthermore, the inventors also demonstrate that a combination of GDF-15 neutralization and ADC treatment resulted in more activated CD4 T cells in the PBMCs as supported based on an increase of 41BB+ CD4 T cells (see Figure 38). Similarly, more activated CD8 T cells were detected in the combination group (ADC, anti-GDF-15 antibody) with more CD8 T cells expressing CD39+ and PD1+ (see Figure 38). The experimental data support that GDF-15 reduces the therapeutic activity of an ADC treatment and that GDF-15 neutralization results in an enhanced anti-tumor efficacy of the ADC. GDF-15 neutralization is therefore expected to improve the ADC activity and their synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting GDF-15-mediated treatment resistance and suppression of ADC-induced immune cell activation. In summary, an anti-GDF-15 antibody or antigen-binding portion thereof allowing to neutralize the function of GDF-15 which is expected to synergize with tumor-targeted treatment regimens and enhance adaptive anticancer immune responses. GDF-15 blockade enhances efficacy of combined ADC and immune checkpoint blockade (ICB) / immune checkpoint inhibition (ICI) in vivo In vivo studies involving syngeneic murine models were used to assess the benefit of neutralizing GDF-15 in combination with an ADC and an anti-PDl antibody (aPDl). MC38 a colorectal cancer cell line overexpressing human Nectin-4 was used for engraftment. A total of 64 female 6-8 week old C57BL / 6 mice were inoculated subcutaneously with 1 x 106 MC38 / hNectin4 tumor cells in 0.1 ml PBS into the right rear flank. Thirteen days after inoculation the tumors reached a mean size of approximately 100 mm3. The mice were then randomly distributed into four study groups with 8 mice each and the treatment started. The day of treatment start was denoted as day 0. Mice were either left untreated as a control, injected intraperitoneally with 10 mg / kg of an anti-GDF-15 antibody biweekly, with 10 mg / kg of an anti-PD-1 antibody intraperitoneally biweekly, or intravenously with 3 mg / kg of Enfortumab vedotin once a week. Double combination groups received a combination of 3 mg / kg Enfortumab vedotin intravenously once a week and 10 mg / kg of an anti-GDF-15 antibody or 10 mg / kg of an anti-PD-1 antibody intraperitoneally biweekly, respectively. Another control group included a combination of 10 mg / kg of an anti-GDF-15 antibody and 10 mg / kg of an anti-PD-1 intraperitoneally biweekly. In the triple combination group, all three compounds were combined. After tumor inoculation, mice were monitored regularly and weighed twice per week. On day 8 after the treatment was started, blood was drawn from the animals to perform flow cytometric analysis of PBMCs. For flow cytometric assessment of the blood, red blood cell lysis was conducted. Subsequently, cells were fixed and permeabilized to enable flow cytometric staining using a commercially available kit (eBioscience, #00-5523-00). Intra-nuclear staining was performed using a cocktail of fluorochrome-conjugated antibodies (aCD45, Biolegend # 103149; aCD4 BD #612761; aCD8 eBiosciences #61-0081-82; Ki67 eBioscience, #69-5698-82; CD44 Biolegend #103006; CD62L Biolegend #104440). Data was then acquired via flow cytometry, and analysis was performed using the Kaluza software. In another syngeneic murine model, MC38 cancer cells overexpressing human Trop-2 were used for engraftment. A total of 64 female 6-8 week old C57BL / 6-hTrop2 mice expressing the human Trop2 epitope were inoculated subcutaneously with 1 x 106 MC38 / hTrop2 tumor cells in 0.1 ml PBS into the right rear flank. Seven days after inoculation, the tumor reached a mean size of approximately 100 mm3. The mice were then randomly distributed into four study groups with 8 mice each and the treatment started. The day of treatment start was denoted as day 0. Mice were either left untreated as a control, injected intraperitoneally with 10 mg / kg of an anti-GDF-15 antibody biweekly or with 0.3 mg / kg of an anti-PD-1 antibody intraperitoneally weekly, or intravenously with 10 mg / kg of Sacituzumab govitecan once a week. Double combination groups received a combination of 10 mg / kg of Sacituzumab govitecan intravenously once a week and 10 mg / kg of an anti-GDF-15 antibody or 0.3 mg / kg of an anti-PD-1 antibody intraperitoneally biweekly, respectively. Another control group received a combination of 10 mg / kg of an anti-GDF-15 antibody and 0.3 mg / kg of an anti-PD-1 antibody intraperitoneally biweekly. In the triple combination group, all three compounds were combined. After tumor inoculation, mice were monitored regularly and weighed twice per week. The tumor size was assessed twice per week using a caliper and tumor volume in mm3 was calculated. A Kaplan-Meier analysis was performed to show the survival of the animals due to the different treatments. Summary of results The inventors have shown that neutralizing GDF-15 improves the efficacy of a treatment using ADCs in combination with immune checkpoint blockage (ICB) / inhibition (ICI). The combination of an anti-GDF-15 antibody with ADC and ICI resulted in an enhanced proliferation of T cells in circulation (see Figure 39). Using the MC38 / hNectin-4 murine model, the combination of Enfortumab Vedotin, aPDl and aGDF-15 resulted in an increased cell proliferation of CD4 and CD8 central-memory T cells (see Figure 39). Ki67 is a classic proliferation marker and higher expression of Ki67 on CD4 & CD8 T cells is observed when GDF-15 was neutralized in addition to the combined treatment with Enfortumab Vedotin and aPDl. The inventors have also demonstrated experimentally in the MC38 / hTrop-2 murine model that the triple combination of anti-GDF-15 antibody, ADC, i.e. Sacituzumab govitecan, and anti-PDl antibody improved the efficacy of the treatment as compared to the ADC in combination with either anti-GDF15 antibody or with anti-PDl antibody, as evidenced by an improved survival of animals in the triple combination group. Hence, the experimental data demonstrate that GDF-15 reduces the therapeutic activity of a combination treatment using an ADC and an anti-PDl antibody and that neutralization of GDF-15 results in an enhanced efficacy of the combination treatment using an ADC and immune checkpoint inhibition / blockage. Therefore, neutralization of GDF-15 is also expected to improve the ADC activity and the synergistic activity with immunotherapies, such as immune checkpoint blockade, by counteracting GDF-15 mediated treatment resistance and GDF-15 mediated suppression of immune-stimulatory activity of ADCs. In summary, an anti-GDF-15 antibody or antigen-binding portion thereof allowing to neutralize the function of GDF-15 is expected to synergize with tumor-targeted treatment regimens and enhance adaptive anticancer immune responses. Sequences SEQ ID No: 1 (Heavy Chain CDR1 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody): GFSLSTSGMG SEQ ID No: 2 (Heavy Chain CDR2 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody): IYWDDDK SEQ ID No: 3 (Heavy Chain CDR3 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody): ARSSYGAMDY SEQ ID No: 4 (Light Chain CDR1 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody): QNVGTN Light Chain CDR2 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody: SAS SEQ ID No: 5 (Light Chain CDR3 Region Peptide Sequence of monoclonal anti-human GDF-15 antibody): QQYNNFPYT SEQ ID No: 6 (heavy chain variable domain of monoclonal anti-human GDF-15 antibody): QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKGLEWLAHIYWDDDKRYNPTLKSRLTIT KDPSKNQVVLTMTNMDPVDTATYYCARSSYGAMDYWGQGTLVTVSSASTKGP SEQ ID No: 7 (light chain variable domain of monoclonal anti-human GDF-15 antibody): DIVLTQSPSFLSASVGDRVTITCKASQNVGTNVAWFQQKPGKSPKALIYSASYRYSGVPDRFTGSGSGTEF TLTISSLQPEDFAAYFCQQYNNFPYTFGGGTKLEIKRT SEQ ID No: 8 (heavy chain of monoclonal anti-human GDF-15 antibody CTL-002 without the leader peptide sequence): QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKGLEWLAHIYWDDDKRYNPTLKSRLTIT KDPSKNQVVLTMTNMDPVDTATYYCARSSYGAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLG SEQ ID No: 9 (light chain of monoclonal anti-human GDF-15 antibody CTL-002 without the leader peptide sequence): DIVLTQSPSFLSASVGDRVTITCKASQNVGTNVAWFQQKPGKSPKALIYSASYRYSGVPDRFTGSGSGTEF TLTISSLQPEDFAAYFCQQYNNFPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 10 (heavy chain variable domain of anti-human GDF-15 antibody H1L5): QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKGLEWLAHIYWDDDKRYNPTLKSRLTIT KDPSKNQVVLTMTNMDPVDTATYYCARSSYGAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 11 (light chain variable domain of anti-human GDF-15 antibody H1L5): DIVLTQSPSFLSASVGDRVTITCKASQNVGTNVAWFQQKPGKSPKALIYSASYRYSGVPDRFTGSGSGTEF TLTISSLQPEDFAAYFCQQYNNFPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID No: 12 (GDF-15 peptide comprising part of the GDF-15 Epitope that binds to Bl-23): EVQVTMCIGACPSQFR SEQ ID No: 13 (GDF-15 peptide comprising part of the GDF-15 Epitope that binds to Bl-23): TDTGVSLQTYDDLLAKDCHCI SEQ ID No: 14 (recombinant mature hGDF-15 protein): GSARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSL HRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI SEQ ID NO: 15 (heavy chain of ponsegromab): QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSYNIDWVRQAPGQGLEWMGGINPIFGTAFYNQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCAREAITTVGAMDHWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQG NV FSCS V M H EALH N H YTQKS LS LS PG SEQ ID NO: 16 (light chain of ponsegromab): EIVLTQSPATLSLSPGERATLSCRTSQSVHNYLAWYQQKPGQAPRLLIYDASTRADGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQQFWSWPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C SEQ ID NO: 17 (heavy chain of Rilogrotug): QVQLVQSGAEVKKPGSSVKVSCKASGYTFSDYNMDWVRQAPGQGLEWMGQINPNNGLIFFNQKFKG RVTLTADKSTSTAYMELSSLRSEDTAVYYCAREAITTVGAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQG N VFSCS V M H E ALH N H YTQKS LS LS PG K SEQ ID NO: 18 (light chain of Rilogrotug): DIQMTQSPSSLSASVGDRVTITCRTSENLHNYLAWYQQKPGKAPKLUYDAKTLADGVPSRFSGSGSGTD YTLTISSLQPEDFATYYCQHFWSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C SEQ ID NO: 19 (heavy chain variable region of AZD8853): QVQLVQSGSELKKPGASVKVSCKASGYTFTDYNMDWIRQSPGKGLEWIGDINPNQGGTFYNQKFKDRA TLTVDKSTSTAYMELRSLRSDDTAVYYCAREEKLYFGLMDYWGQGTTVTVSS SEQ ID NO: 20 (light chain variable region of AZD8853): DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLVYNAKTLAEGVPSRFSGSGSGIDF TLTISSLQPEDFATYYCQHQYGSPPTFGQGTKLEIK References Bauzon, M. et al. (2019) 'Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells', Oncolmmunology, 8(4), p. el565859. Boshuizen, J. et al. (2021) 'Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody-Drug Conjugate and Immune Checkpoint Blockade', Cancer Research, 81(7), pp. 1775-1787. D'Amico, L. et al. (2019) 'A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer', Journal for ImmunoTherapy of Cancer, 7(1), p. 16. Devra Olson et al. (2022) '1187 Enfortumab vedotin induces immunogenic cell death, elicits antitumor immune memory, and shows enhanced preclinical activity in combination with immune checkpoint inhibitors', Journal for ImmunoTherapy of Cancer, 10(Suppl 2), p. A1231. Olson, D. et al. (2022) '1187 Enfortumab vedotin induces immunogenic cell death, elicits antitumor immune memory, and shows enhanced preclinical activity in combination with immune checkpoint inhibitors', in Regular and Young Investigator Award Abstracts. SITC 37th Annual Meeting (SITC 2022) Abstracts, BMJ Publishing Group Ltd, pp. A1229-A1229. Rios-Doria, J. et al. (2017) 'Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies', Cancer Research, 77(10), pp. 2686-2698. Cao, A.T. et al. (2017) 'Abstract 5588: Brentuximab vedotin-driven immunogenic cell death enhances antitumor immune responses, and is potentiated by PD1 inhibition in vivo', Cancer Research, 77(13_Supplement), p. 5588. Kroemer, G. et al. (2022) 'Immunogenic cell stress and death', Nature Immunology, 23(4), pp. 487-500. Schuberth-Wagner, C. et al. (2023) Immuno-suppressive role of tumour-derived GDF-15 on myeloid cells;; Annals of Oncology, Volume 34, S190 Zhou Z, Li W, Song Y, Wang L, Zhang K, Yang J, Zhang W, Su H, Zhang Y. Growth differentiation factor-15 suppresses maturation and function of dendritic cells and inhibits tumor-specific immune response. PLoS One. 2013 Nov 13;8(ll):e78618. Haake M, Haack B, Schafer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokhtari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Almanzar G, Selle M, Thein K, Spath J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rooswinkel RW, Thiem A, Roche PR, Joshi H, Puhringer D, Wockel A, Diessner JE, Rudiger M, Leo E, Cheng PF, Levesque MP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023 Jul 20;14(l):4253. Collins, Denis M., et al. "Acquired resistance to antibody-drug conjugates." Cancers 11.3 (2019): 394. Tiligada, E. "Chemotherapy: induction of stress responses." Endocrine-related cancer 13.Supplement_l (2006): S115-S124. Industrial Applicability An anti-hGDF-15 antibody or antigen-binding portion thereof used in the treatment of cancer in human patients can be industrially manufactured and sold as products for the itemed methods and uses, in accordance with known standards for the manufacture of pharmaceutical products. Accordingly, the present invention is industrially applicable.

Claims

1. An anti-hGDF-15 antibody or antigen-binding portion thereof for use in a method for the treatment of cancer in a human patient in combination with a cancer antigen-targeted drug conjugate that induces cancer cell stress.

2. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 1, wherein the cancer cell stress is immunogenic.

3. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 1 or 2, wherein the cancer cell stress is associated with an induction of hGDF-15 expression in the patient.

4. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-3, wherein the cancer antigen-targeted drug conjugate induces cancer cell death.

5. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-4, wherein the cancer cell death is immunogenic cell death (ICD).

6. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-5, wherein the immunogenic cell death (ICD) is associated with an induction of hGDF-15 expression in the patient.

7. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according toany one of claims 1-6, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is a neutralizing anti-hGDF-15 antibody or antigen-binding portion thereof.

8. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-7, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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.

9. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-8, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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 shown in SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence representedby 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 shown in SEQ ID NO: 7.

10. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-9, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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 shown in SEQ ID NO: 8 and a light chain comprising the amino acid sequence represented by SEQ ID NO: 9 or an amino acid sequence having at least 90% identity, preferably at least 95% identity and more preferably at least 98% identity to the amino acid sequence shown in SEQ ID NO: 9.

11. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-10, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof 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.

12. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-10, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is an anti-hGDF-15 antibody or antigen-binding portion thereof which competes with the antibody defined in claim 11 for specific binding to hGDF-15.

13. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-12, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof binds to a conformational or discontinuous epitope on hGDF-15 comprised by the amino acid sequences of SEQ ID No: 12 and SEQ ID No: 13.

14. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-7, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is visugromab, ponsegromab, Rilogrotug or an antibody having a heavy chain variable region consisting of SEQ ID NO: 19 and a light chain variable region consisting of SEQ ID NO: 20.

15. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-14, wherein the anti-hGDF-15 antibody or antigen-binding portion thereof is visugromab.

16. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-15, wherein the cancer antigen-targeted drug conjugate comprises a drug that induces cancer cell stress which is linked to a cancer antigen-targeting portion.

17. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 16, wherein the drug is an anticancer drug.

18. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 16 or 17, wherein the drug is a chemotherapeutic drug.

19. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16 -18, wherein the drug is a cytotoxic drug.

20. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 19, wherein the cytotoxic drug is selected from the group consisting of a microtubule inhibitor, a topoisomerase I or II inhibitor, a DNA-damaging agent, an inhibitor of protein synthesis, RNA polymerase III inhibitors, transcription inhibitors, apoptosis inducers, NAMPT inhibitors, proteasome inhibitors, kinase inhibitors, PROTAC, NIR-PIT drug and an immune activating agent.

21. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 19 or 20, wherein the cytotoxic drug is a microtubule inhibitor or a topoisomerase I or II inhibitor.

22. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 19-21, wherein the cytotoxic drug is a microtubule inhibitor.

23. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 20-22, wherein the microtubule inhibitor is selected from the group consisting of monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), mertansine (DM-1), auristatin F-HPA, auristatin-0101, DM21, DM4, maytansinoid, eribulin and SC209.

24. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20 or 21, wherein the topoisomerase I inhibitor is selected from the group consisting of Dxd, SN-38, irinotecan, topotecan, rubitecan, exatecan, belotecan, and MLN576 and camptothecin.

25. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20 or 21, wherein the topoisomerase II inhibitor is selected from the group consisting of etopside, idarubicin, mitoxantrone, PNU-159682, daunorubicine, teniposide, epirubicin and doxorubicin.

26. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the DNA-damaging agent is selected from the group consisting of Calicheamicin, SG3199 / PBD dimer, PBD and Indolinobenzodiazepine (IGN).

27. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the inhibitor of protein synthesis is selected from the group consisting of PE38, geldanamycin, thailanstatin A and a carmaphycin B analogue.

28. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the RNA polymerase III inhibitor is selected from the group consisting of a-amanitin, beta-amanitin, phaIloidin, trichothecene T-2, verrucarin A and roridin A.

29. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the transcription inhibitor is selected from the group consisting of triptolide, ST7464AA1, Vorinopstat and dacinostat.

30. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the apoptosis inducer is a BCL-XL inhibitor, such as clezutoclax.

31. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the NAMPT inhibitor is an FK-866 analogue.

32. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the proteasome inhibitor is selected from the group consisting of bortezomib carfilzomib, ixazomib and carmaphycin B analogues.

33. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the kinase inhibitor is selected from the group consisting of genistein, neolymphostin, dasatinib and staurosporine.

34. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the PROTAC is selected from the group consisting of BET / BRD degraders (GNE-987, MZ1 analogues, BRD4 / VHL, BRD4 / CRBN), ERa degraders (ERa / XlAP, ERa / VHL), TGFbR2 degraders (TGFbR2 / VHL), BRM degraders (BRL / VHL), GSTP1 degraders (SMOL006).

35. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the NIR-PIT drug is selected from a water-soluble phthalocyanine derivative, such as the silicon phthalocyanine derivative IR700 (IRDye700DX).

36. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 20, wherein the immune activating agent is selected from the group consisting of a STING agonist, a TLR7 and / or TLR8 agonist and zuvotolimod.

37. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16-19, wherein the drug that induces cancer cell stress is selected from the group consisting of MMAE, MMAF / auristatin-F, Dxd, DM-1, SN-38, camptothecin and DM-4.

38. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 37, wherein the drug that induces cancer cell stress is MMAE.

39. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16-38, wherein the drug is linked to the cancer antigen-targeting portion via a cleavable linker.

40. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16-38, wherein the drug is linked to the cancer antigen-targeting portion via a non-cleavable linker.

41. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16-40, wherein the cancer antigen-targeting portion of the cancer antigen-targeted drug conjugate binds to a cancer cell.

42. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 16-41, wherein the cancer antigen-targeting portion is a ligand, a peptide, or an antibody.

43. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 42, wherein the cancer antigen-targeting portion is an antibody.

44. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 41-43, wherein the cancer antigen-targeting portion binds to a target antigen on a cancer cell.

45. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 44, wherein the target antigen is not hGDF-15.

46. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 44 or 45, wherein the target antigen is selected from a group consisting of Nectin-4, HER2, Trop-2, TF (CD142), CD30, CD22, CD79b, BCMA, CD19, FRa, CD33, LIV-1, HER3, CD25, NaPi2b, B7-H4, c-Met, B7-H3, B7-H4, PTK7, ADAM9, CEACAM5, 5T4, ALK, AXL, GRP20, CDH6, TA-MUC1, KAAG1, DLK1, DLL3, SLAMF7, CA125, C4.4A / LYPD3, CDH3, CDH6, CAIX, CD20, CD26 / DPP4, CD37, CD38, CD138, CD46, ICAM4 / CD54, CD56 / NCAM1, CD70, CD73, CD74, CD205, CD248, C-KIT, CLDN6, CLDN18.2, CLL-1, RET, CRIPTO, DLK-1, DLL3, EGFR, CD105, ENPP3, EPCAM, EPHA2, FAP, FGFR2 / CD332, FLT3, GDNF / GFRA1, GPC2, GPNMB, Guanylyl Cyclase (GCC), IGF-1R, ITGAV, Sialyl-di-Lewis, LGR5, LIV1A, LRRC15, MSLN, STEAP1, PSMA, TMEFF2, NOTCH3, PTK7, SLC44A4, SLC46A3, SLITRK6, TIM-1, LY6E, Cadherin, PD-L1, CD228, FOLRI, CTLA4, GPR20, HGFR, CD123, PSMA, ROR1 and ETBR.

47. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 46, wherein the target antigen is selected from of Nectin-4, HER2, Trop-2, TF (CD142), CD30, CD22, CD79b, BCMA, CD19, FRa and CD33.

48. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-47, wherein the cancer antigen-targeted drug conjugate is an antibodydrug conjugate (ADC).

49. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 48, wherein the ADC is selected from the group consisting of Enfortumab vedotin,Trastuzumab deruxtecan, Trastuzumab emtansine, Sacituzumab govitecan, Tisoumab vedotin, Brentuximab vedotin, Inotuzumab ozogamicin, Moxetumomab pasudotox, Polatuzumab vedotin, Belantamab mafodotin, Loncastuximab tesirine, Mirvetuximab soravtansine-gynx, Gemtuzumab ozagamicin, disitamab vedotin, ladiratuzumab vedotin, datopotamab deruxtecan, patritumab deruxtecan, camidanlumab tesirine, upifitamab rilsodotin, XMT-1592, XMT-1660, XMT-2056, Telisotuzumab vedotin, ABBV-400, mirzotamab clezutoclax, cofetuzumab pelidotin, MORAb-202 (farletuzumab), STR0-OO2, IMGN632, IMGC936, ASP-1929, isacituzumab govitecan, SKB264 and tusamitamab ravtansine.

50. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 49, wherein the ADC is selected from the group consisting of Enfortumab vedotin, Trastuzumab deruxtecan, Trastuzumab emtansine, datopotamab deruxtecan and Sacituzumab govitecan.

51. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-50, wherein the cancer is a solid cancer.

52. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 51, wherein the cancer is selected from the group consisting of urothelial cancer (UC), non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, anal cancer, gastric cancer, liver cancer, bile duct cancer, ovarian cancer, prostate cancer, stomach cancer, esophageal cancer, kidney cancer, thyroid cancer, endometrial cancer, cervical cancer, testicular cancer, melanoma and skin cancer.

53. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 51 or 52, wherein the cancer is urothelial cancer and the drug of the cancer antigen-targeted drug conjugate is a microtubule inhibitor.

54. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 53, wherein the microtubule inhibitor is MMAE.

55. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 53 or 54, wherein the cancer antigen-targeted drug conjugate is enfortumab vedotin.

56. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 51 or 52, wherein the cancer is breast cancer and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor.

57. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 56, wherein the topoisomerase I inhibitor is Dxd.

58. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 56 or 57, wherein the cancer antigen-targeted drug conjugate is trastuzumab deruxtecan.

59. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 51 or 52, wherein the cancer is breast cancer and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor.

60. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 59, wherein the topoisomerase I inhibitor is SN-38.

61. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 59 or 60, wherein the cancer antigen-targeted drug conjugate is sacituzumab govitecan.

62. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 51 or 52, wherein the cancer is NSCLC and the drug of the cancer antigen-targeted drug conjugate is a topoisomerase I inhibitor.

63. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 62, wherein the topoisomerase I inhibitor is Dxd.

64. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 62 or 63, wherein the cancer antigen-targeted drug conjugate is trastuzumab deruxtecan.

65. An anti-hGDF-15 antibody or antigen-binding portion thereof for use in a method of treating cancer in a human patient, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is to be administered in combination with at least one antibody-drug conjugate.

66. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 65, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

67. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 65 or 66, wherein the antibody-drug conjugate is as defined in any one of claims 48-50.

68. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 65-67, wherein the antibody-drug conjugate induces cancer cell stress.

69. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 65-68, wherein the cancer is as defined in claim 51 or 52.

70. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 65-69, wherein the cancer and the drug are as defined in any one of claims 53-64.

71. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 65-70, wherein said anti-hGDF-15 antibody or antigen-binding portionthereof and said antibody-drug conjugate (ADC) are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor.

72. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to claim 71, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

73. An antibody-drug conjugate (ADC) for use in a method of treating cancer in a human patient, wherein said antibody-drug conjugate is to be administered in combination with an anti-hGDF-15 antibody or an antigen-binding portion thereof.

74. The antibody-drug conjugate (ADC) for use according to claim 73, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

75. The antibody-drug conjugate (ADC) for use according to claim 73 or 74, wherein the antibody-drug conjugate is as defined in any one of claims 48-50.

76. The antibody-drug conjugate (ADC) for use according to any one of claims 73-75, wherein the antibody-drug conjugate induces cancer cell stress.

77. The antibody-drug conjugate (ADC) for use according to any one of claims 73-76, wherein the cancer is as defined in claim 51 or 52.

78. The antibody-drug conjugate (ADC) for use according to any one of claims 73-77, wherein the cancer and the drug are as defined in any one of claims 53-64.

79. The antibody-drug conjugate (ADC) for use according to any one of claims 73-78, wherein said antibody-drug conjugate (ADC) and said anti-hGDF-15 antibody or antigenbinding portion thereof are to be administered in combination with an immune checkpoint blocker (ICB), wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor.

80. The antibody-drug conjugate (ADC) for use according to claim 79, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

81. A combination product of an anti-hGDF-15 antibody or antigen-binding portion thereof and an antibody-drug conjugate for use in a method of treating cancer in a human patient.

82. The combination product for use according to claim 81, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

83. The combination product for use according to claim 81 or 82, wherein the antibodydrug conjugate is as defined in any one of claims 48-50.

84. The combination product for use according to any one of claims 81-83, wherein the antibody-drug conjugate induces cancer cell stress.

85. The combination product for use according to any one of claims 81-84, wherein the cancer is as defined in claim 51 or 52.

86. The combination product for use according to any one of claims 81-85, wherein the cancer and the drug are as defined in any one of claims 53-64.

87. The combination product for use according to any one of claims 81-86, wherein said antibody-drug conjugate (ADC) and said anti-hGDF-15 antibody or antigen-binding portion thereof are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor.

88. The combination product for use according to claim 87, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

89. A kit comprising an anti-hGDF-15 antibody or antigen-binding portion thereof and an antibody-drug conjugate.

90. The kit according to claim 89, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

91. The kit according to claim 89 or 90, wherein the antibody-drug conjugate is as defined in any one of claims 48-50.

92. The kit according to any one of claims 89-91, wherein the antibody-drug conjugate induces cancer cell stress.

93. The kit according to any one of claims 89-92 further comprising an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of aPD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor.

94. The kit according to claim 93, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

95. A pharmaceutical composition comprising a combination of an anti-hGDF-15 antibody and an antibody drug conjugate.

96. The pharmaceutical composition according to claim 95, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

97. The pharmaceutical composition according to claim 95 or 96, wherein the antibodydrug conjugate is as defined in any one of claims 48-50.

98. The pharmaceutical composition according to any one of claims 95-97, wherein the antibody-drug conjugate induces cancer cell stress.

99. The pharmaceutical composition according to any one of claims 95-98 further comprising an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor.

100. The pharmaceutical composition according to claim 99, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

101. Use of an anti-hGDF-15 antibody or antigen-binding portion thereof in combination with a cancer antigen-targeted drug conjugate in the manufacture of a medicament for the treatment of cancer in a human patient, optionally, wherein the cancer antigen-targeted drug conjugate is an antibody-drug conjugate (ADC).

102. Use of an anti-hGDF-15 antibody or antigen-binding portion thereof in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the medicament further comprises a cancer antigen-targeted drug conjugate, optionally, wherein the cancer antigen-targeted drug conjugate is an antibody-drug conjugate (ADC).

103. Use of an antibody-drug conjugate (ADC) in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the medicament further comprises an anti-hGDF-15 antibody or an antigen-binding portion thereof.

104. The use according to any one of claims 101-103, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof and said antibody-drug conjugate (ADC) are to be administered in combination with an immune checkpoint blocker (ICB), optionally, wherein the ICB is selected from the list consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor and a LAG-3 inhibitor, preferably a PD-1 inhibitor or a PD-L1 inhibitor, further optionally, wherein the ICB is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, sintilimab, tislelizumab, camrelizumab, balstilimab, envafolimab, pacmilimab, cosibelimab and spartalizumab, preferably nivolumab or pembrolizumab.

105. The use according to any one of claims 101-104, wherein said anti-hGDF-15 antibody or antigen-binding portion thereof is as defined in any one of claims 7-15.

106. The use according to any one of claims 101-105, wherein said antibody-drug conjugate is as defined in any one of claims 48-50.

107. The use according to any one of claims 101-106, wherein said cancer antigen-targeted drug conjugate or said antibody-drug conjugate induces cancer cell stress.

108. The anti-hGDF-15 antibody or antigen-binding portion thereof for use according to any one of claims 1-72, the antibody-drug conjugate (ADC) for use according to any one of claims 73-80, the combination product for use according to any one of claims 81-88, or the use according to any one of claims 101-107, wherein the anti-hGDF-15 antibody or antigenbinding portion thereof and the antigen-targeted drug conjugate or the antibody-drug conjugate are administered at the same or at a different time.

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