Anti-CCR8 monoclonal antibodies and therapeutic uses thereof

Abstract

The present invention relates to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to human CCR8, and are antagonists of the CCL1-CCR8 signaling pathway, in particular wherein the antibody or antigen-binding fragment specifically binds to human CCR8, irrespective of the presence or absence of a post-translational modification, such as a sulfated tyrosine residue at position 15, 16 and / or 17 of the human CCR8. The invention also relates to antibodies or antigen-binding fragments for use in therapy, in particular in the treatment of cancer.

Description

[0001] The present invention relates to a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway, particularly wherein the antibody or antigen-binding fragment specifically binds to human CCR8 regardless of the presence or absence of post-translational modifications (e.g., sulfated tyrosine residues at positions 15, 16, and / or 17 of human CCR8). The present invention also relates to the antibody or antigen-binding fragment for use in therapy, particularly for the treatment of cancer.

[0002] Chemokine (CC motif) receptor 8 (CCR8) (also known as CKRL1, CMKBR8 or CMKBRL2) belongs to the G protein coupled receptor (GPCR) family. CCR8 is mainly expressed on tumor regulatory T (Treg) cells, which are a type of immunosuppressive cells found in the tumor microenvironment. Regulatory T (Treg) cells are one of the essential components of the adaptive immune system, whereby they help maintain tolerance to self-antigens and prevent autoimmune diseases (Vignali DAA et al., Nature Reviews Immunology, 2008, 8 (7): 523-32, doi: 10.1038 / nri2343).

[0003] However, Treg cells have also been found to be highly enriched in the tumor microenvironment of many different cancers (Colombo MP et al., Nature Reviews Cancer, 2007, 7(11):880-7, doi:10.1038 / nrc2250; Nishikawa H et al., Current Opinion in Immunology, 2014, 27:1-7, doi:10.1016 / j.coi.2013.12.005). Based on the transcriptional landscape of tumor-infiltrating regulatory T cells (TITRs), CCR8-positive TITRs have been found to be highly immunosuppressive and defined as specific signaling molecules (De Simone M et al., Immunity, 2016, 45(5):1135-47, doi:10.1016 / j.immuni.2016.10.021).

[0004] A variety of strategies have been proposed to regulate Treg cells in the tumor microenvironment to enhance therapeutic benefits (Elpek KG et al., The Journal of Immunology, 2007, 178(11):6840-8, doi:10.4049 / jimmunol.178.11.6840). In the tumor microenvironment, Treg cells promote immune escape by reducing tumor-associated antigen (TAA)-specific T cell immunity, thereby preventing effective anti-tumor activity. Therefore, high tumor infiltration of Tregs is often associated with an aggressive phenotype and poor prognosis in cancer patients (Shang B et al., Scientific Reports, 2015, 5:15179, doi:10.1038 / srep15179; Plitas G et al., Immunity, 2016, 45(5):1122-34, doi:10.1016 / j.immuni.2016.10.032).

[0005] Due to the high and relatively specific expression of CCR8 on tumor-infiltrating Tregs, CCR8 represents an attractive immunotherapy target to inhibit the trafficking of Treg cells to tumor sites triggered by CCL1 without interfering with the recruitment of other effector T cells that do not express CCR8. In addition, the use of depleting anti-CCR8 mAbs with enhanced cytotoxic activity (i.e., ADCC, CDC, ADCP) can also reduce the number of CCR8 immunosuppressive cells in tumors. To date, several monoclonal antibodies against CCR8 have been used in cancer therapy to modulate and deplete this Treg population.

[0006] In fact, CCR8 expression in tumor-resident Tregs has been reported in various types of human cancer, including breast cancer, bladder cancer, colorectal cancer, lung cancer, pancreatic cancer, melanoma, and angiosarcoma (Tanaka A et al., Eur J Immunol, 2019, 49(8):1140-6, doi:10.1002 / eji.201847659; De Simone et al., Immunity, 2016, 45(5):1135-47, doi:10.1016 / j.immuni.2016.10.021; Plitas G et al., Immunity, 2016, 45(5):1122-34, doi:10.1016 / j.immuni.2016.10.032; Wang T et al., Cancer ... Immunol Immunother, 2020, 69(9): 1855-67, doi: 10.1007 / s00262-020-02583-y; Campbell JR et al., Cancer Res, 2021, 81(11): 2983-94, doi: 10.1158 / 0008-5472.CAN-20-3585; Magnuson AM et al., Proc Natl Acad Sci USA, 2018, 115(45): E10672-81, doi: 10.1073 / pnas.1810580115; Tirosh I et al., Science, 2016, 352(6282): 189-96, doi: 10.1126 / science.aad0501; Islam SA et al., J Exp Med, 2013, 210(10):1889-98, doi:10.1084 / jem.20130240). Interestingly, in patients with pancreatic cancer, higher numbers of CCR8+ Tregs were associated with more advanced stages of the disease and decreased overall survival (Yi G et al., Science Bulletin, 2018, 63(15):972-81, doi:10.1016 / j.scib.2018.05.028). These findings further highlight the broad clinical applicability of CCR8 blocking and / or depleting antibodies in the treatment of various cancers.

[0007] In addition, it has been reported that CCR8 expression also appears in T tumor cells, such as cutaneous T cell lymphoma (CTCL) (Giustiniani J et al., Blood Adv, 2022, 6 (11): 3507-12, doi: 10.1182 / bloodadvances.2021006512). Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common cutaneous T cell lymphomas. It has been shown that CCR8 is overexpressed on the cell surface of CTCL peripheral blood tumor cells and is involved in Sézary cell activation and proliferation (Giustiniani J et al., supra). Increased CCR8 expression has also been detected in adult T cell leukemia / lymphoma patients (Zheng D et al., Front Immunol, 2022, 13: 808347, doi: 10.3389 / fimmu.2022.808347). Adult T-cell leukemia / lymphoma (ATLL) and peripheral T-cell lymphoma (PTCL) are the main subtypes of T-cell lymphoma (Hotta T, Hematology, 2005, 10 Suppl 1:193-6, doi:10.1080 / 10245330512331390393). ATLL is a malignancy of mature T lymphocytes that is triggered by human T-lymphotropic virus type 1 (HTLV-1) (Uchiyama T et al., Blood, 1977, 50(3):481-92, doi:10.1182 / blood.V50.3.481.481; Ishitsuka K et al., Lancet Oncol, 2014, 15(11):e517-26, doi:10.1016 / S1470-2045(14)70202-5). Therefore, CCR8 is considered a therapeutic target in different aggressive T-cell lymphoma subtypes.

[0008] Recent studies have highlighted the clinical applicability of CCR8 blocking and / or depleting antibodies, either as single agents or in combination with other forms of cancer treatment (e.g., radiotherapy, chemotherapy and / or immunotherapy), as well as corresponding antibody-drug conjugates (ADCs). In particular, different combination approaches based on immunotherapy are under investigation, such as combinations with checkpoint inhibitors, co-stimulatory molecules, kinase inhibitors, chimeric antigen receptor (CAR) cell-based therapies and cancer vaccines. Combining multiple cancer immunotherapies is crucial to improving treatment outcomes in future clinical trials.

[0009] It is noteworthy that it is reported that the combination of anti-CCR8 monoclonal antibodies and anti-PD-1 monoclonal antibodies has a synergistic anti-tumor effect (Van Damme H et al., J Immunother Cancer, 2021, 9 (2): e001749, doi: 10.1136 / jitc-2020-001749). The reduction in tumor growth of the combination therapy can be attributed to a more immunogenic tumor microenvironment (TME) rich in effector CD8+ T cells. It is reported that the balance between this suppressive Treg and effector CD8+ T cells is crucial for effective anti-tumor immune response (Van Damme H et al., loc.cit.; Tanaka A et al., Eur J Immunol, 2019, 49 (8): 1140-6, doi: 10.1002 / eji.201847659).

[0010] Combining the use of anti-CCR8 monoclonal antibodies with cancer vaccines has also proven to be of particular interest. For example, preliminary in vivo evidence suggests that Listeria-based cancer vaccine immunotherapy targeting the classic AH1 tumor-associated antigen can be combined with CCR8 monoclonal antibodies, supporting the use of this combination strategy in future clinical trials (Villarreal DO et al., Cancer Res, 2018, 78(18):5340-8, doi:10.1158 / 0008-5472.CAN-18-1119).

[0011] In addition, chimeric antigen receptor (CAR) T cells have been successfully used to treat B-cell leukemia and lymphoma, but they still face many challenges in their use in the treatment of T-cell malignancies and solid tumors, such as the lack of unique tumor antigens, the limitation of their T cell expansion, and the need for third-party donors or genome editing (Benmebarek MR et al., Int J Mol Sci, 2019, 20(6):1283, doi:10.3390 / ijms20061283). CAR T cell therapy is generally still ineffective in solid tumors, mainly due to poor infiltration of the tumor site and T cell suppression. Treg cells suppress immune responses by suppressing factors such as transforming growth factor-β (TGF-β) (Plitas G et al., Immunity, 2016, 45(5): 1122-34, doi: 10.1016 / j.immuni.2016.10.032; Barsheshet Y et al., Proc Natl Acad Sci USA, 2017, 114(23): 6086-91, doi: 10.1073 / pnas.1621280114). Anti-CCR8 CAR T cells have further been shown to prolong survival in an ATLL tumor-bearing mouse model without impairing T cell expansion (Zheng D et al., Front Immunol, 2022, 13: 808347, doi: 10.3389 / fimmu.2022.808347). Recent studies have shown that CCR8-engineered T cells improve CAR T cell therapy for pancreatic cancer (Cadilha BL et al., SciAdv, 2021, 7(24):eabi5781, doi:10.1126 / sciadv.abi5781). The therapeutic potential of this approach could be extended to other Treg-rich solid tumor entities where limited tumor infiltration and intratumoral T cell proliferation hinder treatment success.

[0012] Further reports indicate that combination therapy using anti-CCR8 monoclonal antibodies and Treg-depleting monoclonal antibodies targeting, for example, CD25 (Onizuka S et al., Cancer Res, 1999, 59(13):3128-33; Rech AJ et al., Sci Transl Med, 2012, 4(134):134ra62, doi:10.1126 / scitranslmed.3003330; Shimizu J et al., J Immunol, 1999, 163(10):5211-8) or CCR4 (Sugiyama D et al., Proc Natl Acad Sci USA, 2013, 110(44):17945-50, doi:10.1073 / pnas.1316796110) may be possible.

[0013] Therefore, anti-CCR8 monoclonal antibodies have been proposed for the treatment of various cancers both as monotherapy and in the context of combination therapy approaches.

[0014] However, antibodies targeting CCR8 may also be used for other therapeutic applications besides cancer treatment. Human CCR8 is expressed only in lymphoid organs and the thymus (Napolitano M et al., J Immunol, 1996, 157(7):2759-63; Samson M et al., Eur J Immunol, 1996, 26(12):3021-8, doi:10.1002 / eji.1830261230; Zaballos A et al., Biochem Biophys Res Commun, 1996, 227(3):846-53, doi:10.1006 / bbrc.1996.1595). CCR8 is expressed not only on T reg cells, but also by a subset of memory CD4+ T cells enriched in Th2 cells (Chensue SW et al., J Exp Med, 2001, 193(5):573-84, doi:10.1084 / jem.193.5.573). NKT cells also express CCR4 and CCR8 (Harner S et al., PLoS One, 2011, 6(1):e15714, doi:10.1371 / journal.pone.0015714). CCR8 is also reported to be present in inflammatory macrophages in human chronic obstructive pulmonary disease (COPD) (Reimer MK et al., Clin Vaccine Immunol, 2011, 18(12):2050-9, doi:10.1128 / CVI.05275-11). In vitro studies have shown that CCR8 expression is regulated by T cell receptor (TCR) engagement and the skin tissue microenvironment (McCully ML et al., J Immunol, 2018, 200(5):1639-50, doi:10.4049 / jimmunol.1701377). CCR8 expression on these different immune cell subsets suggests future therapeutic approaches targeting CCR8 for immuno-oncology, autoimmunity, inflammation, or bacterial load.

[0015] Antibodies recognizing CCR8 and corresponding therapeutic applications have been described in the literature (see, for example, WO 2007 / 044756, WO 2018 / 112032, WO 2018 / 112033, WO 2018 / 181425 or EP 3 431 105, WO 2020 / 138489 or EP 3 903 817, WO 2021 / 142002 or US2021 / 0238292, WO 2021 / 152186, WO 2021 / 194942, WO 2021 / 260210, WO 2022 / 003156, WO 2022 / 042690 or WO 2022 / 078277).

[0016] However, there are still major challenges associated with CCR8 targeting, namely considering post-translational modifications (PTMs). It is known that chemokine receptors undergo a variety of post-translational modifications. For example, phosphorylation of specific intracellular serine residues in the C-terminal region of chemokine receptors is essential for their signal transduction function (Olbrich H et al., J Leukoc Biol, 1999, 65 (3): 281-5, doi: 10.1002 / jlb.65.3.281).

[0017] In some chemokine receptors, the extracellular region is also known to be modified after translation. Post-translational modification of the extracellular portion of the receptor located in the cell membrane may also help to regulate its biological activity. Post-translational CCR8 modification and its effect on receptor activity have been reported (Gutiérrez J et al., J Biol Chem, 2004, 279(15):14726-33, doi:10.1074 / jbc.M309689200; Ludeman JP et al., Br J Pharmacol, 2014, 171(5):1167-79, doi:10.1111 / bph.12455).

[0018] Therefore, current approaches to targeting CCR8 or other chemokine receptors have focused on providing antibodies that bind to a specific form of the receptor, ie, with a particular post-translational modification.

[0019] Although anti-CCR8 antibodies reported in the prior art have shown promising results, there is an ongoing need to provide new and improved antibodies targeting CCR8, in particular anti-CCR8 antibodies with enhanced therapeutic effects in the treatment of various different types of cancer.

[0020] The present invention solves this problem and provides anti-CCR8 monoclonal antibodies (mAbs) that recognize unmodified CCR8 and post-translationally modified CCR8. Therefore, the present invention provides antibodies that specifically bind to and recognize epitopes of human CCR8, regardless of the presence or absence of post-translational modifications (e.g., sulfated tyrosine residues at positions 15, 16, and / or 17 of human CCR8). The antibodies provided herein show excellent specific binding characteristics to sulfated and non-sulfated CCR8, and also bind to CCR8 expressed under physiological conditions, and show a highly favorable therapeutic effect.

[0021] Therefore, the present invention provides a monoclonal antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway; wherein the antibody or antigen-binding fragment specifically binds to:

[0022] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0023] And further, wherein the antibody or antigen-binding fragment specifically binds to one or more of the following:

[0024] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0025] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0026] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0027] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0028] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0029] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7) or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15; and - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0030] In the context of the present invention, antibodies that specifically bind to human CCR8 have been produced that exhibit highly advantageous properties, including the ability to bind to human CCR8 with different post-translational modifications or different conformations. In particular, the antibodies (and antigen-binding fragments) provided herein bind to human CCR8 with non-sulfated tyrosine residues at positions Y15, Y16, and Y17, as well as human CCR8 with sulfated tyrosine residues at one or more of these positions, as also demonstrated in Example 10. This specific binding property that distinguishes the antibodies of the present invention from the aforementioned anti-CCR8 antibodies (also as shown in Example 10) is very advantageous because it allows targeting cells expressing CCR8, such as CCR8-positive immune cells (e.g., CCR8-positive tumor-infiltrating Treg cells, CCR8-positive tumor-associated macrophages, CCR8-positive natural killer T cells (NKT cells)) and / or CCR8-positive cancer cells (e.g., Sézary syndrome cancer cells), regardless of the sulfation state of CCR8 expressed on the surface of the corresponding cells (which may vary depending on the cancer type and patient to be treated). Specifically, since the antibodies of the present invention target CCR8-positive cells, regardless of whether there is a post-translational modification of CCR8, particularly whether there is a sulfated tyrosine residue, more particularly whether there is a sulfated Tyr-15 and / or Tyr-16 and / or Tyr-17, they can be used to deplete cells expressing CCR8, such as CCR8-positive immune cells (e.g., CCR8-positive tumor-infiltrating Treg cells, CCR8-positive tumor-associated macrophages, CCR8-positive natural killer T cells (NKT cells)) and / or CCR8-positive cancer cells (e.g., Sézary syndrome cancer cells), regardless of whether there is a sulfated tyrosine residue, thereby resulting in improved therapeutic efficacy in cancer treatment. Therefore, the antibodies and antigen-binding fragments of the present invention are particularly suitable for the treatment of cancer.

[0031] Furthermore, by generating antibodies targeting human CCR8 with or without sulfated Tyr-15 and / or Tyr-16 and / or Tyr-17, it has been demonstrated that these sulfated residues are not crucial for antigen-antibody binding and that the corresponding antibodies are able to bind to a variety of CCR8 conformations.

[0032] The inventors have also surprisingly found that the antibodies and antigen-binding fragments provided herein are antagonists of the CCL1-CCR8 signaling pathway, which allow, for example, blocking CCL1-CCR8 molecular interactions and / or CCL1-induced CCR8-Gi2 signaling. This suggests that targeting sulfated tyrosine residues of human CCR8 is not critical for regulating CCR8-triggered signaling pathways.

[0033] The antibodies (and antigen-binding antibody fragments) of the present invention are also advantageous in that they can exert potent antagonist activity, preferably insurmountable antagonist activity, on the CCL1-CCR8 signaling pathway not only at a neutral physiological pH of 7.4, but also at the acidic pH typically found in the tumor microenvironment (TME). Thus, as reported in the literature, the extracellular pH (pHHe) of tumor stroma is more acidic (pH 6.2–6.9) compared to normal tissue (pH 7.3–7.4) (Griffiths JR, Br J Cancer, 1991, 64(3):425-27, doi:10.1038 / bjc.1991.326; Wike-Hooley JL et al., Radiother Oncol, 1984, 2(4):343-66, doi:10.1016 / s0167-8140(84)80077-8), which is partly caused by the overstimulation of several ion transporters, such as Na + / H + exchange protein (NHE; Griffiths JR, loc.cit.), Na + -dependent and non-dependent HCO3 - / Cl - exchange proteins and monocarboxylate transporters, which increase H +ions and acidifies the pHe in tumors (Madshus IH, Biochem J, 1988, 250(1):1-8, doi:10.1042 / bj2500001). In addition, most cancer cells rely on aerobic glycolysis to generate the energy needed for cellular processes, a phenomenon known as the Warburg effect, which is one of the main factors inducing the acidic TME in the extracellular area of ​​tumor cells (Warburg O, Science, 1956, 123(3191):309-14, doi:10.1126 / science.123.3191.309). It has also been reported that acidic TME is associated with tumor progression and metastasis (Cardone RA et al., Nat Rev Cancer, 2005, 5(10):786-95, doi:10.1038 / nrc1713; Xie R et al., Oncol Rep, 2017, 37(3):1451-60, doi:10.3892 / or.2017.5386). In addition, acidic TME can weaken the tumor's response to some anticancer chemotherapies (Mahoney BP et al., Biochem Pharmacol, 2003, 66(7):1207-18, doi:10.1016 / s0006-2952(03)00467-2). Therefore, it is very advantageous for therapeutic antibodies to maintain or even preferentially exert their activity under the acidic pH conditions of TME. Notably, the antibodies (and antigen-binding fragments) provided herein have been found to exert highly potent antagonist activity even at the acidic pH present in the TME, making these antibodies particularly suitable for therapeutic treatment of cancer. Specifically, the antibodies (and antigen-binding fragments) of the present invention have been found to exhibit potent activity as antagonists of the CCL1-CCR8 signaling pathway, even under experimental conditions that mimic the acidic tumor microenvironment, as demonstrated in Example 14. Thus, the monoclonal antibodies (or antigen-binding fragments thereof) of the present invention specifically bind to human CCR8 and are antagonists of the CCL1-CCR8 signaling pathway, preferably in the range of pH 6.2 to 6.9, more preferably at pH 6.5, with antagonistic activity (particularly preferably insurmountable antagonistic activity) against the CCL1-CCR8 signaling pathway. Furthermore, the antibodies or antigen-binding fragments of the present invention preferably have antagonistic activity (particularly preferably insurmountable antagonistic activity) against CCL1-induced CCR8–Gi2 signaling in the range of pH 6.2 to 6.9, more preferably at pH 6.5.

[0034] Many corresponding exemplary antibodies are provided herein, which have been characterized based on their amino acid sequences. Consistent with this, the present invention specifically relates to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to human CCR8 and have CDRs and / or have the heavy chain variable domains (VH) and light chain variable domains (VL) described in any of the embodiments listed in this specification. The present invention also provides monoclonal antibodies or antigen-binding fragments thereof that specifically bind to human CCR8 and have the heavy chain and light chain sequences listed in any of the embodiments described herein.

[0035] The present invention also relates to nucleic acids encoding the heavy and / or light chains of the antibodies or antigen-binding fragments provided herein. The nucleic acid can be, for example, mRNA.

[0036] The present invention also relates to a vector (which is preferably an expression vector) comprising the nucleic acid of the present invention. Furthermore, the present invention relates to a host cell comprising the nucleic acid or vector of the present invention.

[0037] The present invention also relates to a method for producing an antibody or antigen-binding fragment of the present invention, comprising culturing a host cell as provided herein and isolating the antibody or antigen-binding fragment. The host cell may be a CHO cell (e.g., a CHO-K1 cell). The present invention also relates to an antibody or antigen-binding fragment (as described above) obtainable (or obtained) by this method.

[0038] The present invention also relates to a composition (which is preferably a pharmaceutical composition) comprising the antibody or antigen-binding fragment of the present invention or the nucleic acid of the present invention.

[0039] The invention also provides lipid particles comprising one or more nucleic acids of the invention (which can be, for example, mRNA).

[0040] The present invention also relates to antibodies or antigen-binding fragments (as described herein) for use in therapy (or as a medicament), in particular for the treatment of cancer. The present invention also relates to nucleic acids (as described herein), compositions (as described herein) or lipid particles (as described herein) for use in therapy (or as a medicament), in particular for the treatment of cancer.

[0041] In addition, the present invention relates to the use of an antibody or antigen-binding fragment (as described herein) in the preparation of a medicament for treating cancer. The present invention also relates to the use of a nucleic acid (as described herein), a composition (as described herein) or a lipid particle (as described herein) in the preparation of a medicament for treating cancer.

[0042] The present invention also provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment (as described herein). The subject to be treated can specifically be a human. The present invention also relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a nucleic acid (as described herein), (ii) a composition (as described herein), or (iii) a lipid particle (as described herein). In any of these methods, the subject to be treated can specifically be a human.

[0043] The present invention is further illustrated by the following drawings:

[0044] Figure 1 The results show the effect of reference anti-CCR8 mAb L263G8 on hCCR8-transfected CHO cells ( Figure 1 .1) HUT78 cells ( Figure 1 .2) and human activated T cells ( Figure 1 .3) Cellular reactivity. Representative experiments. See Examples 7, 8, and 9.

[0045] Figure 2 The reactivity of mAbs to a panel of CCR8-related peptides analyzed by ELISA is shown. Mean values ​​+ / - SD of two independent experiments are shown. See Example 10.

[0046] Figure 3 Shows at least 80% of CD45+CD4+CD25+CD127 低 Immunophenotype of human activated T cells composed of cells. Representative experiments. See Example 11.

[0047] Figure 4 The reactivity of mAbs against ascites ovarian cancer lymphocytes as detected by flow cytometry is shown. Representative experiments. See Example 11.

[0048] Figure 5 The reactivity of mAbs on peripheral blood mononuclear cells (PBMCs) from healthy donors is shown. Figure 5 .1 shows the gating strategy that allows discrimination of different immune cells in PBMCs. Figure 5 Figure 2 shows the binding of anti-CCR8 mAbs to PBMCs. The average percentage of binding to different immune cells from two independent donors is shown. See Example 12.

[0049] Figure 6Shown are the effects of mAbs on hCCL1 binding to hCCR8 as analyzed by flow cytometry and / or the effects of mAbs on hCCL1 binding to hCCR8-transfected CHO and HEK-293 cell lines as analyzed by HTRF. Mean values ​​are from two independent experiments. See Example 13.

[0050] Figure 7 Shown are the effects of mAbs on CCL1-induced hCCR8 Gi2 signaling in transiently transfected HEK-293 cell lines as analyzed by BRET. Mean + / - SD of two independent experiments. See Example 14.

[0051] Figure 8 Shown is the duration of action of mAbs against the CCL1-induced hCCR8 Gi2 signaling pathway in transiently transfected HEK 293 cells. The assay was performed with and without an elution step to remove excess unbound antibody from the solution. Six hours after mAb elution, the mAb retained its hCCR8 antagonist activity, demonstrating a prolonged duration of action against CCR8. Mean values ​​are ± SD from two independent experiments. See Example 14.

[0052] Figure 9 The BRET assay shows that the exemplary mAb has an insurmountable antagonist effect on the CCL1-induced Gi2 signaling pathway in transiently transfected HEK-293 cells. Representative experiments were performed in duplicate. See Example 14.

[0053] Figure 10 Shown are the effects of mAbs on CCL1-induced hCCR8 Gi2 signaling in transiently transfected HEK-293 cell lines at pH 6.5 or pH 7.4 as analyzed by BRET. Mean + / - SD of two independent experiments. See Example 14.

[0054] Figure 11 The antibody-dependent cellular cytotoxicity (ADCC) effect of the antibody of the present invention on the HUT78 cell line expressing CCR8 was shown. Figure 11 .1-11.4 shows the dose response curves of the percentage of specific lytic ADCC induced by anti-CCR8 mAb. See Example 16.

[0055] Figure 12 The antibody-dependent cellular phagocytosis (ADCP) activity of anti-CCR8 antibodies against HUT78 as target cells and monocyte-derived macrophages as effector cells is shown. The phagocytic percentages of three independent donors are shown. See Example 17.

[0056] As described above, the present invention relates to a monoclonal antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway; wherein the antibody or antigen-binding fragment specifically binds to:

[0057] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0058] And further, wherein the antibody or antigen-binding fragment specifically binds to one or more (preferably all) of the following:

[0059] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0060] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0061] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0062] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0063] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0064] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0065] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0066] For the sake of brevity, the monoclonal antibodies (or antigen-binding fragments thereof) that specifically bind to human CCR8 provided according to the present invention are also interchangeably referred to herein as "anti-CCR8 antibodies" or "anti-CCR8 mAbs."

[0067] Antibodies are well known in the art and are also referred to as immunoglobulin molecules. In general, immunoglobulin molecules are able to specifically bind to a target (e.g., in this case, human CCR8) through at least one antigen recognition site, which is typically located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses not only complete (e.g., full-length) antibodies, particularly monoclonal antibodies, but also any modified antibodies, antibody constructs, and fusion proteins (or other molecules) thereof, as well as antigen-binding fragments thereof and any modified antibodies, antibody constructs, and fusion proteins (or other molecules) comprising one or more antigen-binding antibody portions or fragments. As known in the art, non-limiting examples of antigen-binding antibody fragments include Fab, Fab', F(ab')2 or Fv, single-chain antibodies (e.g., single-chain variable region fragments (scFv)), heavy chain antibodies, single domain antibodies (e.g., nanobodies, single V H Domain antibodies (or V H H fragment) or IgNAR single domain antibody (or V NARIn some embodiments, the present invention relates to an antibody comprising a light chain, a heavy chain, a polyclonal antibody ...

[0068] The term "monoclonal antibody" is used herein according to its meaning as known and understood in the art. Monoclonal antibodies can be obtained by different techniques known in the art and are therefore not limited by the methods for obtaining them. For example, monoclonal antibodies can be prepared by hybridoma methods (see, for example, Kohler G et al., Nature, 1975, 256, 495-7; Freysdottir J, Methods Mol Med, 2000, 40: 267-79, doi: 10.1385 / 1-59259-076-4: 267; or Hnasko RM et al., Methods Mol Biol, 2015, 1318: 15-28, doi: 10.1007 / 978-1-4939-2742-5_2). Monoclonal antibodies, including fully human antibodies and humanized antibodies, can also be produced in transgenic animals (particularly transgenic mice), for example, using commercially available mice that have been engineered to express specific human immunoglobulins. Corresponding transgenic mice include, e.g. TransChromo(TC)Mouse TM 、 Kymouse TM 、AlivaMab-Mouse、 or Merus Mouse; see also, e.g., Foltz IN et al., Immunol Rev, 2016, 270(1):51-64, doi:10.1111 / imr.12409; Murphy AJ et al., Proc Natl Acad Sci USA, 2014, 111(14):5153-8, doi:10.1073 / pnas.1324022111; Lonberg N, Handb Exp Pharmacol, 2008, 181(181):69-97, doi:10.1007 / 978-3-540-73259-4_4; Ma B et al., “Transgenic Animals for the Generation of Human Antibodies”, in: Rüker F et al., (eds), “Introduction to Antibody Engineering", 2021, Springer, doi:10.1007 / 978-3-030-54630-4_5; WO 91 / 09967; WO 92 / 011018; WO 94 / 04679; WO 98 / 45332; or US2021 / 0040182.Monoclonal antibodies can also be prepared by recombinant antibody library display technology, including, for example, by phage display, yeast display or ribosome / mRNA display (see, e.g., Winter G et al., Annu Rev Immunol, 1994, 12:433-55, doi: 10.1146 / annurev.iy.12.040194.002245; Hammers CM et al., J Invest Dermatol, 2014, 134(2):e17, doi: 10.1038 / jid.2013.521; Boder ET et al., Arch Biochem Biophys, 2012, 526(2):99-106, doi: 10.1016 / j.abb.2012.03.009; Sheehan J et al., Microbiol Spectr, 2015, 3(1):AID-0028-2014, doi:10.1128 / microbiolspec.AID-0028-2014; Feldhaus MJ et al., J Immunol Methods, 2004, 290(1-2):69-80, doi:10.1016 / j.jim.2004.04.009; Hoogenboom HR, Nat Biotechnol, 2005, 23(9):1105-16, doi:10.1038 / nbt1126; He M et al., Expert Rev Proteomics, 2005, 2(3):421-30, doi:10.1586 / 14789450.2.3.421; US ​​5,565,332; US 5,580,717; US 5,733,743; or US 6,265,150). Each of the documents mentioned in this paragraph is incorporated herein by reference in its entirety.

[0069] Antibody molecules typically contain a heavy chain variable region (V H ) and light chain variable region (V L), which are involved in antigen binding. Such VH and VL regions can be further divided into (i) hypervariable regions termed "complementarity determining regions" or "CDRs," and (ii) more conserved regions termed "framework regions" or "FRs" (or the synonym "FW"). Typically, each VH or VL region is composed of three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1–CDR1–FR2–CDR2–FR3–CDR3–FR4. Although it is often apparent from the context whether one is referring to the CDRs or FRs of the heavy or light chain variable region, the designators "H" or "L" may be used herein to distinguish between CDRs and FRs. Thus, for example, the CDRs and FRs of the heavy chain variable domain may be referred to as follows (from N-terminus to C-terminus): [FR-H1]–(CDR-H1)–[FR-H2]–(CDR-H2)–[FR-H3]–(CDR-H3)–[FR-H4]. Likewise, the CDRs and FRs of the light chain variable domain can be referred to as follows (from N-terminus to C-terminus): [FR-L1]–(CDR-L1)–[FR-L2]–(CDR-L2)–[FR-L3]–(CDR-L3)–[FR-L4]. CDRs and framework regions may be identified or assigned using methods / numbering schemes known in the art, including, for example, the Kabat definition, the Chothia definition (specifically including the so-called "pre-1989 / post-1997 Chothia definition" as described in Al-Lazikani et al., 1997, cited below), the Martin (enhanced Chothia) definition, the AbM definition, the Contact definition, or the IMGT definition; see, e.g., Kabat EA et al., "Sequences of proteins of immunological interest", 5th ed., 1991, U.S. Department of Health and Human Services, National Institutes of Health (NIH), Publication No. 91-3242; Chothia C et al., Nature, 1989, 342(6252):877-83, doi:10.1038 / 342877a0; Chothia C et al., J Mol. Biol,1987,196(4):901-17,doi:10.1016 / 0022-2836(87)90412-8; Al-Lazikani B et al., J Mol Biol,1997,273(4):927-48,doi:10.1006 / jmbi.1997.1354; Almagro JC,J Mol Recognit,2004,17(2):132-43,doi:10.1002 / jmr.659; Martin AC et al., Proc Natl Acad Sci USA, 1989, 86(23):9268-72, doi:10.1073 / pnas.86.23.9268; Rees AR et al., “Antibody combining sites: structure and prediction”, in Sternberg MJE (ed.): “Protein Structure Prediction”, Oxford University Press, Oxford, 1996, 141-72; Lefranc MP, Immunol Today, 1997, 18(11):509, doi:10.1016 / s0167-5699(97)01163-8; Lefranc MP, Immunologist, 1999, 7(4):132-6; Lefranc MP et al., Dev Comp Immunol,2003,27(1):55-77,doi:10.1016 / s0145-305x(02)00039-3; Lefranc MP et al., Dev Comp Immunol,2005,29(3):185-203,doi:10.1016 / j.dci.2004.07.003; Lefranc MP et al., Dev Comp Immunol, 2005, 29(11):917-38, doi:10.1016 / j.dci.2005.03.003; Lefranc MP, Cold Spring Harb Protoc, 2011, 2011(6), doi:10.1101 / pdb.ip85; Lefranc MP, Cold Spring Harb Protoc, 2011, 2011(6). doi: 10.1101 / pdb.ip86; or Lefranc MP et al., Nucleic Acids Res, 2015, 43(Database Journal): D413-22, doi: 10.1093 / nar / gku1056; the entire contents of each of which are incorporated herein by reference. Unless otherwise expressly stated, CDR sequences are identified herein according to the IMGT numbering system (or "IMGT unique numbering"); see, for example, any of the above references by Lefranc MP. .

[0070] As described above, the anti-CCR8 antibodies of the present invention can be, for example, humanized antibodies or fully human antibodies. The corresponding humanized antibodies are typically human immunoglobulins (as recipient antibodies), in which the CDR sequences of the human immunoglobulin are partially or completely (preferably completely) replaced by CDR sequences from a non-human antibody (a donor antibody with the desired binding properties), such as a murine antibody. The human immunoglobulin (recipient antibody) can be, for example, human IgG (e.g., human IgG1, human IgG2, human IgG3, or human IgG4), human IgM, human IgA (e.g., human IgA1 or human IgA2), human IgD, or human IgE; preferably, the human immunoglobulin is human IgG, more preferably human IgG1 or human IgG4, and even more preferably human IgG1. Furthermore, in some cases, one or more framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may optionally contain one or more amino acid residues that are not present in the recipient antibody or in the "imported" CDR or framework sequences, but are included to further improve and optimize the performance of the antibody. In some embodiments, the humanized antibody comprises at least one, preferably two, variable regions from a human immunoglobulin (e.g., from human IgG, such as human IgG1 or IgG4, particularly human IgG1), wherein all CDRs correspond to the CDRs of a non-human (e.g., mouse) immunoglobulin, and all (or substantially all) FR regions are FR regions of a human immunoglobulin. The humanized antibody preferably further comprises a human immunoglobulin constant region (or Fc region) or at least a portion thereof. The generation of humanized antibodies may also involve affinity maturation. Methods and techniques for producing humanized antibodies are well known in the art, including those described above and / or in Almagro JC et al., Front Biosci, 2008, 13:1619-33, doi:10.2741 / 2786; Kim JH et al., Methods Mol Biol, 2012, 907:237-45, doi:10.1007 / 978-1-61779-974-7_13; Safdari Y et al., Biotechnol Genet Eng Rev, 2013, 29:175-86, doi:10.1080 / 02648725.2013.801235; or Kuramochi T et al., Methods Mol Biol, 2012, 907:237-45, doi:10.1007 / 978-1-61779-974-7_13. Biol, 2014, 1060: 123-37, doi: 10.1007 / 978-1-62703-586-6_7; each of which is incorporated herein by reference.

[0071] Thus, the present invention provides a humanized form (or humanized version) of any antibody or antigen-binding fragment described herein, including any of the antibodies described in the Examples section and any of the antibodies (or antigen-binding fragments) according to any of options (A-1) to (A-13) described below. Specifically, the antibody (or antigen-binding fragment) of the present invention may comprise six CDRs as defined in any of options (A-1) to (A-13) and may further comprise a human acceptor framework (e.g., a human immunoglobulin framework). Exemplary humanized antibodies are also provided herein, including antibodies having VH and VL sequences as shown in any of options (B-12) to (B-14) below, in particular antibodies 2-12 to 2-16 as described in the Examples section.

[0072] In some embodiments, the anti-CCR8 antibodies of the present invention are chimeric antibodies, for example, antibodies having a variable region (or a portion of a variable region) from a first species (e.g., mouse) and a constant region from a second species (preferably human). Typically, the light chain and heavy chain variable regions of a chimeric antibody correspond to the variable regions of an antibody from a non-human mammalian species (e.g., mouse, rat, or rabbit), while the constant region of the chimeric antibody corresponds to the constant region of a human antibody (or is homologous to the constant region of a human antibody). Optionally, one or more amino acid substitutions / replacements or modifications may be made in the variable region and / or constant region. Methods and techniques for producing chimeric antibodies are well known in the art and include those described above.

[0073] As mentioned above, the monoclonal antibody (or its antigen-binding fragment) of the present invention specifically binds to human CCR8. The concept of antibody "specific binding" to a certain target antigen (or its epitope) is well known in the art. Specifically, if the antibody binds to a specific target antigen (or epitope) with greater affinity, avidity, more readily and / or with a longer duration (preferably with greater affinity) than it binds to other alternative antigens, the antibody can be referred to as "specifically binding" the target antigen (or epitope). In addition, the antibody of a specific epitope of "specific binding" (antigen) can be an antibody that is bound to the epitope with greater affinity, avidity, more readily and / or with a longer duration (preferably with greater affinity) than other epitopes of the same antigen. It should be understood that "specific binding" does not necessarily require exclusive binding to the corresponding target, although this exclusive (or almost exclusive) binding is typically desired. Therefore, an antibody that specifically binds to a first antigen can specifically bind or not specifically bind to a second antigen (which is different from the first antigen). In some embodiments, an antibody that "specifically binds" a target antigen does not (or does not significantly) bind to other antigens (or similarly, an antibody that "specifically binds" a particular epitope may not (or may not significantly) bind to other epitopes on the same antigen), which may be reflected, for example, in that only baseline binding activity is detectable for other antigens (or other epitopes). In some embodiments, the anti-CCR8 antibodies of the present invention may therefore exhibit some (residual) binding activity to targets other than human CCR8, but the level is only significantly reduced relative to the binding activity to human CCR8. For example, the property of a monoclonal antibody (or antigen-binding fragment thereof) of the present invention to "specifically bind" to human CCR8 may be characterized by an affinity of the antibody (or antigen-binding fragment) for the target antigen (human CCR8) that is at least 10 times higher (i.e., more affinity) than for a non-target antigen; affinity may be determined and expressed, for example, as K D values, where the lower K D A value of α indicates greater affinity. In some embodiments, the antibodies (or antigen-binding fragments) of the invention may not exhibit detectable binding to non-target antigens.

[0074] As used herein, the term "epitope" refers to a site on a target antigen that is recognized and bound by an antibody. An epitope can be linear, and in this case, typically has a length of 6 to 15 amino acid residues. Alternatively, an epitope can be conformational. The epitope to which an antibody (or antigen-binding fragment) binds can be determined by conventional methods, for example, by epitope mapping, as further described below.

[0075] The term "CCR8" refers to CC chemokine receptor 8 (also known as CC motif chemokine receptor type 8). CC chemokine receptors (CCRs) belong to the G protein-coupled receptor (GPCR) family, which has seven transmembrane helices; they specifically bind to cytokines of the CC chemokine family. CCR8 may also be referred to as CCR-8, CY6, GPRCY6, TER1, CDw198, CKRL1, CMKBR8, CMKBRL2 or CC-CKR-8. Unless otherwise indicated or inconsistent with the context, "CCR8" refers to the CCR8 protein (which is encoded by the CCR8 gene). In addition, "CCR8" refers to human CCR8 ("hCCR8") or a homolog thereof, including a mammalian CCR8 homolog or a non-mammalian CCR8 homolog; corresponding examples specifically include mouse CCR8 ("mCCR8"), rat CCR8, cynomolgus monkey CCR8, rhesus monkey CCR8, chimpanzee CCR8, chicken CCR8, dog CCR8 or bovine CCR8. "CCR8" preferably refers to human CCR8. The human CCR8 gene is described in, for example, NCBI gene ID 1237, or Ensembl ID ENSG00000179934, or HGNC gene ID 1609. The human CCR8 protein and its amino acid sequence are described in, for example, Uniprot accession number P51685, or NCBI reference sequence NP_005192.1. Specifically, the human CCR8 protein may have the sequence of (or consist of) human isoform 1 (P51685-1) or human isoform 2 (P51685-2) described by Uniprot. Human CCR8 may also refer to the protein encoded by the mRNA described by NCBI reference sequence NM_005201.4. Preferably, human CCR8 refers to a protein having (or consisting of) the following amino acid sequence:

[0076] MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVLVVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSSMFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGVLQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLVLIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIYAFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL(SEQ ID NO:9)

[0077] Sequences of other mammalian or non-mammalian homologs of human CCR8 are also described in Uniprot or NCBI (or other databases known in the art). Thus, murine (mouse) CCR8 and its sequence are described, for example, in Uniprot accession number P56484 or NCBI reference sequence NP_031746.1; rat CCR8 and its sequence are described, for example, in NCBI reference sequence XP_008764924.1; cynomolgus monkey CCR8 and its sequence are described, for example, in Uniprot accession number G7NYJ2 or NCBI reference sequence XP_015300839.1; rhesus monkey CCR8 and its sequence are described, for example, in Uniprot accession number G7NYJ2 or NCBI reference sequence XP_015300839.1; CCR8 is a CCR8 protein that is expressed in a variety of mammalian cells and has been described in various cell types, including accession number O97665 or NCBI reference sequence XP_001084047.1; chimpanzee CCR8 and its sequence are described, for example, in NCBI reference sequence XP_526178.3; chicken CCR8 and its sequence are described, for example, in NCBI reference sequence NP_001026162.1; dog CCR8 and its sequence are described, for example, in NCBI reference sequence XP_542719.1; and bovine CCR8 and its sequence are described, for example, in NCBI reference sequence NP_001181891.1. The different isoforms or variants of CCR8 that may exist in some species are each specifically encompassed by the term CCR8. The CCR8 protein may also be modified, for example, post-translationally, or may be unmodified. Specifically, post-translational modifications of CCR8 are reported, for example, in the following literature: Gutiérrez J et al., Journal of Biological Chemistry, 2004, 279(15):14726-33, doi:10.1074 / jbc.M309689200; or Ludeman JP et al., British Journal of Pharmacology, 2014, 171(5):1167-79, doi:10.1111 / bph.12455. These post-translational modifications of CCR8 may include tyrosine sulfation, catalyzed by enzymes such as tyrosyl protein sulfotransferase-1 or 2 (TPST-1 or TPST-2) (see, for example, Danan LM et al., J Am Soc Mass Spectrom, 2008, 19(10): 1459-66, doi: 10.1016 / j.jasms.2008.06.021). Interestingly, sulfation of TPST-1 and chemokine receptors such as CXCR4 is associated with the metastatic potential of nasopharyngeal carcinoma (Xu J et al., PLoS One, 2013, 8(3): e56114, doi: 10.1371 / journal.pone.0056114).It is reported that such post-translational modifications also play a key role in pathological conditions, as has been previously demonstrated for another chemokine receptor (e.g., CCR5) in the context of HIV invasion (Farzan M et al., Cell, 1999, 96(5):667-76, doi:10.1016 / s0092-8674(00)80577-2). In addition, the term CCR8 also encompasses recombinant or synthetic forms of CCR8. Each sequence described under the above reference number, accession number, or ID number is individually incorporated herein by reference.

[0078] As described above, the monoclonal antibody (or its antigen-binding fragment) of the present invention specifically binds to human CCR8, in particular to human CCR8 expressed on the surface of cells. Preferably, the antibody (or antigen-binding fragment) specifically binds to the extracellular domain of human CCR8. Therefore, the antibody (or antigen-binding fragment) can specifically bind to an epitope formed by any one or more extracellular portions of human CCR8 (i.e., one or more of those portions of human CCR8 extending from the plasma membrane to the extracellular space), wherein the one or more extracellular portions include (i) an N-terminal extracellular portion (which extends from the N-terminus to the first transmembrane (TM) helix of human CCR8 protein), (ii) a first extracellular loop (which connects the second TM helix to the third TM helix), (iii) a second extracellular loop (which connects the fourth TM helix to the fifth TM helix), and / or (iv) a third extracellular loop (which connects the sixth TM helix to the seventh TM helix) of human CCR8. Different parts of CCR8, including its three extracellular loops, are known in the art (see, e.g., Barington L et al., J Biol Chem, 2016, 291(31):16208-20, doi:10.1074 / jbc.M115.706747). In some embodiments, the antibody (or antigen binding fragment) specifically binds to the N-terminal extracellular portion of human CCR8. Thus, in some embodiments, the antibody (or antigen binding fragment) specifically binds to an epitope in the N-terminal extracellular portion of human CCR8. In some embodiments, the antibody (or antigen binding fragment) specifically binds to the first extracellular loop of human CCR8. Thus, in some embodiments, the antibody (or antigen binding fragment) specifically binds to an epitope in the first extracellular loop of human CCR8. In some embodiments, the antibody (or antigen binding fragment) specifically binds to the second extracellular loop of human CCR8. Thus, in some embodiments, the antibody (or antigen binding fragment) specifically binds to an epitope in the second extracellular loop of human CCR8. In some embodiments, the antibody (or antigen-binding fragment) specifically binds to the third extracellular loop of human CCR8. Thus, in some embodiments, the antibody (or antigen-binding fragment) specifically binds to an epitope in the third extracellular loop of human CCR8.

[0079] Preferably, the antibody (or antigen-binding fragment) specifically binds to the N-terminal 20 to 50 amino acid residues of SEQ ID NO: 9 (i.e., the first 20 to 50 amino acid residues counted from the N-terminus of SEQ ID NO: 9), particularly the N-terminal 30 to 40 amino acid residues of SEQ ID NO: 9, more particularly the N-terminal 34 amino acid residues of SEQ ID NO: 9. Therefore, it is preferred that the antibody (or antigen-binding fragment) specifically binds to an epitope within the N-terminal 20 to 50 amino acid residues of SEQ ID NO: 9 (i.e., the first 20 to 50 amino acid residues counted from the N-terminus of SEQ ID NO: 9), particularly an epitope within the N-terminal 30 to 40 amino acid residues of SEQ ID NO: 9, more particularly an epitope within the N-terminal 34 amino acid residues of SEQ ID NO: 9.

[0080] Human CCR8 contains multiple tyrosine (Y) residues, particularly in its N-terminal extracellular portion, which can exist in sulfated or non-sulfated forms. Sulfation of tyrosine residues in proteins is a post-translational modification in which a sulfate group is added to the corresponding tyrosine residue, converting the side chain hydroxyl group (-OH) of the tyrosine residue into a sulfate group (-O-SO3H) (see, e.g., Moore KL, J Biol Chem, 2003, 278(27):24243-6, doi:10.1074 / jbc.R300008200; or Moore KL, Proc Natl Acad Sci USA, 2009, 106(35):14741-2, doi:10.1073 / pnas.0908376106). Sulfation of tyrosine residues can be catalyzed by enzymes such as tyrosyl protein sulfotransferase-1 or 2 (TPST-1 or TPST-2) (see, e.g., Danan LM et al., J Am Soc Mass Spectrom, 2008, 19(10):1459-66, doi:10.1016 / j.jasms.2008.06.021). In certain types of cancer, CCR8 expressed by tumor-infiltrating Treg cells and / or by cancer cells may have one or more sulfated tyrosine (Y) residues, particularly at one or more positions corresponding to Y15, Y16 and / or Y17 of SEQ ID NO:9, whereas these tyrosine residues may be present in non-sulfated form in other types of cancer. Therefore, it is advantageous that the antibodies (or antigen-binding fragments) of the present invention are able to specifically bind to human CCR8, regardless of whether the corresponding tyrosine residue is present in a sulfated or non-sulfated form. The ability of an antibody to specifically bind to CCR8 with sulfated or non-sulfated tyrosine residues can be determined by any suitable binding assay or experiment (e.g., as described in the Examples herein below). Although such binding assays can be performed with different sulfated (or non-sulfated) forms of the complete CCR8 protein (particularly the fully human CCR8 protein), it is also possible (and often more convenient) to use different sulfated (or non-sulfated) forms of a partial sequence of a CCR8 protein (also referred to as a CCR8 fragment or CCR8 peptide) comprising the corresponding tyrosine residue. For example, in such a binding assay, a peptide consisting of a partial sequence of about 20 to about 50 amino acid residues (preferably about 30 to about 40 amino acid residues) from SEQ ID NO: 9 (preferably from the N-terminal extracellular portion of SEQ ID NO: 9) can be used, which comprises amino acid residues Y15, Y16, and Y17 of SEQ ID NO: 9.More preferably, a peptide comprising (or preferably consisting of) the N-terminal 20 to 50 amino acid residues of SEQ ID NO: 9 (i.e., the first 20 to 50 amino acid residues starting from SEQ ID NO: 9) can be used, and even more preferably, a peptide comprising (or particularly consisting of) the N-terminal 30 to 40 amino acid residues of SEQ ID NO: 9 can be used. Even more preferably, a peptide / protein comprising (or particularly consisting of) the N-terminal 34 amino acid residues of SEQ ID NO: 9 can be used. It will be understood that different sulfated (or non-sulfated) forms of such peptides, wherein one or more of tyrosine residues Y15, Y16, and Y17 are sulfated or non-sulfated, are typically used in binding experiments to determine the ability of an antibody to specifically bind to different forms of the peptide, and therefore to determine the ability of the antibody to specifically bind to sulfated and / or non-sulfated forms of CCR8. The preparation of corresponding exemplary sulfated and non-sulfated CCR8 peptides is described in Example 1. Thus, in some embodiments, one or more (e.g., all) of the peptides described in Example 1 can be used. Other sulfated and non-sulfated CCR8 peptides can be prepared, for example, according to or in analogy to the procedures described in Seibert C et al., Methods Enzymol, 2016, 570:357-88, doi: 10.1016 / bs.mie.2015.09.004; each of which is incorporated herein by reference.

[0081] Thus, as explained above, the antibodies (or antigen-binding fragments) of the present invention specifically bind to:

[0082] (i) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0083] and also specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0084] (ii) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0085] (iii) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0086] (iv) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0087] (v) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0088] (vi) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0089] (vii) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0090] (viii) human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0091] It will be appreciated that options (i) to (viii) above define the presence of sulfated or non-sulfated tyrosine residues at positions Y15, Y16 and Y17 of human CCR8 or positions Y15, Y16 and Y17 of a partial sequence of human CCR8. It will also be appreciated that in the amino acid sequences recited, the presence of tyrosine residues ( Y ) are underlined indicating that the corresponding tyrosine residues are sulfated.

[0092] In some embodiments, the antibodies (or antigen-binding fragments) of the present invention specifically bind to (i) and (ii), or (i) and (iii), or (i) and (iv), or (i) and (v), or (i) and (vi), or (i) and (vii), or (i) and (viii). In other embodiments, the antibodies (or antigen-binding fragments) of the present invention specifically bind to (i), (ii), and (iii); or (i), (ii), and (iv); or (i), (ii), and (v); or (i), (ii), and (vi); or (i), (ii), and (vii); or (i), (ii), and (viii); or (i), (ii), and (viii); or (i), (iii), and (iv); or (i), (iii), and (v); or (i), (iii), and (vi); or (i), (iii), and (vii); or specifically binds to (i), (iii) and (viii); or specifically binds to (i), (iv) and (v); or specifically binds to (i), (iv) and (vi); or specifically binds to (i), (iv) and (vii); or specifically binds to (i), (iv) and (viii); or specifically binds to (i), (v) and (vii); or specifically binds to (i), (v) and (viii); or specifically binds to (i), (vi) and (vii); or specifically binds to (i), (vi) and (viii); or specifically binds to (i), (vi) and (vii); or specifically binds to (i), (vi) and (viii); or specifically binds to (i), (vi) and (viii); or specifically binds to (i), (vii) and (viii).In other embodiments, the antibodies (or antigen-binding fragments) of the invention specifically bind to (i), (ii), (iii), and (iv); or specifically bind to (i), (ii), (iii), and (v); or specifically bind to (i), (ii), (iii), and (vi); or specifically bind to (i), (ii), (iii), and (vii); or specifically bind to (i), (ii), (iii), and (viii); or specifically bind to (i), (ii), (iv), and (v); or specifically bind to (i), (ii), (iv), and (vi); or specifically bind to (i), (ii), (iv), and (vii); or specifically bind to or specifically binds to (i), (ii), (iv) and (viii); or specifically binds to (i), (ii), (v) and (vi); or specifically binds to (i), (ii), (v) and (vii); or specifically binds to (i), (ii), (v) and (viii); or specifically binds to (i), (ii), (vi) and (viii); or specifically binds to (i), (ii), (vi) and (viii); or specifically binds to (i), (ii), (vii) and (viii); or specifically binds to (i), (iii), (iv) and (v); or specifically binds to (i), (iii), (iv) and (vi); or specifically binds to ( i), (iii), (iv) and (vii); or specifically binds to (i), (iii), (iv) and (viii); or specifically binds to (i), (iii), (v) and (vii); or specifically binds to (i), (iii), (v) and (viii); or specifically binds to (i), (iii), (v) and (vii); or specifically binds to (i), (iii), (vi) and (vii); or specifically binds to (i), (iii), (vi) and (viii); or specifically binds to (i), (iii), (vi) and (viii); or specifically binds to (i), (iv), (v) and (vi); or Specific binding to (i), (iv), (v) and (vii); or specific binding to (i), (iv), (v) and (viii); or specific binding to (i), (iv), (vi) and (vii); or specific binding to (i), (iv), (vi) and (viii); or specific binding to (i), (iv), (vii) and (viii); or specific binding to (i), (v), (vi) and (vi); or specific binding to (i), (v), (vi) and (viii); or specific binding to (i), (v), (vii) and (viii); or specific binding to (i), (vi), (vii) and (viii).

[0093] Therefore, the present invention provides a monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway; wherein the antibody or the antigen-binding fragment specifically binds to:

[0094] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0095] And further, wherein the antibody or antigen-binding fragment specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0096] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0097] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0098] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0099] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0100] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0101] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0102] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0103] Preferably, the antibodies (or antigen-binding fragments) of the invention specifically bind to:

[0104] - a peptide consisting of the sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1) having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0105] and also specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0106] - by the sequence MDYTLDLSVTTVTD Y a peptide consisting of YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0107] - by the sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3), having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0108] - by the sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4), having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0109] - by the sequence MDYTLDLSVTTVTD YY The peptide consisting of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5) has sulfated tyrosine residues at positions Y15 and Y16 and a non-sulfated tyrosine residue at position Y17.

[0110] - by the sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6), having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0111] - by the sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), having sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15; and

[0112] - by the sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) has sulfated tyrosine residues at positions Y15, Y16, and Y17.

[0113] More preferably, the antibodies (or antigen-binding fragments) of the present invention specifically bind to two or more non-sulfated forms of human CCR8 (i.e., two or more forms / variants of human CCR8 in which at least one of the tyrosine residues at positions Y15, Y16, and Y17 is non-sulfated). It is therefore particularly preferred that the antibodies (or antigen-binding fragments) of the present invention specifically bind to:

[0114] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0115] and also specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0116] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0117] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0118] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0119] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0120] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6), or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17, and a non-sulfated tyrosine residue at position Y16; and

[0121] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YYPDIFSSPCDAELIQTNG (SEQ ID NO: 7) or consists thereof, having sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15.

[0122] Therefore, in a particularly preferred embodiment, the present invention provides a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway; wherein the antibody or antigen-binding fragment specifically binds to:

[0123] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0124] and also specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0125] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0126] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0127] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0128] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYor consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0129] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6), or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17, and a non-sulfated tyrosine residue at position Y16; and

[0130] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7) or consists thereof, having sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15.

[0131] It is particularly preferred that the antibodies (or antigen-binding fragments) of the invention specifically bind to:

[0132] - a peptide consisting of the sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1) having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0133] and also specifically binds one or more (preferably two or more; more preferably three or more; even more preferably five or more; still more preferably all) of the following:

[0134] - by the sequence MDYTLDLSVTTVTD Y a peptide consisting of YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0135] - by the sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3), having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0136] - by the sequence MDYTLDLSVTTVTDYY YPDIFSSPCDAELIQTNG (SEQ ID NO: 4), having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0137] - by the sequence MDYTLDLSVTTVTD YY The peptide consisting of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5) has sulfated tyrosine residues at positions Y15 and Y16 and a non-sulfated tyrosine residue at position Y17.

[0138] - by the sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6), having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16; and

[0139] - by the sequence MDYTLDLSVTTVTDY YY The peptide consisting of PDIFSSPCDAELIQTNG (SEQ ID NO: 7) has sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15.

[0140] Preferably, the dissociation constant (K D ) is about 100 nM or less, more preferably K D is about 50 nM or less, even more preferably K D is about 30 nM or less, even more preferably K D is about 20 nM or less, even more preferably K D is about 15 nM or less, and even more preferably K D is about 10 nM or less. Specifically, it is preferred that the KD of the antibody or antigen-binding fragment of the present invention specifically binds to its target antigen (e.g., any specific antigen mentioned herein above or below) is about 100 nM or less, more preferably about 50 nM or less, even more preferably about 30 nM or less, even more preferably about 20 nM or less, even more preferably about 15 nM or less, and even more preferably about 10 nM or less. The dissociation constant (K D ) is often used as a measure of antibody affinity (or binding activity), particularly a measure of the affinity of an antibody for its target antigen. As understood in the art, the K of an antibody for a target DThe K value is inversely proportional to its affinity (or binding activity) for that target. Thus, for example, the K of an antibody or antibody binding fragment that specifically binds to its antigen is D "At least" 50 nM or 50 nM "or better" should generally be understood as the K of binding to its antigen. D Alternatively, or in addition, the association rate (k) of an antibody or antigen-binding fragment of the invention that specifically binds to its target antigen is 50 nM "or less". a or k on ) can be about 1×10 5 M - 1 s -1 or higher, preferably k a About 2×10 5 M -1 s -1 or higher, more preferably k a About 5×10 5 M -1 s -1 or higher.

[0141] The binding properties of the antibodies and antigen-binding fragments provided herein, including binding specificity or affinity, can be established by any suitable method known in the art and / or any method described herein that allows for quantitative binding parameters. Methods for analyzing the binding specificity and binding parameters of antibodies or antigen-binding fragments are described in, for example: Harlow E et al., "Using Antibodies: A Laboratory Manual", 1999, Cold Spring Harbor Laboratory Press; or Greenfield EA, "Antibodies: A Laboratory Manual", 2nd edition, 2014, Cold Spring Harbor Laboratory Press (which are incorporated by reference into the text). Non-limiting examples of suitable studies include binding studies and / or blocking / competition studies with structurally and / or functionally closely related molecules. These studies can be performed by methods such as FACS analysis, flow cytometric titration analysis (FACS titration), surface plasmon resonance (SPR; for example using ), isothermal titration calorimetry (ITC), fluorescence titration or by radiolabeled ligand binding assays. Other methods include, for example, any of Western blots, ELISA (e.g., competitive ELISA), RIA, ECL, and IRMA assays. The specificity and selectivity of the antibodies and antigen-binding fragments of the present invention are preferably determined by measuring antibody affinity, for example, by determining the dissociation constant (K D ) to determine.D When using surface plasmon resonance spectroscopy, it is preferred to use, for example, Specifically, the dissociation constant (KD) can be measured using The dissociation constant (K) is determined by a surface plasmon resonance assay in which an antigen (e.g., human CCR8) is immobilized on a biosensor chip using an injection flow rate of about 5 μl / min and a temperature of about 25° C. to obtain a density of about 10 response units (RU), and in which the antibody (or antigen-binding fragment) is subsequently injected at a flow rate of about 25 μl / min and a temperature of about 25° C. Additionally or alternatively, the dissociation constant (K D ) can be used Surface plasmon resonance was determined according to the method described in Murphy M et al., Curr Protoc Protein Sci, 2006, Chapter 19: Unit 19.14, doi: 10.1002 / 0471142301.ps1914s45.

[0142] In preferred embodiments, the antibodies (or antigen-binding fragments) of the present invention specifically bind to human CCR8 and at least one other mammalian (non-human) CCR8, for example, they specifically bind to human CCR8 and cynomolgus monkey CCR8, or they specifically bind to human CCR8 and murine CCR8. This species cross-reactivity is advantageous because it significantly facilitates the development of the corresponding antibodies (or antigen-binding fragments) into pharmaceutical products.

[0143] As described above, the antibody or antigen-binding fragment of the present invention is an antagonist of the CCL1-CCR8 signaling pathway, preferably an antagonist of CCL1-induced CCR8-Gi2 signaling.

[0144] In particular, it is preferred that the antibodies or antigen-binding fragments of the present invention are insurmountable antagonists of the CCL1-CCR8 signaling pathway. Even more preferably, the antibodies or antigen-binding fragments are insurmountable antagonists of CCL1-induced CCR8–Gi2 signaling. Such antibodies that function as insurmountable antagonists of the CCL1-CCR8 signaling pathway have been generated in the context of the present invention, as demonstrated in Example 14. Due to this insurmountable antagonist activity, the corresponding antibodies (and antigen-binding fragments) exert particularly potent, sustained, and uniform therapeutic effects, even in the presence of high concentrations of the endogenous ligand CCL1. Indeed, this insurmountability renders the corresponding antibodies and antigen-binding fragments resistant to various concentrations of the endogenous CCR8 ligand present in the tumor microenvironment and, therefore, less dependent on the type of cancer / tumor and the patient being treated. Insurmountable antagonist activity can be the result of either allosteric or orthosteric blockade. The insurmountable mAb antagonists provided according to the present invention have the ability to inhibit the maximal response of CCR8 to CCL1, regardless of the concentration of CCL1. Therefore, the antibodies of the present invention that are insurmountable antagonists of the CCL1-CCR8 signaling pathway allow for a wider range of pharmacological responses under various pathological conditions using different CCL1 concentrations. Due to the insurmountable nature of their antagonist activity, these mAbs are less dependent on CCL1 concentrations, which makes them particularly advantageous in therapeutic applications. This constitutes a new strategy for blocking Treg conversion and suppressive function, which does not compromise antagonistic mAb activity even in the presence of various CCL1 concentrations, and has the highest potential therapeutic benefit. Therefore, in a preferred embodiment, the antibodies (or antigen-binding fragments) of the present invention are insurmountable antagonists of the CCL1-CCR8 signaling pathway, which impart advantageously improved therapeutic efficacy.

[0145] When referring to an antagonist of a specific receptor or an antagonist of a specific receptor signaling pathway, the term "antagonist" as used herein refers to a substance / agent that binds to the corresponding receptor and inhibits, blocks, prevents, or reduces the corresponding biological response, i.e., a substance / agent that inhibits, blocks, prevents, or reduces signal transduction caused by the binding of a ligand to a receptor. For example, an "antagonist of the CCL1-CCR8 signaling pathway" refers to a substance / agent (e.g., an antibody or antigen-binding fragment thereof) that inhibits, blocks, prevents, or reduces (or in other words, is capable of inhibiting, blocking, preventing, or reducing) signal transduction caused by the binding of the ligand CCL1 to the receptor CCR8 (preferably the binding of human CCL1 to human CCR8).

[0146] The term "insurmountable antagonist" as used herein refers to an antagonist as defined above, whose action on the corresponding receptor inhibits / reduces the maximum response of the agonist (see, for example, Kenakin T, "A Pharmacology Primer", 5th edition, Academic Press (2018)). Therefore, even the addition of an excess of agonist / ligand (relative to the antagonist) cannot completely overcome the inhibitory / blocking effect of the antagonist on the receptor. In other words, an insurmountable antagonist reduces the intensity of the maximum response that can be elicited by the corresponding agonist / ligand (which can be determined, for example, by establishing a dose-response curve of agonist / ligand with different doses / concentrations). In principle, an insurmountable antagonist can bind to an allosteric site of the receptor (i.e., a binding site that is different from the active site of the receptor to which the ligand binds; in this case, the antagonist does not compete with the ligand for binding to the active site of the receptor), or alternatively, it can bind to the active site of the receptor; the present invention specifically and individually relates to each of these meanings.

[0147] The antagonist activity (or antagonistic effect) of the antibodies or antigen-binding fragments of the present invention on the CCL1-CCR8 signaling pathway can be determined using methods or assays known in the art or approaches based on these known methods or assays (see, for example, Liu L et al., Biochem Pharmacol, 2021, 188: 114565, doi: 10.1016 / j.bcp.2021.114565; or Avet C et al., Elife, 2022, 11:e74101, doi:10.7554 / eLife.74101; each of which is incorporated herein by reference. For example, the property that the antibody or antigen-binding fragment of the present invention is an antagonist of the CCL1-CCR8 signaling pathway can be determined by testing the ability of the antibody or antigen-binding fragment to inhibit, block, prevent or reduce the signal transduction caused by the binding of the ligand CCL1 (particularly human CCL1) to the receptor CCR8 (particularly human CCR8), preferably by testing the ability to inhibit, block, prevent or reduce the CCR8-G1 induced by CCL1. 2 signaling pathway. For example, any of the assays described in Example 14 can be used to determine whether an antibody or antigen-binding fragment is an antagonist of the CCL1-CCR8 signaling pathway. When the assay described in Example 14 (or any other assay or method, e.g., as described above) is used, if any level of inhibition, reduction, prevention, or blocking of CCL1-CCR8 signaling is observed, then the antibody or antigen-binding fragment can be confirmed to be an antagonist of the CCL1-CCR8 signaling pathway. However, preferably, the antibodies or antigen-binding fragments of the present invention provide for the inhibition, reduction, prevention, or blocking of CCL1-CCR8 signaling pathway. The present invention provides at least 10% inhibition of the CCL1-CCR8 signaling pathway (i.e., reducing CCL1-CCR8 signaling by at least 10% relative to the level of CCL1-CCR8 signaling in the absence of the antibody or antigen-binding fragment (a "positive control")), more preferably providing at least 20% inhibition of the CCL1-CCR8 signaling pathway, even more preferably at least 30% inhibition, even more preferably at least 40% inhibition, even more preferably at least 50% inhibition, even more preferably at least 60% inhibition, even more preferably at least 70% inhibition, even more preferably at least 80% inhibition, and even more preferably at least 90% inhibition. such percentage of inhibition can be determined using any of the above methods / assays, e.g., an assay as described in Example 14. In the case of an "unbeatable" antagonist of the CCL1-CCR8 signaling pathway, the inhibition (or reduction, prevention, or blocking) of the CCL1-CCR8 signaling pathway cannot be completely reversed by adding an excess (e.g., about 10-fold molar excess, preferably about 50-fold molar excess, more preferably about 100-fold molar excess, even more preferably about 180-fold molar excess, and even more preferably about 940-fold molar excess) of the ligand CCL1 relative to the antibody or antigen-binding fragment.The property / characteristic of an antibody or antigen-binding fragment being an insurmountable antagonist of the CCL1-CCR8 signaling pathway can be determined, for example, using any of the assays described in Example 14 (e.g., assays according to Protocols #1, #2, #3, or #4 described in Example 14).

[0148] As described above, the antibodies or antigen-binding fragments of the present invention are antagonists (preferably non-overcome antagonists) of the CCL1-CCR8 signaling pathway. In particular, it is preferred that the antibodies or antigen-binding fragments are antagonists (more preferably non-overcome antagonists) of CCL1-induced CCR8-Gi2 signaling. Therefore, it is particularly preferred that the antibodies or antigen-binding fragments of the present invention are non-overcome antagonists of CCL1-induced CCR8-Gi2 signaling.

[0149] The antagonistic effect of an antibody or antigen-binding fragment of the present invention on CCL1-induced CCR8-Gi2 signaling can be determined using methods or assays known in the art, or approaches based on these known methods or assays (including, for example, any of the assays / methods described above). For example, the property of an antibody or antigen-binding fragment of the present invention as an antagonist of CCL1-induced CCR8-Gi2 signaling can be determined by testing the antibody or antigen-binding fragment's ability to inhibit, block, prevent, or reduce CCR8-Gi2 signaling induced by binding of the ligand CCL1 (particularly human CCL1). For example, any of the assays described in Example 14 can be used to determine whether an antibody or antigen-binding fragment is an antagonist of CCL1-induced CCR8-Gi2 signaling. When using the assay described in Example 14 (or any other assay or method, e.g., as described above), if any level of inhibition, reduction, prevention, or blocking of CCL1-induced CCR8-Gi2 signaling is observed, the antibody or antigen-binding fragment can be confirmed to be an antagonist of CCL1-induced CCR8-Gi2 signaling. However, preferably, the antibodies or antigen-binding fragments of the invention provide at least 10% inhibition of CCL1-induced CCR8-Gi2 signaling (i.e., a reduction in signaling of at least 10% relative to the level of signaling in the absence of the antibody or antigen-binding fragment (a "positive control")), more preferably at least 20% inhibition of CCL1-induced CCR8-Gi2 signaling, even more preferably at least 30% inhibition, even more preferably at least 40% inhibition, even more preferably at least 50% inhibition, even more preferably at least 60% inhibition, even more preferably at least 70% inhibition, even more preferably at least 80% inhibition, and yet even more preferably at least 90% inhibition; such percentage inhibition can be determined using any of the above methods / assays, for example, as described in Example 14. In the case of an "unbeatable" antagonist of CCL1-induced CCR8-Gi2 signaling, inhibition (or reduction, prevention, or blocking) of the corresponding signaling pathway (i.e., CCL1-induced CCR8-Gi2 signaling) cannot be completely reversed by adding an excess (e.g., about 10-fold molar excess, preferably about 50-fold molar excess, more preferably about 100-fold molar excess, even more preferably about 180-fold molar excess, and even more preferably about 940-fold molar excess) of the ligand CCL1 relative to the antibody or antigen-binding fragment. Specifically, the property / characteristic of an antibody or antigen-binding fragment being an unbeatable antagonist of CCL1-induced CCR8-Gi2 signaling can be determined, for example, using any of the assays described in Example 14 (e.g., assays according to Protocols #1, #2, #3, or #4 described in Example 14).

[0150] Preferably, the antibody or antigen-binding fragment of the present invention inhibits the binding of CCL1 to CCR8 (preferably inhibits the binding of human CCL1 to human CCR8) with an IC 50 is about 20 nM or less (e.g., about 1 nM to about 20 nM), more preferably IC 50 is about 13 nM or lower, even more preferably IC 50 is about 10 nM or lower, and even more preferably IC 50 In particular, it is preferred that the antibody (or antigen-binding fragment) of the present invention inhibits the binding of hCCL1 to hCCR8 expressed on the cell surface (e.g., expressed on the cell surface of hCCR8-transfected CHO cells) with an IC of about 6 nM or less. 50 is about 20 nM or less (e.g., about 1 nM to about 20 nM), more preferably IC 50 is about 13 nM or lower, even more preferably IC 50 is about 10 nM or lower, and even more preferably IC 50 This inhibition can be determined, for example, using the assay described in Example 13.

[0151] In a preferred embodiment, the antibodies (or antigen-binding fragments) of the present invention comprise one or more CDRs (preferably all three heavy chain CDRs and / or all three light chain CDRs; more preferably all six CDRs) of any of the exemplary antibodies described in the Examples section below. Specifically, the antibodies (or antigen-binding fragments) of the present invention preferably comprise:

[0152] (A-1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence VARFYGISPYAMDY (SEQ ID NO: 12); and / or (preferably: and)

[0153] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0154] (A-2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and / or (preferably: and)

[0155] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); or

[0156] (A-3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and / or (preferably: and)

[0157] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); or

[0158] (A-4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence VARSSGSGPYAMDY (SEQ ID NO: 26); and / or (preferably: and)

[0159] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0160] (A-5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence VARSSGSGPYAMDY (SEQ ID NO: 26); and / or (preferably: and)

[0161] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0162] (A-6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and / or (preferably: and)

[0163] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31); or

[0164] (A-7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and / or (preferably: and)

[0165] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36); or

[0166] (A-8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and / or (preferably: and)

[0167] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36); or

[0168] (A-9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and / or (preferably: and)

[0169] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46); or

[0170] (A-10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence of HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence of SEVRRGYFDV (SEQ ID NO: 49); and / or (preferably: and)

[0171] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52); or

[0172] (A-11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and / or (preferably: and)

[0173] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76); or

[0174] (A-12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and / or (preferably: and)

[0175] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91); or

[0176] (A-13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence of INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence of ARVARSSGSGPYAMDY (SEQ ID NO: 94); and / or (preferably: and)

[0177] A light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence SQSTHVPYT (SEQ ID NO: 15).

[0178] The above CDR sequences (according to IMGT numbering) are also summarized in the following table:

[0179]

[0180]

[0181] As is known in the art, it is possible to deviate from the specific CDR sequences of the exemplary antibodies while still retaining the functionality and specific binding exhibited by the corresponding exemplary antibodies, for example, as in standard humanization protocols. Such variants having one or more amino acid substitutions / replacements in the CDRs and retaining the desired functional properties (e.g., as generally described herein for the antibodies of the invention) can be readily identified using conventional techniques known in the art.

[0182] Therefore, in other embodiments, the antibody (or antigen-binding fragment) of the present invention comprises a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 as defined in any one of options (A-1) to (A-13) above, wherein a single amino acid residue in each of these CDRs (preferably one, two or three of these CDRs; more preferably one or two of these CDRs; even more preferably only one of these CDRs) is optionally substituted with another amino acid residue (i.e., optionally replaced with a different amino acid residue). The resulting variant is an antibody (or antigen-binding fragment) of the present invention, i.e., a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway, wherein the antibody or antigen-binding fragment specifically binds to:

[0183] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0184] And further, wherein the antibody or antigen-binding fragment specifically binds to one or more of the following:

[0185] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0186] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0187] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0188] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0189] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0190] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0191] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0192] Thus, in this embodiment, the antibody (or antigen-binding fragment) of the present invention comprises a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 as defined in any one of options (A-1) to (A-13) above, wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally substituted (i.e., replaced) with a different amino acid residue; preferably Preferably, wherein in one, two or three CDRs selected from said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally substituted (i.e., replaced) with a different amino acid residue; more preferably, wherein in one or two CDRs selected from said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally substituted (i.e., replaced) with a different amino acid residue.

[0193] Preferably, any such single amino acid substitution is a conservative amino acid substitution (i.e., substitution / replacement with another amino acid having similar physicochemical properties to the original amino acid), more preferably a highly conservative amino acid substitution (i.e., substitution / replacement with another amino acid having highly similar physicochemical properties to the original amino acid). Therefore, when a single amino acid residue in any CDR is optionally substituted (i.e., replaced) with another amino acid residue, preferably, the following conservative amino acid substitution rules, more preferably the following highly conservative amino acid substitution rules, are used to select the other amino acid residue:

[0194] Conservative amino acid substitution rules

[0195]

[0196]

[0197] Highly conserved amino acid substitution rules

[0198]

[0199] In addition, in a preferred embodiment, the antibody (or antigen-binding fragment) of the present invention comprises a heavy chain variable domain (VH) and / or a light chain variable domain (VL), wherein the VH domain and the VL domain each have an amino acid sequence having at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity with the VH domain and VL domain of any one of the exemplary antibodies described in the Examples section below. Specifically, the antibody (or antigen-binding fragment) of the present invention preferably comprises:

[0200] (B-1) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSKVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVQQIHGKSPEWIGGINPNGDTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARFYGISPYAMDYWGQGTSVTVSS) (SEQ ID NO: 53); and / or (preferably: and)

[0201] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPYTFGGGTNLEIK (SEQ ID NO: 54); or

[0202] (B-2) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55); and / or (preferably: and)

[0203] a light chain variable domain (VL) having an amino acid sequence that is at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) identical to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTYVPPTFGGGTKLEIK (SEQ ID NO: 56); or

[0204] (B-3) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELLKPGTSVKISCTTSGYTFSDYTLHWVKQSHGKSLEWIGGITPKNGDTRYDPRFKDKATLTIDKSSSAAYMELRSLTSEDSAVYYCARVARFYGVSPYAMDYWGQGASVTVSS (SEQ ID NO: 57); and / or (preferably: and)

[0205] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSNSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLEITRVEAEDLGVYFCSQTTHVPYTFGGGTKLEIK (SEQ ID NO: 58); or

[0206] (B-4) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 59); and / or (preferably: and)

[0207] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60); or

[0208] (B-5) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGKSLEWVGGINPDNGNTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 61); and / or (preferably: and)

[0209] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60); or

[0210] (B-6) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55); and / or (preferably: and)

[0211] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MDFLVQIFSFLLISASVAMSRGENVLTQSPAIMSASPGEKVTMTCRASSSVSSSYLHWYQQKSGASPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQYSGYPYTFGGGTKLEIK (SEQ ID NO: 62); or

[0212] (B-7) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYRVSWIRQPPGKGLEWLGVIWGGRSTYYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCAKQGDGYYALDYWGQGTSVTVSS (SEQ ID NO: 63); and / or (preferably: and)

[0213] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSYGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFHGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 64); or

[0214] (B-8) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVSWIRQPPGKGPEWLGVIWGGGNTYYNSVLKSRLSISNDNSKSQVFLRMNSLQTADTAIYYCARPRRDYYALDYWGQGTSVTVAS (SEQ ID NO: 65); and / or (preferably: and)

[0215] a light chain variable domain (VL) having an amino acid sequence that is at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) identical to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYTNGNTFLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 66); or

[0216] (B-9) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MGWSSIILFLVATASGVHSQVQLQQPGSELVRPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGNIWPGSASTNYDEKFKNKATLTVDTSSSTAYMQLSSLTSEDSAVYYCIRGGKGAMDYWSQGTSVTVSS (SEQ ID NO: 67); and / or (preferably: and)

[0217] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQIPLSLPVSLGDQASISCRSSQSLENSYGNTYLNWYLQKPGQSPQLLIYRVSNRFSGVLDRFSGSGSGTDFTLKISRVEAEDLGVYFCLQVTHVPPTFGAGTKLELK (SEQ ID NO: 68); or

[0218] (B-10) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MERHWIFLLLLSVTAGVHSQVQVQQSGAELARPGASVKMSCKASGYTFTTYAMHWVKQRPGQGLEWIGHINPSSGYSNYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSEVRRGYFDVWGAGTTVTVSS (SEQ ID NO: 69); and / or (preferably: and)

[0219] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCRTSQDIRNYLNWYQQKPDGTVKLLISYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPPTFGGGTRVEIK (SEQ ID NO: 70); or

[0220] (B-11) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKASVYSFTGSYMHWVKQSHVKSLEWIGRINPYNGATSYNQNFKDKASLTVDKSSSTAYMELHSLTSEDSAVYYCATTLLRLLDYWGQGTTLTVSS (SEQ ID NO: 77); and / or (preferably: and)

[0221] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of MRFSAQLLGLLVLWIPGSTADIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPWTFGGGTKLEIK (SEQ ID NO: 78); or

[0222] (B-12) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSS (SEQ ID NO: 96); and / or (preferably: and)

[0223] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIK (SEQ ID NO: 97); or

[0224] (B-13) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS) (SEQ ID NO: 98); and / or (preferably: and)

[0225] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99); or

[0226] (B-14) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS) (SEQ ID NO: 100); and / or (preferably: and)

[0227] a light chain variable domain (VL) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99); or

[0228] (B-15) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) sequence identity to the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 101); and / or (preferably: and)

[0229] A light chain variable domain (VL) having an amino acid sequence that is at least 80% (more preferably at least 85%, even more preferably at least 90%, even more preferably at least 92%, even more preferably at least 95%, yet even more preferably at least 97%, yet more preferably 100%) identical to the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 102).

[0230] For each of the above options (B-1) to (B-15), the VH domain and the VL domain are each defined by a percentage of sequence identity with a reference sequence, and in each case, the percentage of sequence identity is indicated with a preferred value (lower endpoint). Although in principle the sequence identity of any particular domain can be selected independently of the sequence identity of any other domain, it is generally preferred to select the same percentage value (lower endpoint) for the sequence identity of the VH domain and the sequence identity of the VL domain of the same antibody (or antigen-binding fragment). Thus, for example, if in option (B-1) the VH domain is selected to have an amino acid sequence that has "at least 90%" sequence identity with SEQ ID NO: 53, then it is preferred to select the same percentage of sequence identity for the VL domain, i.e., to select the VL domain to have an amino acid sequence that has "at least 90%" sequence identity with SEQ ID NO: 54. This applies similarly to the percentage of sequence identity for any other VH and VL domain pairs disclosed herein.

[0231] The above VH and VL domain sequences are also summarized in the table below:

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] In a particularly preferred embodiment, the antibody (or antigen-binding fragment) of the present invention comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), both of which are cumulatively defined as: (i) the above options (A-1) and (B-1); or (ii) the above options (A-2) and (B-2); or (iii) the above options (A-3) and (B-3); or (iv) the above options (A-4) and (B-4); or (v) the above options (A-5) and (B-5); or (vi) the above options (A-6) and (B-6); or (vii) the above options (A-7) and (B-7); or (viii) options (A-8) and (B-8) above; or (ix) options (A-9) and (B-9) above; or (x) options (A-10) and (B-10) above; or (xi) options (A-11) and (B-11) above; or (xii) options (A-12) and (B-12) above; or (xiii) options (A-13) and (B-13) above; or (xiv) options (A-13) and (B-14) above; or (xv) options (A-13) and (B-15) above.

[0238] In a preferred embodiment, the antibody (or antigen-binding fragment) of the present invention comprises a heavy chain (HC) and / or a light chain (LC), wherein the HC and the LC each have an amino acid sequence that has at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity with the HC and LC, respectively, of any of the exemplary antibodies described in the Examples section below. Specifically, the antibody (or antigen-binding fragment) of the present invention preferably comprises:

[0239] (C-1) Heavy chain (HC) having the same amino acid sequence as EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCV RGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 103) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0240] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 104); or

[0241] (C-2) Heavy chain (HC) having the same amino acid sequence as EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCV RGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 105) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0242] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 104); or

[0243] (C-3) Heavy chain (HC) having the same amino acid sequence as QVQLVQSGPVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCAR VARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 106) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0244] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 107); or

[0245] (C-4) Heavy chain (HC) having the same amino acid sequence as QVQLQQSGPVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCAR VARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 108) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0246] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 107); or

[0247] (C-5) Heavy chain (HC) having the same amino acid sequence as EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCAR VARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 109) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0248] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 110); or

[0249] (C-6) Heavy chain (HC) having the same amino acid sequence as EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCAR VARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 111) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0250] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 110); or

[0251] (C-7) Heavy chain (HC) having the same amino acid sequence as EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCAR VARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 112)) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0252] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 110); or

[0253] (C-8) Heavy chain (HC) having the same amino acid sequence as EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCAR VARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 113) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0254] a light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) (SEQ ID NO: 110); or

[0255] (C-9) Heavy chain (HC) having the same amino acid sequence as EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCAR VARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNWALPAPISKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 114) having an amino acid sequence of at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) sequence identity; and / or (preferably: and)

[0256] A light chain (LC) having an amino acid sequence that is at least 90% (more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, yet even more preferably at least 99%, yet more preferably 100%) identical to the amino acid sequence of DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 110).

[0257] For each of the above options (C-1) to (C-9), the heavy chain and light chain are each defined by a percentage of sequence identity with a reference sequence, and in each case, the percentage of sequence identity is indicated with a preferred value (lower endpoint). Although in principle the sequence identity of any chain can be selected independently of the sequence identity of the corresponding other chain, it is generally preferred to select the same percentage value (lower endpoint) for the sequence identity of the heavy chain and the sequence identity of the light chain of the same antibody (or antigen-binding fragment). Thus, for example, if in option (C-2) the heavy chain domain is selected to have an amino acid sequence having "at least 99%" sequence identity with SEQ ID NO: 105, it is preferred to select the same percentage of sequence identity for the light chain, i.e., the light chain is selected to have an amino acid sequence having "at least 99%" sequence identity with SEQ ID NO: 104. This applies similarly to the percentage of sequence identity for any other heavy and light chain sequence pairs disclosed herein.

[0258] The above heavy chain (HC) and light chain (LC) sequences are also summarized in the table below:

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In a particularly preferred embodiment, the antibody (or antigen-binding fragment) of the present invention comprises a heavy chain and a light chain, both of which are cumulatively defined as: (i) the above option (A-12) and (C-1); or (ii) the above option (A-12) and (C-2); or (iii) the above option (A-13) and (C-3); or (iv) the above option (A-13) and (C-4); or (v) the above option (A-13) and (C-5); or (vi) the above option (A-13) and (C-6); or (vii) the above option (A-13) and (C-7); or (viii) the above option (A-13) and (C-8); or (ix) the above option (A-13) and (C-9).

[0266] In other embodiments, the antibody (or antigen-binding fragment) of the invention is as defined in any one of options (C-1) to (C-9) above, but the corresponding heavy chain (HC) sequence additionally has a C-terminal lysine residue, i.e., the glycine (G) at the C-terminus of the corresponding HC sequence is replaced by glycine-lysine (GK).

[0267] The present invention specifically relates to a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and has the CDRs defined in any one of options (A-1) to (A-13) above. Furthermore, the present invention also relates to a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and has a heavy chain variable domain (VH) and a light chain variable domain (VL) defined in any one of options (B-1) to (B-15) above. The present invention also relates to a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human CCR8 and has a heavy chain (HC) and a light chain (LC) defined in any one of options (C-1) to (C-9) above.

[0268] In other embodiments, the antibodies (or antigen-binding fragments) of the present invention bind to the same epitope in human CCR8 as any of the specific antibodies described in the Examples section below. Specifically, the antibodies (or antigen-binding fragments) of the present invention may bind to the same epitope in human CCR8 as the antibodies (or antigen-binding fragments) comprising:

[0269] (D-1) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 53, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 54; or

[0270] (D-2) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 55, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 56; or

[0271] (D-3) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 57, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 58; or

[0272] (D-4) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 59, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 60; or

[0273] (D-5) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 61, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 60; or

[0274] (D-6) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 55, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 62; or

[0275] (D-7) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 63, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 64; or

[0276] (D-8) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 65, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 66; or

[0277] (D-9) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 67, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 68; or

[0278] (D-10) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 69, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 70; or

[0279] (D-11) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 77, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 78; or

[0280] (D-12) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 96, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 97; or

[0281] (D-13) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 98, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 99; or

[0282] (D-14) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 100, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 99; or

[0283] (D-15) a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 101, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 102.

[0284] The specific epitope to which any of the antibodies (or antigen-binding fragments) mentioned above (D-1) to (D-15) bind can be identified by any suitable epitope mapping method known in the art (see, for example, Morris GE (ed.), "Epitopemapping protocols", Methods in Molecular Biology, Vol. 66, 1996, Humana Press, doi: 10.1385 / 0896033759; or Opuni KFM et al., Mass Spectrom Rev, 2018, 37(2): 229-241, doi: 10.1002 / mas.21516; which are incorporated herein by reference). For example, peptides of different lengths derived from human CCR8 can be screened for binding to the antibody to identify the smallest peptide that can specifically bind to the antibody. The corresponding peptide that specifically binds to the antibody can be identified by, for example, mass spectrometry. Alternatively, NMR spectroscopy or X-ray crystallography can be used to identify the epitope bound by the antibody. Once identified, fragments of an epitope that binds to an antibody of the invention can be used as immunogens to obtain other antibodies that specifically bind to the same epitope.

[0285] The antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein, for example, the antibody of any one of options (A-1) to (A-13) above or any one of options (B-1) to (B-15) above) preferably comprise an Fc region, more preferably a human IgG Fc region (for example, an Fc region of human IgG1, IgG2, IgG3 or IgG4), even more preferably a human IgG1 or IgG4 Fc region, and still even more preferably a human IgG1 Fc region.

[0286] The term "Fc region" is well known in the art and generally refers to the C-terminal region of an immunoglobulin heavy chain, which contains at least a portion of a constant region (and which can interact with Fc receptors). In human IgG, IgA or IgD class antibodies, the Fc region is generally composed of two identical polypeptide chains, each of which includes the second and third constant domains of the two heavy chains of the antibody. In human IgM or IgE class antibodies, the Fc region is generally composed of two identical polypeptide chains, each of which includes the second, third and fourth heavy chain constant domains of the corresponding antibody. The term "Fc region" includes native sequence Fc regions and variant Fc regions. As described above, the "Fc region" is preferably a human IgG Fc region (e.g., a human IgG1 Fc region), which can extend from the Cys-226 residue (or from the Pro-230 residue) to the C-terminus of each heavy chain. Unless otherwise indicated, the numbering of amino acid residues in the Fc region is indicated herein according to the EU numbering system (also called the EU index; see, e.g., Kabat EA et al., "Sequences of proteins of immunological interest", Fifth Edition, 1991, U.S. Department of Health and Human Services, National Institutes of Health (NIH), Publication No. 91-3242).

[0287] It is noteworthy that the C-terminal lysine residue (Lys-447) of the Fc region of human IgG (e.g., IgG1) may or may not be present. Cleavage of the C-terminal lysine from the Fc region of an antibody is well known in the art (see, e.g., Harris RJ, J Chromatogr A, 1995, 705(1):129-34, doi:10.1016 / 0021-9673(94)01255-d; Dick LW Jr, Biotechnol Bioeng, 2008, 100(6):1132-43, doi:10.1002 / bit.21855; Liu H et al., Biotechnol Prog, 2016, 32(5):1103-12, doi:10.1002 / btpr.2327; or Faid V et al., Eur J Pharm Sci, 2021, 159: 105730, doi: 10.1016 / j.ejps.2021.105730) and the extent to which this may occur may be greater or lesser (or not occur at all), depending on how the corresponding antibody is produced. For example, when IgG antibodies are recombinantly produced in CHO cells, endogenous carboxypeptidases from the CHO cells can cleave the terminal lysine residue from the C-terminus of the heavy chain of the IgG antibody, which can result in the production of a heterogeneous antibody population, including antibodies with one C-terminal lysine residue on each of the two heavy chains, antibodies with only one C-terminal lysine residue (i.e., only on one of the two heavy chains), and antibodies without any C-terminal lysine residue on either heavy chain. As is known in the art, the production of a homogeneous antibody population with or without a C-terminal lysine residue can be achieved, for example, by appropriately adjusting the antibody production process. The present invention particularly relates to an antibody (or antigen-binding fragment) as described herein having an Fc region (particularly a human IgG Fc region, such as a human IgG1 Fc region) containing a C-terminal lysine residue. However, the present invention also particularly relates to an antibody (or antigen-binding fragment) as described herein having an Fc region lacking a C-terminal lysine residue, particularly an Fc region (particularly a human IgG Fc region, such as a human IgG1 Fc region) that does not contain any C-terminal lysine residue. In addition, the present invention further relates to an antibody (or antigen-binding fragment) as described herein having an Fc region (particularly a human IgG Fc region, such as a human IgG1 Fc region) lacking a C-terminal glycine-lysine residue (i.e., residues 446 and 447 according to the EU index), particularly an Fc region that does not have any C-terminal glycine-lysine residue.

[0288] Preferably, the antibody or antigen-binding fragment (including any of the exemplary or preferred antibodies described herein, for example, an antibody according to any one of options (A-1) to (A-13) above or any one of options (B-1) to (B-15) above) has antibody-dependent cellular cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and / or antibody-dependent cellular phagocytosis (ADCP) activity. More preferably, the antibody or antigen-binding fragment has ADCC activity and / or ADCP activity, even more preferably ADCC activity.

[0289] As is known in the art, the core fucosylation level of the Fc region of an antibody (or antigen-binding fragment) affects its binding to Fcγ receptors (FcγR), particularly FcγRIIIa, on effector cells, and thereby affects its ADCC activity and / or its ADCP activity. Specifically, it has been reported that antibodies with reduced core fucose levels or completely afucosylated antibodies (which do not have any fucose units) exhibit significantly increased ADCC activity by increasing the affinity of the (IgG) Fc region to FcγRIIIa on immune cells (see, e.g., Okazaki A et al., J Mol Biol, 2004, 336(5):1239-49, doi:10.1016 / j.jmb.2004.01.007; Jiang XR et al., Nat Rev Drug Discov, 2011, 10(2):101-11, doi:10.1038 / nrd3365; WO 03 / 035835; or EP 1 469 065 A1), and that reduction or absence of core fucose also promotes ADCP activity mediated by FcγRIIIa-positive monocytes and macrophages (see, e.g., Golay et al., J Mol Biol, 2004, 336(5):1239-49, doi:10.1016 / j.jmb.2004.01.007; Jiang XR et al., Nat Rev Drug Discov, 2011, 10(2):101-11, doi:10.1038 / nrd3365; WO 03 / 035835; or EP 1 469 065 A1). J et al., Blood, 2013, 122(20):3482-91, doi:10.1182 / blood-2013-05-504043; or Herter et al., J Immunol, 2014, 192(5):2252-60, doi:10.4049 / jimmunol.1301249).

[0290] Therefore, it is preferred that the antibody or antigen-binding fragment of the present invention (including any of the exemplary or preferred antibodies described herein, for example, an antibody according to any of the above options (A-1) to (A-13), any of the above options (B-1) to (B-15), or any of the above options (C-1) to (C-9)) comprises an Fc region with reduced core fucose levels or no core fucose units at all. It is particularly preferred that the antibody (or antigen-binding fragment) of the present invention comprises a hypofucosylated or afucosylated Fc region (particularly afucosylated human IgG Fc region, more preferably afucosylated human IgG1 or IgG4 Fc region, even more preferably afucosylated human IgG1 Fc region). Such hypofucosylated or afucosylated antibodies (or antigen-binding fragments) exhibit increased ADCC, CDC, and / or ADCP activity and are therefore particularly effective in depleting tumor-infiltrating regulatory T cells expressing CCR8 (CCR8-positive).

[0291] As is known in the art, antibodies with an Fc region lacking core fucose or with a greatly reduced level of core fucose (e.g., a human IgG Fc region, such as IgG1 or IgG4) can be produced by glycoengineering techniques. For example, low-fucosylated or afucosylated antibody can be obtained by using a production cell line that overexpresses N-acetylglucosaminyltransferase III (GnTIII) in the Golgi apparatus (or, ideally, overexpresses both GnTIII and Golgi α-mannosidase II (αManII)), which results in the generation of bisected oligosaccharide structures at the Fc region of the antibody and inhibits fucosylation (see, e.g., Ferrara C et al., Biotechnol Bioeng, 2006, 93(5):851-61, doi:10.1002 / bit.20777). Alternatively, afucosylated antibodies can be obtained, for example, using a fucosyltransferase-deficient production cell line (e.g., a fucosyltransferase-deficient CHO cell line); such a fucosyltransferase-deficient cell line can be generated, for example, by silencing the expression of α-1,6-fucosyltransferase (FUT8) or by disrupting two FUT8 alleles by homologous recombination (see, e.g., Mori K et al., Biotechnol Bioeng, 2004, 88(7):901-8, doi:10.1002 / bit.20326; or Yamane-Ohnuki N et al., Biotechnol Bioeng, 2004, 87(5):614-22, doi:10.1002 / bit.20151). In addition, cell lines in which the Golgi GDP-fucose transporter gene (Slc35c1) has been inactivated to eliminate fucosylation reactions in the Golgi apparatus can also be used to produce afucosylated antibodies (see, for example, Chan KF et al., Biotechnol J, 2016, 11(3):399-414, doi:10.1002 / biot.201500331). As another alternative, fucosylation inhibitors, such as 2-fluorofucose or 5-alkynylfucose (particularly 2-deoxy-2-fluoro-L-fucose), can also be used during recombinant expression to generate afucosylated antibodies (see, for example, Okeley NM et al., Proc Natl Acad Sci USA, 2013, 110(14):5404-9, doi:10.1073 / pnas.1222263110).In addition to the above techniques, other methods for producing afucosylated antibodies (or antigen-binding fragments) are described in the literature (see, for example, Yamane-Ohnuki N et al., MAbs, 2009, 1(3):230-6, doi:10.4161 / mabs.1.3.8328; Yu X et al., BioDrugs, 2017, 31(3):151-166, doi:10.1007 / s40259-017-0223-8; or Pereira NA et al., MAbs, 2018, 10(5):693-711, doi:10.1080 / 19420862.2018.1466767). Therefore, the present invention relates to the use of a hypofucosylated or afucosylated production cell line (i.e., a host cell for hypofucosylation or afucosylation) to produce the antibody or antigen-binding fragment of the present invention, such as, for example, (i) a production cell line (or host cell) that overexpresses N-acetylglucosaminyltransferase III (GnTIII) in the Golgi apparatus (preferably, a production cell line (or host cell) that overexpresses N-acetylglucosaminyltransferase III (GnTIII) and Golgi α-mannosidase II (αManII) in the Golgi apparatus); (ii) a production cell line (or host cell) that overexpresses fucose (iii) a producer cell line (or host cell) in which the GDP-fucose transporter gene (Slc35c1) is inactivated; or (iv) a producer cell line (or host cell) exposed to (or incubated with) one or more fucosylation inhibitors (e.g., 2-fluorofucose or 5-alkynylfucose, in particular 2-deoxy-2-fluoro-L-fucose); the present invention also relates to antibodies or antigen-binding fragments obtainable (or obtained) by using such producer cell lines (or host cells).

[0292] In addition, it is preferred that the antibody or antigen-binding fragment of the present invention (including any of the exemplary or preferred antibodies described herein, for example, an antibody according to any one of the above options (A-1) to (A-13) or any one of the above options (B-1) to (B-15)) comprises an Fc region (for example, as described above) having one or more mutations that enhance ADCC activity, CDC activity, and / or ADCP activity. These mutations have been described in the literature (see, for example, Wang X et al., Protein Cell, 2018, 9(1):63-73, doi:10.1007 / s13238-017-0473-8; Chiu ML et al., Antibodies (Basel), 2019, 8(4):55, doi:10.3390 / antib8040055;or Liu R et al., Antibodies (Basel), 2020, 9(4):64, doi:10.3390 / antib9040064). For example, an antibody (or antigen-binding fragment) comprising a human IgG Fc region having one or more (preferably two or more, three or more, four or more, five or more, six or more, seven or more, or even all) mutations selected from the following mutations: S132I, L142P, A162V, S166N, S219Y, K222N, H224L, T225S, P227S, P232S, E233D (or E233G), L235V, G236A, S239D, V240I, F241L, F243L (or F243I), K246T (or K246I), P2 47H (or P247L), K248M, L251F, R255L (or R255Q), E258D (or E258G), H268D, D270E, F275Y, V279L, V281M, V282M, V284A, G285E, K288N (or K288M), K290E (or K290T), P291S, R292P (or R292L or R292G), S298A (or S298N), Y300L, S304G, V305I, E308D, N315I, K317N, E318K (or E318D )、Y319F、K320E、K326E(or K326N or K326W)、A330L(or A330S)、I332E、E333A(or E333S)、K334A(or K334E or K334N or K334I)、A339V、Q347H、M352L、P353Q、T359N、T366S(or T366N)、K370N、G371D、F372Y(or F372L)、S375C、I377F(or I377N)、V379L(or V379M)、E380D、W381R、N384K、 G385E, E389G, K392R, T394M, P395S, P396L (or P396H), V397M, L398V (or L398Q), S400P, D401V, S407I (or S407R), K409R, K414N, S415I, N421K and S440N, in particular L235V, G236A, S239D, F243L, R292P, S298A, Y300L, V305I, A330L, I332E, E333A, K334A, I332E and P396L (numbered according to the EU index;Including, for example, combinations S239D / I332E, S239D / A330L / I332E, G236A / S239D / I332E, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L, L235V / F243L / R292P / Y300L / P396L, L235 V / F243L / R292P / Y300L / K326W / E333S / P396L, S239D / F243L / R292P / Y300L / V305I / A330L / I332E / P396L or S298A / E333A / K334A); these mutations result in enhanced interaction with human FcγRIIIa, thereby leading to enhanced ADCC activity and / or ADCP activity (see, e.g., Lazar et al., GA et al., Proc Natl Acad Sci USA, 2006, 103(11):4005-10, doi:10.1073 / pnas.0508123103; Stavenhagen JB et al., Cancer Res, 2007, 67(18):8882-90, doi:10.1158 / 0008-5472.CAN-07-0696; or WO 2004 / 063351). Antibodies (or antigen-binding fragments) comprising a human IgG1 Fc region having one or more mutations (including any combination of mutations) disclosed in WO 2004 / 063351, in particular Table 2, 3 or 4 of WO 2004 / 063351 (which are incorporated herein by reference in their entirety) can also be used. In addition, antibodies (or antigen-binding fragments) comprising a human IgG1 Fc region having one or more (preferably two or more, three or more, four or more, or even all) mutations selected from S267E, H268F, S324T, K326A (or K326W), E333A and E345R (numbered according to the EU index; including, for example, the combination K326A / E333A, K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T, E345R or S267E / H268F / S324T) can be used; such mutations result in enhanced CDC activity. Particularly preferably, the antibody (or antigen-binding fragment) of the present invention comprises a human IgG1 Fc region having any of the following mutations: (i) S239D / I332E; (ii) S239D / A330L / I332E; (iii) L235V / F243L / R292P / Y300L / P396L;or (iv) L235V / F243L / R292P / Y300L / K326W / E333S / P396L (numbering according to the EU index). Even more preferably, the antibody (or antigen-binding fragment) of the invention comprises a human IgG1 Fc region having S239D / I332E mutations (numbering according to the EU index). ;

[0293] Preferably, the antibody or antigen-binding fragment of the present invention (including any of the exemplary or preferred antibodies described herein, for example, the antibody according to any of the above options (A-1) to (A-13) or any of the above options (B-1) to (B-15)) has depleting activity against CCR8-positive immune cells.

[0294] Furthermore, it is preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein, such as antibodies according to any of the above options (A-1) to (A-13) or any of the above options (B-1) to (B-15)) have one or more (preferably all) of the following cellular activities:

[0295] - depletion of CCR8-positive cells (preferably CCR8-positive T cells and / or CCR8-positive macrophages, more preferably CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells); even more preferably CCR8-positive regulatory T cells; still more preferably CCR8-positive tumor-infiltrating regulatory T cells);

[0296] - inhibiting CCL1-induced migration of CCR8-positive cells (preferably CCR8-positive T cells and / or CCR8-positive macrophages, more preferably CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells); even more preferably CCR8-positive regulatory T cells); and / or

[0297] - Inhibiting CCL1-induced activation of CCR8-positive cells (preferably CCR8-positive T cells and / or CCR8-positive macrophages, more preferably CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells); even more preferably CCR8-positive regulatory T cells).

[0298] These cellular activities can be assessed using any suitable assay, for example, as described in the Examples herein below and / or in the literature.

[0299] Therefore, it is preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein) have the activity of depleting CCR8-positive cells (i.e., depleting CCR8-positive cells), preferably the activity of depleting CCR8-positive T cells and / or CCR8-positive macrophages, more preferably the activity of depleting CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells), and even more preferably the activity of depleting CCR8-positive regulatory T cells (particularly CCR8-positive tumor-infiltrating regulatory T cells).

[0300] In addition, it is preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein) have the activity of inhibiting CCL1-induced CCR8-positive cell migration (i.e., inhibiting CCL1-induced migration of CCR8-positive cells), preferably the activity of inhibiting CCL1-induced migration of CCR8-positive T cells and / or CCR8-positive macrophages, more preferably the activity of inhibiting CCL1-induced migration of CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells), and even more preferably the activity of inhibiting CCL1-induced migration of CCR8-positive regulatory T cells.

[0301] In addition, it is preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein) have the activity of inhibiting CCL1-induced activation of CCR8-positive cells (i.e., inhibiting CCL1-induced activation of CCR8-positive cells), preferably the activity of inhibiting CCL1-induced activation of CCR8-positive T cells and / or CCR8-positive macrophages, more preferably the activity of inhibiting CCL1-induced activation of CCR8-positive regulatory T cells and / or CCR8-positive natural killer T cells (NKT cells), and even more preferably the activity of inhibiting CCL1-induced activation of CCR8-positive regulatory T cells.

[0302] It is also preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein) have the activity of inhibiting CCL1-induced CCR8 internalization.

[0303] Furthermore, it is preferred that the antibodies or antigen-binding fragments of the present invention (including any of the exemplary or preferred antibodies described herein, for example, antibodies according to any of the above options (A-1) to (A-13) or any of the above options (B-1) to (B-15)) have depletion activity against CCR8-positive cancer cells. Preferably, the CCR8-positive cancer cells are from lymphoma, more preferably from cutaneous T-cell lymphoma, and even more preferably from Sézary syndrome.

[0304] Furthermore, it is preferred that the antibodies or antigen-binding fragments of the invention do not bind to peripheral immune cells from healthy donors. In particular, it is preferred that the antibodies or antigen-binding fragments do not bind to peripheral immune cells extracted from PBMCs from healthy donors. This can be assessed by flow cytometry, for example, using the protocol described in Example 12.

[0305] The present invention also relates to the antibodies or antigen-binding fragments provided herein (including any of the exemplary or preferred antibodies or antigen-binding fragments described herein, e.g., those according to any of options (A-1) to (A-13) above or any of options (B-1) to (B-15) above), wherein the antibody or antigen-binding fragment is incorporated into a chimeric antigen receptor (CAR).Chimeric antigen receptors (CARs) generally combine antigen binding and immune cell (e.g., T cell or NK cell) activation functions into a single receptor and can be used for CAR cell therapy (particularly for CAR T cell therapy, including CAR α-β-T cell therapy or CAR γ-δ-T cell therapy, or for CAR NK cell therapy); see, e.g., Yong CSM et al., Immunol Cell Biol, 2017, 95(4):356-63, doi:10.1038 / Icb.2016.128; Newick K et al., Annu Rev Med, 2017, 68:139-52, doi:10.1146 / annurev-med-062315-120245; Miliotou AN et al., Curr Pharm Biotechnol, 2018, 19(1): 5-18, doi: 10.2174 / 1389201019666180418095526; Martinez M et al., Front Immunol, 2019, 10: 128, doi: 10.3389 / fimmu.2019.00128; Ahmad A, Int J Mol Sci, 2020, 21(12): 4303, doi: 10.3390 / ijms21124303; Hong M et al., Cancer Cell, 2020, 38(4): 473-88, doi: 10.1016 / j.ccell.2020.07.005; Xie G et al. al., EBioMedicine, 2020, 59: 102975, doi: 10.1016 / j.ebiom.2020.102975; Khawar MB et al., Front Immunol, 2021, 12: 707542, doi: 10.3389 / fimmu.2021.707542; Qin VM et al., Cancers (Basel), 2021, 13(3): 404, doi: 10.3390 / cancers13030404; Saura-Esteller J et al., Front Immunol, 2022, 13: 915837, doi: 10.3389 / fimmu.2022.915837; or Zhang L et al., Biomark Res, 2022, 10(1):12, doi:10.1186 / s40364-022-00364-6 (each of which is incorporated herein by reference).CARs typically consist of four regions, namely, (i) an antigen recognition domain (which can be, for example, a single-chain variable fragment (scFv) or a single-domain antibody), (ii) an extracellular hinge region, (iii) a transmembrane domain, and (iv) an intracellular immune cell signaling domain. The intracellular immune cell signaling domain is preferably an intracellular T cell signaling domain (particularly an intracellular α-β T cell signaling domain; for example, a CD3-ζ cytoplasmic domain, which can be combined with one or more costimulatory domains, for example, a costimulatory domain derived from CD28, 4-1BB, CD27, OX40, ICOS, or any combination thereof), an intracellular γ-δ-T cell signaling domain (for example, a CD3-ζ cytoplasmic domain, which can be combined with one or more costimulatory domains, for example, a costimulatory domain derived from CD28, 4-1BB, CD27, OX40, ICOS, or any combination thereof), or an intracellular natural killer cell (NK cell) signaling domain (for example, a CD3-ζ cytoplasmic domain, a DAP10 cytoplasmic domain, and / or a DAP12 cytoplasmic domain, any of which can be combined with one or more costimulatory domains, for example, a costimulatory domain derived from CD28, 4-1BB, 2B4, CD27, OX40, ICOS, or any combination thereof). Therefore, the present invention also provides a chimeric antigen receptor (CAR) comprising an antibody or antigen-binding fragment of the present invention. In particular, the present invention provides a chimeric antigen receptor (CAR), which includes the following parts (or preferably consists of the following parts) (preferably in this order): antigen recognition domain, it is an antibody of the present invention or antigen-binding fragment (for example, single-chain variable fragment (scFv) or single-domain antibody, preferably according to any one of the above options (A-1) to (A-13) or the above options (B-1) to (B-15)) defined in a single-chain variable fragment); Extracellular hinge region; Transmembrane domain; With intracellular signaling domain (particularly T cell or NK cell signaling domain; For example, CD3-ζ cytoplasmic domain, preferably CD3-ζ cytoplasmic domain combined with one or more costimulatory domains, such as CD28, 41BB, CD27, OX40, ICOS or its any combination). The present invention also relates to immune cells (e.g., T cells (including, for example, α-β-T cells or γ-δ-T cells) or natural killer (NK) cells, preferably T cells) expressing a chimeric antigen receptor (CAR) according to the present invention. Such cells can be produced as follows: for example, by obtaining immune cells (e.g., T cells or NK cells) from the blood of a subject / patient to be treated or from the blood of a healthy donor (which should belong to the same species as the subject / patient to be treated, and is preferably a human), and by modifying the immune cells to express a CAR according to the present invention.The present invention also relates to the therapeutic application of such CAR and immune cells (particularly T cells or NK cells) expressing such CAR, in particular their use in treating cancer. Therefore, the present invention relates to the same therapeutic use as described herein and the same treatment methods associated with the antibody or antigen-binding fragment of the present invention, wherein the use or the method include administering immune cells (preferably T cells (for example, α-β-T cells or γ-δ-T cells) or NK cells) expressing the chimeric antigen receptor (CAR) of the present invention (rather than administering antibodies or antigen-binding fragments of the present invention).

[0306] The present invention also relates to antibodies or antigen-binding fragments provided herein (including any of the exemplary or preferred antibodies or antigen-binding fragments described herein, such as those according to any one of the above options (A-1) to (A-13), any one of the above options (B-1) to (B-15), or any one of the above options (C-1) to (C-9)), wherein the antibody or antigen-binding fragment is incorporated into an antibody-drug conjugate (ADC). Accordingly, the present invention provides an antibody-drug conjugate comprising (preferably consisting of) an antibody or antigen-binding fragment of the present invention, a linker, and a drug. The preparation of antibody-drug conjugates is well known in the art and has been described, for example, in: Casi G et al., J Control Release, 2012, 161(2):422-8, doi:10.1016 / j.jconrel.2012.01.026; Zolot RS et al., Nat Rev Drug Discov, 2013, 12(4):259-60, doi:10.1038 / nrd3980; Perez HL et al., Drug Discov Today, 2014, 19(7):869-81, doi:10.1016 / j.drudis.2013.11.004; Thomas A et al., Lancet Oncol, 2016, 17(6):e254-e262, doi:10.1016 / S1470-2045(16)30030-4; Beck A et al., Nat Rev Drug Discov, 2017, 16(5):315-337, doi:10.1038 / nrd.2016.268; Chau CH et al., Lancet, 2019, 394(10200):793-804, doi:10.1016 / S0140-6736(19)31774-X; Joubert N et al., Pharmaceuticals (Basel), 2020, 13(9):245, doi:10.3390 / pH13090245; Khonozul P et al., Mol Cancer Res, 2020, 18(1): 3-19, DOI: 10.1158 / 1541-7786.MCR-19-0582; Baah S et al., Molecules, 2021, 26(10): 2943, doi: 10.3390 / molecules26102943; or Drago JZ et al., Nat Rev Clin Oncol, 2021, 18(6): 327-344, doi: 10.1038 / s41571-021-00470-8 (all of which are incorporated herein by reference in their entirety).The drug contained in the antibody-drug conjugate of the present invention is preferably an anticancer drug (e.g., any anticancer drug described herein, particularly as described in the context of combined therapy), more preferably a cytotoxic drug (or cytotoxic anticancer drug). It should be understood that prodrugs (or precursors) of cytotoxic drugs (or cytotoxic anticancer drugs) can also be used as drugs contained in the antibody-drug conjugate of the present invention. Many drugs for ADC are known in the art and can be used in the antibody-drug conjugate of the present invention, including any drug mentioned in any literature cited in this paragraph. In particular, the drug can be, for example, a tubulin inhibitor (e.g., monomethyl auristatin A (MMAE), monomethyl auristatin F (MMAF) or maytansine), a DNA binder (e.g., calicheamicin), a topoisomerase 1 inhibitor (e.g., SN-38 or exatecan), or a glucocorticoid receptor modulator (GRM; e.g., dexamethasone, budesonide, or any GRM mentioned in Hobson AD et al., J Med Chem, 2022, 65(6):4500-4533, doi:10.1021 / Acs.jmedchem.1c02099, which is incorporated herein by reference). In an antibody-drug conjugate, a linker couples the antibody (or antigen-binding fragment) to the drug. The linker can be cleavable or non-cleavable. For example, the linker can be a cleavable linker containing a disulfide bond, a hydrazone bond, or a peptide bond, or it can be a non-cleavable linker containing a thioether bond.Suitable linkers are known in the art and are described, for example, in: Nolting B, Methods Mol Biol, 2013, 1045:71-100, doi: 10.1007 / 978-1-62703-541-5_5; Lu J et al., Int J Mol Sci, 2016, 17(4):561, doi: 10.3390 / ijms17040561; Tsuchikama K et al., Protein Cell, 2018, 9(1):33-46, doi: 10.1007 / s13238-016-0323-0; Bargh JD et al., Chem Soc Rev, 2019, 48(16):4361-4374, doi: 10.1039 / c8cs00676h; Bargh JD et al., Chem Sci, 2020, 11(9): 2375-2380, doi: 10.1039 / c9sc06410a; Bargh JD et al., Chem Commun (Camb), 2021, 57(28): 3457-3460, doi: 10.1039 / d1cc00957e; Su Z et al., Acta Pharm Sin B, 2021, 11(12): 3889-3907, doi: 10.1016 / j.apsb.2021.03.042; Sheyi R et al., Pharmaceutics, 2022, 14(2): 396, doi: 10.3390 / pharmaceutics14020396; or Bulger PG et al., Org Process Res Dev, 2023, 27(7): 1248-1257, doi: 10.1021 / Acs.oprd.3c00136 (all of which are incorporated herein by reference in their entirety); any linker mentioned in any of these documents or any other document cited in this paragraph can be used as a linker in the antibody-drug conjugates of the present invention.

[0307] The antibodies and antigen-binding fragments of the present invention can be prepared by various techniques routinely used in the art. For example, antibodies can be prepared by immunizing a non-human animal with an antigen of interest (e.g., a CCR8 peptide as described above or in Example 1), followed by isolation of antigen-reactive antibody-producing B cells. To this end, human CCR8 or a partial sequence thereof, such as any of the CCR8 peptides described herein, can be used to identify positive clones, i.e., clones that produce antibodies that specifically bind to human CCR8 or a corresponding partial sequence (or a corresponding CCR8 peptide). Methods for isolating and selecting clones that produce antibodies with desired characteristics are well known in the art. For example, for immunization of non-human animals, the immunogen used (e.g., CCR8 peptide) can be coupled to an adjuvant-carrier (e.g., keyhole limpet hemocyanin KLH) and / or can be administered with an adjuvant composition (e.g., Freund's complete adjuvant or Freund's incomplete adjuvant) to enhance immunogenicity. Animals can be immunized according to a standard schedule, such as weekly, monthly, or a combination of weekly and monthly immunizations, depending on the animal, antigen, and antibody titer. To determine the immune response of the animal, antibody titers in serum can be tested according to standard procedures. Peripheral blood mononuclear cell (PBMC) fractions of positive animals can be isolated and antigen-reactive B cells can be purified using standard techniques such as ELISA or column-based techniques to purify reactive B cells from serum (see, e.g., Seeber S et al., PLoS One, 2014, 9(2):e86184, doi:10.1371 / journal.pone.0086184). Clones that bind to the antigen of interest can then be selected for subsequent recombination processing.

[0308] Other examples of methods suitable for producing or separating antibodies and antibody antigen-binding fragments of the present invention include methods for selecting recombinant antibodies from peptide or protein libraries (e.g., phage, ribosomes, oligonucleotides, RNA, cDNA or yeast display libraries) using purpose binding activity. For example, antibodies or Fabs can be screened from these libraries by selecting specific binding to human CCR8 or its partial sequence (e.g., any CCR8 peptide as described herein, including those described in Example 1). Corresponding display libraries are well known in the art and can be obtained from various commercial suppliers, including, for example, MorphoSys (Planegg, Germany) or Bioinvent (Lund, Sweden). Selected clones can then be processed according to conventional methods for subsequent recombination treatment.

[0309] Therefore, the present invention also provides nucleic acid molecules encoding anti-CCR8 antibodies (or antigen-binding fragments) as described herein, further comprising nucleic acid molecules encoding anti-CCR8 heavy and / or light chain variable domains disclosed herein. In particular, the present invention relates to one or more nucleic acid molecules encoding the heavy and light chains of the antibodies or antigen-binding fragments provided herein. In this regard, the term "nucleic acid molecule" (or synonymous terms, such as "nucleic acid," "nucleic acid sequence," or "polynucleotide") includes genomic DNA, cDNA, or RNA (e.g., mRNA) that can drive the expression of the antibodies or antigen-binding fragments of the present invention. The nucleic acid molecules of the present invention may be of natural or synthetic or semi-synthetic origin. Thus, for example, nucleic acid molecules can be synthesized according to conventional protocols of organic chemistry, according to recombinant methods, or, for example, semi-synthetically produced by combinatorial chemical synthesis and recombinant methods.

[0310] In particular, the present invention provides nucleic acids (or polynucleotides) encoding:

[0311] (1) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 53 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 54; or

[0312] (2) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 55 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 56; or

[0313] (3) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 57 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 58; or

[0314] (4) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 59 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 60; or

[0315] (5) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 61 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 60; or

[0316] (6) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 55 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 62; or

[0317] (7) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 63 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 64; or

[0318] (8) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 65 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 66; or

[0319] (9) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 67 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 68; or

[0320] (10) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 69 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 70; or

[0321] (11) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 77 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 78.

[0322] (12) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 96 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 97; or

[0323] (13) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 98 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 99; or

[0324] (14) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 100 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 99; or

[0325] (15) a heavy chain variable domain (VH) having the sequence of SEQ ID NO: 101 and / or a light chain variable domain (VL) having the sequence of SEQ ID NO: 102; or

[0326] (16) a heavy chain (HC) having the sequence of SEQ ID NO: 103 and / or a light chain (LC) having the sequence of SEQ ID NO: 104; or

[0327] (17) a heavy chain (HC) having the sequence of SEQ ID NO: 105 and / or a light chain (LC) having the sequence of SEQ ID NO: 104; or

[0328] (18) a heavy chain (HC) having the sequence of SEQ ID NO: 106 and / or a light chain (LC) having the sequence of SEQ ID NO: 107; or

[0329] (19) a heavy chain (HC) having the sequence of SEQ ID NO: 108 and / or a light chain (LC) having the sequence of SEQ ID NO: 107; or

[0330] (20) a heavy chain (HC) having the sequence of SEQ ID NO: 109 and / or a light chain (LC) having the sequence of SEQ ID NO: 110; or

[0331] (21) a heavy chain (HC) having the sequence of SEQ ID NO: 111 and / or a light chain (LC) having the sequence of SEQ ID NO: 110; or

[0332] (22) a heavy chain (HC) having the sequence of SEQ ID NO: 112 and / or a light chain (LC) having the sequence of SEQ ID NO: 110; or

[0333] (23) a heavy chain (HC) having the sequence of SEQ ID NO: 113 and / or a light chain (LC) having the sequence of SEQ ID NO: 110; or

[0334] (24) A heavy chain (HC) having the sequence of SEQ ID NO: 114 and / or a light chain (LC) having the sequence of SEQ ID NO: 110.

[0335] The present invention also provides vectors comprising nucleic acid molecules encoding the antibodies or antigen-binding fragments of the present invention. As used herein, the term "vector" particularly relates to circular or linear nucleic acid molecules that can be autonomously replicated in the host cell into which it is introduced. Examples of vectors suitable for the present invention include cosmids, plasmids (e.g., naked plasmids or plasmids contained in liposomes), viruses (e.g., slow viruses, retroviruses, adenoviruses or adeno-associated viruses) or phages. Various other suitable vectors are known in the art. Suitable vectors and their uses are also described in, for example, Green MR et al., "Molecular Cloning: A Laboratory Manual," 4th edition, 2012, Cold Spring Harbor Laboratory Press. It should be understood that other nucleic acid sequences may be present in the vector, such as sequences that control vector replication and / or desired sequence expression in the host cell system. For example, the vector may comprise nucleic acid molecules encoding the antibodies or antigen-binding fragments of the present invention, which may be operably linked to one or more regulatory sequences and / or may be under the control of one or more regulatory sequences. Such regulatory sequences include DNA sequences that promote the expression of the coding sequence operatively linked thereto (or the expression of the coding sequence operably linked thereto as necessary). Vectors may also contain control sequences that affect, for example, expression and / or replication. These regulatory and control sequences may be appropriately selected based on the host cell used. For example, in prokaryotes, control sequences typically include promoters, ribosome binding sites, and terminators. In eukaryotes, control sequences typically include promoters, terminators, and in some cases, enhancers, transactivators, and / or transcription factors.

[0336] The carrier of the present invention is preferably an expression vector. The expression vector can instruct the nucleic acid molecules of the present invention to replicate and express in a host cell, so that the expression of the heavy chain and / or light chain variable domain of any antibody described herein can be provided. In some embodiments, the carrier can include other sequences to ensure that not only the heavy chain and light chain variable domains are expressed, but also the remaining heavy chain and light chain constant regions are expressed, so that full-length antibodies (e.g., full-length IgG antibodies) are expressed. The suitable expression vector described in the literature can be easily determined for any specific cell system using conventional methods. Preferably, the carrier provided herein includes a polynucleotide encoding an antibody or antigen-binding fragment of the present invention, which is operably connected to one or more regulatory or control sequences. The carrier provided herein preferably also includes a promoter. The carrier can also include a selectable marker gene, a replication origin, and / or a transcription termination signal. The expression vector can be used to drive transient expression or constitutive expression in a host cell.

[0337] The nucleic acid molecules and / or vectors of the present invention can be designed to transfect prokaryotic or eukaryotic host cells by any method known in the art or described herein. Examples of these methods include chemical-based methods (e.g., using polyethyleneimine, calcium phosphate, liposomes, or DEAE-dextran), non-chemical methods (e.g., electroporation, nuclear transfection, sonoporation, optical transfection, gene electrotransfer, or hydrodynamic delivery), particle-based methods (e.g., gene guns, magnetic transfection, or impalefection), phage-based methods, or viral methods. For example, expression vectors derived from viruses such as retroviruses, vaccinia viruses, adeno-associated viruses, herpes viruses, Semliki Forest viruses, or bovine papilloma viruses can be used to transfect nucleic acid molecules into target cell populations. In addition, baculovirus systems can also be used as vectors in eukaryotic expression systems.

[0338] Prokaryotic hosts include all capable of transforming, transducing or transfecting with the antibacterial of expressing protein with DNA or RNA molecules. Particularly, prokaryotic hosts can include gram-negative and gram-positive bacteria, for example, escherichia coli, Salmonella typhimurium (S.typhimurium), Serratia marcescens (Serratia marcescens), Corynebacterium spp. (for example, Corynebacterium glutamicum (Corynebacterium glutamicum)), Pseudomonas (Pseudomonas spp.) (Pseudomonas fluorescens (Pseudomonas fluorescens)), Lactobacillus (Lactobacillus spp.), Streptomyces (Streptomyces spp.), Salmonella (Salmonella spp.) or Bacillus subtilis (Bacillus subtilis). Eukaryotic hosts include, for example, yeast, higher plants, insects and mammalian cells. Examples of suitable mammalian host cells include Hela cells, HEK-293 cells, H9 cells, Per.C6 cells, Jurkat cells, mouse NIH3T3 cells, NS / 0 cells, SP2 / 0 cells, C127 cells, COS cells (e.g., COS1 or COS 7 cells), CV1 cells, quail QC1-3 cells, mouse L cells, mouse sarcoma cells, Bowes melanoma cells, or Chinese hamster ovary (CHO) cells, preferably CHO cells (e.g., CHO-K1 cells). The host cell of the present invention can be a directly engineered cell, e.g., a cell that has been directly transfected with a vector or polynucleotide disclosed herein, or it can be a daughter cell or progeny of a directly transfected cell.

[0339] When a recombinant expression vector encoding an antibody heavy chain and / or light chain variable domain as disclosed herein is introduced into a host cell, the antibody or antigen binding fragment can be produced by culturing the host cell for a period of time, which is sufficient to allow the antibody or antigen binding fragment to be expressed in the host cell, or preferably, the antibody or antigen binding fragment is allowed to be secreted into the culture medium where the host cell grows. Standard protein purification methods can be used to recover the antibody and / or antigen binding fragment from the culture medium. Therefore, the present invention also provides a method for producing an antibody (or antigen binding fragment) of the present invention, comprising culturing a host cell comprising a polynucleotide encoding the antibody or antigen binding fragment or an expression vector containing the polynucleotide. The method may also include separating the expressed antibody or antigen binding fragment from the culture (e.g., from a cell fraction and / or from the culture medium). The present invention also provides antibodies or antigen binding fragments obtainable by any method described herein.

[0340] Although the antibodies of the present invention can be expressed in prokaryotic or eukaryotic host cells, it is preferred to express the antibodies in eukaryotic cells, and even more preferably to express them in mammalian host cells, because such eukaryotic cells (particularly mammalian cells) can be more easily used to assemble and secrete correctly folded and immunocompetent antibodies. Examples of mammalian host cells that can be used to express antibodies or antigen-binding fragments of the present invention specifically include Chinese hamster ovary (CHO) cells, NSO myeloma cells, COS cells, or SP2 cells. Preferably, CHO cells (e.g., CHO-K1 cells) are used as host cells.

[0341] The transformed host cells can be grown in bioreactors and cultured according to techniques known in the art to achieve optimal cell growth. The antibodies or antigen-binding fragments of the invention can then be isolated from cell fractions or growth medium by conventional methods such as affinity chromatography, gel filtration (size exclusion chromatography), anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography, high pressure liquid chromatography (HPLC), reversed-phase HPLC, or immunoprecipitation.

[0342] The antibody or Fab produced by recombinant production can have a variable region and a constant region (if present), and the variable region and constant region are derived from the germline immunoglobulin sequences of the species separated after standard immunity known in the art and selection procedures, such as can comprise the germline immunoglobulin sequences of mice, rats or rabbits. However, the antibody sequence can be subjected to in vitro mutagenesis, wherein the CDR sequences are combined with the framework sequences from another species, such as from people, as known in the humanization process. Therefore, the amino acid sequence of variable heavy chain and light chain domain can also be such a sequence, although it is derived from germline heavy chain or light chain sequence and is relevant to germline heavy chain or light chain sequence, it can not be naturally present in any endogenous antibody germline library (antibody germline repertoire).

[0343] Antibody derivatives can be produced, for example, by adding exogenous sequences to modify immunogenicity or to reduce, enhance or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life or any other suitable characteristic.

[0344] Also provided are humanized forms of the antibodies disclosed herein (particularly antibodies (and antigen-binding fragments thereof) comprising the CDRs disclosed above). Humanization refers to the use of CDR recombinant engineering antibodies from non-human donor immunoglobulins in the context of human-derived framework and constant regions. During the engineering process, framework and / or CDR residues can be changed to maintain binding affinity and activity. Methods for humanizing antibodies are well known in the art and are also as described above. Specifically, the present invention provides human IgG antibodies (e.g., complete / intact human IgG1, IgG2, IgG3 or IgG4 antibodies, particularly IgG1 antibodies), in which six CDRs are replaced by the six CDRs described in any one of the above options (A-1) to (A-13).

[0345] The present invention also provides a composition (preferably a pharmaceutical composition) comprising one or more pharmaceutically acceptable excipients and: (i) an antibody or antigen-binding fragment thereof of the present invention; or (ii) a nucleic acid (or polynucleotide) encoding the antibody or antigen-binding fragment according to (i); or (iii) a vector comprising the polynucleotide according to (ii); or (iv) a host cell comprising the nucleic acid (or polynucleotide) according to (ii) and / or the vector according to (iii), said host cell expressing the antibody or antigen-binding fragment according to (i).

[0346] The present invention further relates to the diagnostic applications of antibodies and antigen-binding fragments provided herein. Specifically, the antibodies and antigen-binding fragments of the present invention can be used as markers / reagents in immunohistochemistry, for example, to diagnose cancer and / or stratify and / or evaluate therapeutic effects for cancer treatment by testing a sample (e.g., biopsy) from a subject. Therefore, the present invention relates to the in vitro uses of antibodies or antigen-binding fragments (as described herein) in diagnostic methods, particularly in vitro uses in methods for diagnosing cancer in a subject using a sample (e.g., blood sample or biopsy sample, particularly cancer / tumor biopsy sample) obtained from the subject. The present invention further relates to antibodies or antigen-binding fragments (as described herein), which are used for diagnosis, particularly for in vivo methods for diagnosing cancer in a subject, and relate to corresponding diagnostic methods.

[0347] As described above, the present invention further relates to antibodies or antigen binding fragments (such as described herein), which are used to treat cancer. The present invention further relates to the use of antibodies or antigen binding fragments in the manufacture of drugs for treating cancer, and methods for treating cancer in subjects in need thereof, the methods comprising administering a therapeutically effective amount of antibodies or antigen binding fragments to the subject. The present invention also relates to corresponding cancer treatments using nucleic acids, compositions, lipid particles, antibody-drug conjugates, or immune cells expressing chimeric antigen receptors (CARs), particularly T cells (e.g., α-β-T cells or γ-δ-T cells) or NK cells, as described herein.

[0348] The cancer to be treated according to the present invention may be a solid cancer or a blood cancer. Preferably, the cancer may be selected from lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), renal cancer (or kidney cancer; e.g., renal cancer), gastrointestinal cancer, stomach cancer (or gastric cancer; e.g., gastric adenocarcinoma), colorectal cancer (e.g., colorectal cancer), colon cancer, anal cancer, urogenital cancer, bladder cancer, urothelial cancer (e.g., urothelial carcinoma), liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian cancer), uterine cancer (e.g., uterine corpus cancer or uterine sarcoma), prostate cancer (e.g., hormone-resistant lineage cancer). prostate cancer), testicular cancer, bile duct cancer (or bile duct cancer; e.g., cholangiocarcinoma), hepatobiliary cancer, gallbladder cancer (e.g., gallbladder cancer), thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer), neuroblastoma, brain cancer (e.g., glioblastoma), breast cancer (e.g., triple-negative breast cancer, specifically including triple-negative breast cancer expressing COX-2 or breast cancer with BRCA1 and / or BRCA2 gene mutations), head and / or neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkel cell cancer (e.g., Merkel cell carcinoma), epidermoid carcinoma, squamous cell carcinoma cell cancer (or squamous cell carcinoma; including, for example, oral squamous cell carcinoma / squamous cell oral cancer, squamous cell skin cancer, squamous cell lung cancer, squamous cell thyroid cancer, squamous cell esophageal cancer, or squamous cell vaginal cancer), bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral cancer, thymic cancer (e.g., thymoma), neuroendocrine cancer (e.g., neuroendocrine cancer), goblet cell cancer (e.g., goblet cell carcinoid), spleen cancer, blood cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia), The cancer to be treated may also be a carcinoma or a sarcoma. In addition, the cancer to be treated (including any of the above-mentioned specific types of cancer) may be a CCR8-positive cancer (particularly a cancer in which CCR8 is expressed by cancer cells, by cells of the tumor microenvironment, and / or by tumor-infiltrating cells (e.g., by tumor-infiltrating Treg cells)). The cancer to be treated (including any of the above-mentioned specific types of cancer) may also be a metastatic cancer.

[0349] As mentioned above, the cancer to be treated according to the present invention may be a blood cancer (eg lymphoma or leukemia). In this case, the hematological cancer is preferably selected from the group consisting of: Hodgkin's lymphoma, including, for example, the nodular sclerosis subtype of Hodgkin's lymphoma, the mixed cellularity subtype of Hodgkin's lymphoma, the lymphocyte-rich subtype of Hodgkin's lymphoma, or the lymphocyte-depleted subtype of Hodgkin's lymphoma; non-Hodgkin's lymphoma, including, for example, follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma); nodular lymphocyte-predominant Hodgkin's lymphoma; peripheral / cutaneous T-cell lymphoma, including, for example, mycosis fungoides, Sézary syndrome, T-zone lymphoma, lymphoepithelioid lymphoma (e.g., Lennert lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; malignant immunoproliferative disorders, including, for example, macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin disease), or immunoproliferative intestinal disease (e.g., thalassemia); multiple myeloma, including, for example, Kahler disease or myelomatosis; plasma cell leukemia; lymphocytic leukemia, including, for example, acute lymphoblastic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; myeloid leukemia, including, for example, acute Myelocytic leukemia, chronic myelocytic leukemia, subacute myelocytic leukemia, myeloid sarcoma (e.g., chlorosarcoma or granulocytic sarcoma), acute promyelocytic leukemia, or acute myelomonocytic leukemia; myeloproliferative neoplastic diseases, including, for example, polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute polycythemia or erythroleukemia, including, for example, acute polycythemia vera or DiGuglielmo disease; chronic polycythemia, including, for example, Heilmeyer- disease; acute megakaryoblastic leukemia; mast cell leukemia; acute panmyeloproliferative disorder; acute myelofibrosis; and Letterer-Siwe disease.

[0350] Particularly preferably, the cancer to be treated according to the present invention is selected from ovarian cancer, colorectal cancer, colon cancer, gastric cancer, esophageal cancer (e.g. esophageal squamous cell carcinoma or esophageal adenocarcinoma), breast cancer (e.g. triple-negative breast cancer), lung cancer (e.g. non-small cell lung cancer), bladder cancer, uterine cancer (e.g. uterine corpus cancer), urothelial cancer (e.g. urothelial malignancy), Kaposi's sarcoma, skin cancer (e.g. melanoma), head and / or neck cancer (e.g. head and neck squamous cell carcinoma), kidney cancer (e.g. renal cell carcinoma) and lymphoma (e.g. non-Hodgkin's lymphoma, such as cutaneous T-cell lymphoma (e.g. Sézary syndrome)); even more preferably, the cancer is ovarian cancer, colorectal cancer, gastric cancer, breast cancer or cutaneous T-cell lymphoma (e.g. Sézary syndrome).

[0351] The present invention also relates to the use of the antibodies or antigen-binding fragments provided herein as antagonists of the CCL1-CCR8 signaling pathway. The antibodies and antigen-binding fragments provided herein can be used as research tools for antagonizing the CCL1-CCR8 signaling pathway. Therefore, the present invention relates to the in vitro use of the antibodies or antigen-binding fragments provided herein as antagonists (e.g., insurmountable antagonists) of the CCL1-CCR8 signaling pathway, and particularly to the in vitro use of the antibodies or antigen-binding fragments provided herein as research tools for antagonists (e.g., insurmountable antagonists) of the CCL1-CCR8 signaling pathway. The present invention also relates to methods for antagonizing (e.g., insurmountably antagonizing) the CCL1-CCR8 signaling pathway, particularly in vitro methods, which include applying the antibodies or antigen-binding fragments described herein. The present invention also relates to methods for antagonizing (e.g., insurmountably antagonizing) the CCL1-CCR8 signaling pathway, which include applying the antibodies or antigen-binding fragments provided herein to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The present invention also provides a method for antagonizing (e.g., irreversibly antagonizing) the CCL1-CCR8 signaling pathway, the method comprising contacting a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal) with an antibody or antigen-binding fragment described herein. The terms "sample," "test sample," and "biological sample" include, but are not limited to, cells, cell cultures, or cellular or subcellular extracts; biopsy material obtained from an animal (e.g., a human), or an extract thereof. It should be understood that the term "in vitro" in this particular context is used in the sense of "outside a living human or animal," which specifically includes experiments performed with cells, cell extracts, or subcellular extracts and / or biomolecules in an artificial environment (e.g., an aqueous solution or culture medium that can be provided in, for example, a flask, test tube, petri dish, microtiter plate, etc.). In addition, it should be understood that the above-mentioned in vitro uses and methods may also be characterized as "non-therapeutic" in vitro uses and methods.

[0352] The antibodies (or antigen-binding fragments) or nucleic acids provided herein can be administered as such, or can be formulated as a medicament (or pharmaceutical composition). The medicament / pharmaceutical composition can optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or solubilizing agents.

[0353] In particular, the pharmaceutical composition may comprise one or more preservatives, in particular one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0354] Pharmaceutical composition can be prepared by the technology known to those skilled in the art, for example, in " Remington:TheScience and Practice of Pharmacy ", Pharmaceutical Publishing House, the technology announced in the 22nd edition. Usually, pharmaceutical composition can be formulated into dosage forms such as for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, local, aerosol or vaginal administration. Oral dosage forms include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstruction, dispersible powders and granules, medicinal gum (medicated gum), chewable tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersants and powders and granules for reconstruction. Emulsions are preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovules (ovula). Dosage forms for nasal administration can be administered by inhalation or insufflation, for example, by a metered dose inhaler.Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0355] The antibodies, nucleic acids or pharmaceutical compositions of the invention (hereinafter referred to as "active agents") can be administered to a subject by any convenient route of administration, whether systemic / peripheral or at the site of the desired effect. In general, corresponding routes of administration include, inter alia, oral (e.g., as tablets, capsules or as absorbable solutions), topical (e.g., transdermal, intranasal, ocular, buccal and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid or intrasternal, by, for example, implanted reservoirs, e.g., subcutaneous or intramuscular), pulmonary (e.g., by inhalation or insufflation therapy, using, e.g., an aerosol, e.g., through the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal or vaginal administration.

[0356] Preferably, the antibody, nucleic acid or pharmaceutical composition is administered parenterally, particularly by intravenous administration (eg, by intravenous injection or intravenous infusion).

[0357] The example of parenteral administration includes one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardial, intracranial, intramuscular or subcutaneous administration of the activating agent or pharmaceutical composition, and / or by using an infusion technique. For parenteral administration, activating agent can be used in the form of sterile aqueous solution, and the sterile aqueous solution can contain other substances, such as enough salts or glucose so that solution and blood are isotonic. If desired, the aqueous solution can suitably buffer (preferably buffered to pH 3-9). Aseptically preparing suitable parenteral preparations can easily complete by standard pharmaceutical techniques well known to those skilled in the art.

[0358] The active agent or pharmaceutical composition may also be administered orally, for example, in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavorings or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0359] Tablets can contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and certain complex silicates, and granulation binders such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc can be included. Similar types of solid compositions can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, they can be used in combination with various sweeteners or flavorings, colorants or dyes, emulsifiers and / or suspending agents, and diluents (e.g., water, ethanol, propylene glycol and glycerol) and combinations thereof.

[0360] For oral administration, the active agent or pharmaceutical composition can be administered by oral ingestion, especially by swallowing. Thus, the active agent or pharmaceutical composition can be administered to enter the gastrointestinal tract through the mouth, which can also be referred to as "oral-gastrointestinal" administration.

[0361] Alternatively, the active agent or pharmaceutical composition may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.The active agents of the invention may also be administered transdermally or transdermally, for example by use of a skin patch.

[0362] Described activating agent or pharmaceutical composition also can be used by slow-release system.Suitable slow-release composition comprises semipermeable polymer matrix, and its shape is film or microcapsule etc.Slow-release matrix comprises, for example, the copolymer of polylactic acid, L-glutamic acid and gamma-ethyl-L-glutamic acid, poly-(2-hydroxyethyl methacrylate), ethylene-vinyl acetate copolymer or poly-D-(-)-3-hydroxybutyric acid.Slow-release pharmaceutical composition also comprises the activating agent of liposome embedding.

[0363] Specifically, the present invention also relates to lipid particles (including, for example, lipid nanoparticles or liposomes) containing one or more nucleic acids of the present invention. Thus, the nucleic acids of the present invention can be provided in the form of lipid particles. Such lipid particles and their preparation are known in the art and have been described, for example, in: Müller RH et al., Eur J Pharm Biopharm, 2000, 50(1):161-77, doi:10.1016 / s0939-6411(00)00087-4; Saupe A et al., “Solid Lipid Nanoparticles”, in: Mozafari MR (ed.), “Nanocarrier Technologies”, 2006, Springer, doi:10.1007 / 978-1-4020-5041-1_3; Cullis PR et al., Mol Ther, 2017, 25(7):1467-75, doi:10.1016 / j.ymthe.2017.03.013; Hou X et al., Nat Rev Mater, 2021, 6(12): 1078-94, doi: 10.1038 / s41578-021-00358-0; Tenchov R et al., ACS Nano, 2021, 15(11): 16982-17015, doi: 10.1021 / acsnano.1c04996; or Sultana A et al., Medicine in Drug Discovery, 2022, 15: 100134, doi: 10.1016 / j.medidd.2022.100134; each of which is incorporated herein by reference.

[0364] Thus, the present invention relates to an active agent or pharmaceutical composition as provided herein, wherein the corresponding compound or pharmaceutical composition is administered by any of the following routes: oral route; topical route, including transdermal, intranasal, ocular, buccal or sublingual route; parenteral route using injection techniques or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ocular route, including intravitreal or intracameral route; rectal route; or vaginal route. A particularly preferred route of administration is parenteral administration (e.g., intravenous administration).

[0365] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dosage level and frequency of administration for any particular individual subject can vary and will depend on a variety of factors, including the activity of the specific active agent used, the metabolic stability and duration of action of the active agent, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual subject being treated.

[0366] The antibodies (or antigen-binding fragments) or nucleic acids of the present invention or corresponding pharmaceutical compositions can be administered in a monotherapy (e.g., without administering any additional therapeutic agent at the same time, or without administering any additional therapeutic agent for the same disease to be treated with the antibody or nucleic acid). However, the antibodies (or antigen-binding fragments) or nucleic acids or corresponding pharmaceutical compositions can also be administered in combination with one or more other therapeutic agents. If the antibody or nucleic acid is used in combination with a second therapeutic agent that is active for the same disease or condition (e.g., cancer), the dose of each active agent can be different from the dose when the corresponding active agent is used alone, specifically, one or two active agents at a lower dose can be used. The combination of an antibody or nucleic acid with one or more other therapeutic agents can include simultaneous / concomitant administration of the antibody or nucleic acid and other therapeutic agents (in a single pharmaceutical formulation or in separate pharmaceutical formulations), or sequential / separate administration of the antibody or nucleic acid and other therapeutic agents. If administered sequentially, the antibody or nucleic acid of the present invention or one or more other therapeutic agents can be administered first. If administered simultaneously, the one or more additional therapeutic agents can be included in the same pharmaceutical formulation as the antibody or nucleic acid, or they can be administered in two or more different (separate) pharmaceutical formulations. The use of separate pharmaceutical formulations is particularly advantageous if the antibody or nucleic acid and the additional therapeutic agent are administered by different routes of administration, for example, if the antibody or nucleic acid is administered parenterally (eg, intravenously) and the additional therapeutic agent is administered orally.

[0367] Preferably, the one or more other therapeutic agents administered in combination with the antibodies (or antigen-binding fragments) or nucleic acids of the invention are one or more anticancer drugs. The anticancer drugs to be administered in combination with the antibodies or nucleic acids of the invention can be selected from, for example: tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, or vascular endothelial growth factor receptor kinase inhibitors); cytotoxic drugs (e.g., antimetabolites, such as purine and pyrimidine analog antimetabolites); antimitotic agents (e.g., microtubule stabilizing drugs or antimitotic alkaloids); platinum coordination complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine agents (e.g., adrenocortical steroids, androgens, anti-androgens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists, or somatostatin analogs); or compounds that target enzymes or receptors of specific metabolic pathways that are overexpressed in tumor cells and / or otherwise involved in dysregulation (or misregulation) (e.g., ATP and GTP phosphodiesterase inhibitors, histone Deacetylase inhibitors, protein kinase inhibitors (e.g., serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitor) and various growth factors, their receptors and corresponding kinase inhibitors (e.g., epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors); methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), poly ADP ribose polymerase inhibitors (PARP inhibitors), epidermal growth factor receptor (EGFR) inhibitors / antagonists, targeted cancer therapies, cellular cancer therapies and cancer vaccines.

[0368] Alkylating agents that can be used as anticancer drugs in combination with the antibodies or nucleic acids of the present invention can be, for example, nitrogen mustards (e.g., cyclophosphamide, nitrogen mustard (chlormethylamine), uracil, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), nitrosoureas (e.g., carmustine, streptozotocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), alkyl sulfonates (e.g., busulfan, mannosulfuron, or trooxsulfuron), aziridines (e.g., hexamethylmelamine (hexamethylmelamine), triethylenemelamine, thiotepa (ThioTEPA) (N,N'N'-triethylenethiophosphoramide), carboquinone, or triiminoquinone), hydrazines (e.g., procarbazine), triazenes (e.g., dacarbazine), or imidazotetrazines (e.g., temozolomide). The platinum coordination complex that can be used as an anticancer drug in combination with the antibody or nucleic acid of the present invention can be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin or triplatinum tetranitrate. The cytotoxic drug that can be used as an anticancer drug in combination with the antibody or nucleic acid of the present invention can be, for example, antimetabolites, including folic acid analog antimetabolites (e.g., aminopterin, methotrexate, pemetrexed or raltitrexed), purine analog antimetabolites (e.g., cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin or 6-thioguanine) and pyrimidine analog antimetabolites (e.g., cytarabine, decitabine, 5-fluorouracil (including its prodrug form capecitabine and fluridine), floxuridine, gemcitabine, enocitabine or saccitabine). The antimitotic agent that can be used as an anticancer drug in combination with the antibody or nucleic acid of the present invention can be, for example, a taxane (e.g., docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel, or nab-paclitaxel (e.g., )), vinca alkaloids (e.g., vinblastine, vincristine, vinflunine, vindesine or vinorelbine), epothilones (e.g., epothilone A, epothilone B, epothilone C, epothilone D, epothilone E or epothilone F) or epothilone B analogs (e.g., ixabepilone / azaepothilone B). Antitumor antibiotics that can be used as anticancer drugs in combination with the antibodies or nucleic acids of the present invention can be, for example, anthracyclines (e.g., aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin or daurubicin), anthracenediones (e.g., mitoxantrone or pixantrone), or antitumor antibiotics isolated from Streptomyces (e.g., actinomycins (including actinomycin D), bleomycin, mitomycins (including mitomycin C) or plicamycin). Tyrosine kinase inhibitors that can be used as anticancer drugs in combination with the antibodies or nucleic acids of the present invention can be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib or vemurafenib. Topoisomerase inhibitors that can be used as anticancer drugs in combination with the antibodies or nucleic acids of the present invention can be, for example, topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin, belotecan, rubitecan or lamellarin D) or topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide or doxorubicin). The PARP inhibitor that can be used as an anticancer drug in combination with the antibody or nucleic acid of the present invention can be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP 9722, MK 4827, E7016 or 3-aminobenzamide. The EGFR inhibitor / antagonist that can be used as an anticancer drug in combination with the antibodies or nucleic acids of the present invention can be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, pociterinib, ABT-414, AV-412, PD 153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab or matuzumab. Other anticancer drugs can also be used in combination with the antibodies or nucleic acids of the present invention.Anticancer drugs may include biological or chemical molecules such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irovin, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvcidib, seliciclib, aminolevulinic acid, methylaminolevulinic acid, and methylaminolevulinic acid. aminolevulinate), iproxicam, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demeclocycline, elisimol, elsamitrucin, etoglucid, lonidamine, lucanthone, masoprocol, dibromomannitol, mitoguanzone, mitotane, oblimersen, omacetin, sitimagene, ceradenovec, flurbiprofen, testolactone, thiazofurine, tipifarnib, vorinostat, iniparib, or copanlisib.

[0369] In addition, biopharmaceuticals, such as antibodies or antibody fragments / constructs directed against tumor markers / factors / cytokines involved in cancer or proliferative diseases, can also be used in combination therapy with the antibodies or nucleic acids of the present invention. Examples of such biomolecules are anti-HER2 antibodies (e.g., trastuzumab, ), anti-CD20 antibodies (such as rituximab, ), anti-CD19 / CD3 constructs, or anti-TNF antibodies (see, e.g., Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328). Other antibodies and / or antibody fragments / constructs useful in combination therapy methods with any of the antibodies or nucleic acids of the invention can be found, e.g., in Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328; or Roxana A, Maedica, 2006, 1(1):63-65.

[0370] Anti-cancer drugs that can be used in combination with the antibodies or nucleic acids of the present invention can also be immuno-oncology therapeutics (e.g., antibodies or antibody fragments / constructs) that target, for example, any one of CTLA-4, PD-1, PD-L1, TIGIT, TIM3, LAG3, OX40, ICOS, CSF1R, IDO, CD40, CD25, or CCR4. Such immuno-oncology therapeutics include, for example, anti-CTLA-4 antibodies (particularly antagonistic or pathway-blocking anti-CTLA-4 antibodies; e.g., ipilimumab or tesimumab), anti-PD-1 antibodies (particularly antagonistic or pathway-blocking anti-PD-1 antibodies; e.g., nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab (CT-011), cemiprilimab, dustalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalizumab, zimbalizumab, AMP-224, AMP-514 (or MEDI0680), JTX-4014, INCMGA00012 (or MGA012), or APE02058), anti-PD-L1 antibodies (particularly pathway-blocking anti-PD-L1 antibodies; for example, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, MEDI6469, or bintrafusp alfa), anti-TIGIT antibodies (e.g., tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI939, or M6223), anti-TIM3 antibodies (particularly pathway-blocking anti-TIM3 antibodies; e.g., cobolimab (or TSR-022), sabatolimab (or M BG453), BMS-986258, Sym023, TQB2618, LY3321367 or SHR-1702), anti-LAG3 antibodies (particularly antagonist or pathway-blocking anti-LAG3 antibodies; for example, relatlimab (or BMS-986016), ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701 or IMP731), anti-OX40 antibodies (particularly agonist anti-OX40 antibodies;For example, ivuxolimab (or PF-8600), MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101 or MOXR0916), anti-ICOS antibodies (particularly agonist anti-ICOS antibodies; for example, feladilimab (or GSK3359609), vopratelimab (or JTX-2011), BMS-986226, alomfilimab (or SAR445256 or KY1044), MEDI-570 or XmAb23104), anti-CSF1R antibodies (particularly pathway-blocking anti-CSF1R antibodies; for example, IMC-CS4 or RG7155), anti-IDO antibodies (particularly pathway-blocking anti-IDO antibodies), anti-CD40 antibodies (particularly agonist anti-CD40 antibodies; for example, CP-870,893 or Chi Lob 7 / 4), anti-CD25 antibodies (particularly Treg-depleting anti-CD25 antibodies; for example, daclizumab, inolimomab or RG6292), or anti-CCR4 antibodies (particularly Treg-depleting anti-CCR4 antibodies; for example, mogamulizumab). Further examples of immuno-oncology therapies include anti-HER2 antibodies (for example, trastuzumab), anti-CD20 antibodies (for example, rituximab), anti-CD19 / CD3 constructs, and anti-TNF antibodies.

[0371] Specifically, the antibody or nucleic acid of the present invention or the corresponding pharmaceutical composition or lipid particle is preferably administered in combination with an immune checkpoint inhibitor, more preferably in combination with an antibody (or an antigen-binding fragment thereof) against any one of CTLA-4, PD-1, PD-L1, TIGIT, TIM3, LAG3, OX40 or ICOS. Corresponding preferred examples include, but are not limited to, any one of the anti-CTLA-4 antibodies ipilimumab or tesimumab; any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, pidilizumab, cemiplizumab, dustalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalizumab, zimbalizumab, AMP-224, AMP-514, JTX-4014, INCMGA00012, or APE02058; any one of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, or bintrafusp any of the anti-TIGIT antibodies tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI939, or M6223; any of the anti-TIM3 antibodies cobolimab, sabatolimab, BMS-986258, Sym023, TQB2618, or LY332 any of the anti-LAG3 antibodies relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, or IMP731; any of the anti-OX40 antibodies ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101, or MOXR0916; and / or any of the anti-ICOS antibodies alomfilimab, feladilimab, vopratelimab, BMS-986226, MEDI-570, or XmAb23104.Therefore, the present invention relates to an antibody or nucleic acid (as described herein), or a pharmaceutical composition or lipid particle for use in treating cancer, wherein the antibody or nucleic acid (or pharmaceutical composition or lipid particle) is administered in combination with one or more immune checkpoint inhibitors, wherein the one or more immune checkpoint inhibitors are preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti-OX40 antibodies and / or anti-ICOS antibodies; more preferably, the one or more immune checkpoint inhibitors are selected from ipilimumab, tesimulan, or Antibodies, nivolumab, pembrolizumab, pidilizumab, cemiplizumab, dustalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimbalimab, AMP-224, AMP-514, JTX-4014, INCMGA00012, APE02058, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP837 4. SEA-TGT, BGB-A1217, IBI939, M6223, cobolimab, sabatolimab, BMS-986258, Sym023, TQB2618, LY3321 367, SHR-1702, relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, IMP731 , ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101, MOXR0916, alomfilimab, feladilimab, vopratelimab, BMS-986226, MEDI-570 and XmAb23104.

[0372] Therefore, in a preferred embodiment, the present invention relates to an antibody (or antigen-binding fragment) for use in treating cancer, wherein the treatment comprises administering one or more immune checkpoint inhibitors in combination. The present invention also relates to any nucleic acid, composition or lipid particle described herein for use in treating cancer, wherein the treatment comprises administering one or more immune checkpoint inhibitors in combination. The present invention also relates to the use of an antibody or antigen-binding fragment of the invention (or a nucleic acid, composition or lipid particle of the invention) in the preparation of a medicament for treating cancer, wherein the treatment comprises administering one or more immune checkpoint inhibitors in combination. The present invention also relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of the invention (or a nucleic acid, composition or lipid particle of the invention) and a therapeutically effective amount of one or more immune checkpoint inhibitors. The one or more immune checkpoint inhibitors are preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti-OX40 antibodies and anti-ICOS antibodies (or any combination thereof).More preferably, the one or more immune checkpoint inhibitors are selected from ipilimumab, tesimumab, nivolumab, pembrolizumab, pidilizumab, cemiplizumab, dustalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimbalimab, AMP-224, AMP-514, JTX-4014, INCMGA00012, APE02058, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI 939, M6223, cobolimab, sabatolimab, BMS-986258, Sym023, TQB2618, LY3321367, SHR-1702, relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, IMP731, ivuxolimab, MEDI05 62. MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS986178, INBRX-10 6. IBI101, MOXR0916, alomfilimab, feladilimab, vopratelimab, BMS-986226, MEDI-570 and XmAb23104.

[0373] As described above, in order to treat cancer, the antibodies or nucleic acids of the present invention (or corresponding pharmaceutical compositions or lipid particles) can also be used in combination with targeted cancer therapies, for example, by administering one or more therapeutic agents targeting genes or proteins that support cancer cell survival and / or growth in combination with the antibodies or nucleic acids, preferably one or more tyrosine kinase inhibitors (TKI). There is no particular limitation on the tyrosine kinase inhibitors administered in combination with the antibodies or nucleic acids of the present invention, but preferably one or more active agents selected from the following: anaplastic lymphoma kinase (ALK) inhibitors (e.g., alectinib, ocatinib, belizatinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, foritinib, lorlatinib, ripretinib, CEP-37440, TQ-B3139, PLB1003 or TPX-0131), Bcr-Abl Tyrosine kinase inhibitors (e.g., aximinib, bafitinib, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, or rebastinib), EGFR inhibitors / antagonists (e.g., afatinib, brigatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, osimertinib, pelitinib, vandetanib, ABT-414, AP26113, AV-412, BMS-690514, CUDC-101, PD-L1 inhibitors) 153035, PKI-166, XL647, cetuximab, matuzumab, nimotuzumab, panitumumab, or zalutumumab), FMS-like tyrosine kinase 3 (FLT3) inhibitors (e.g., gilteritinib, lestaurinib, midostaurin, quizartinib, sorafenib, or sunitinib), fibroblast growth factor receptor (FGFR) inhibitors / antagonists (e.g., erdafitinib, BGJ398,PD173074 or ZD4547), Janus kinase (JAK) inhibitors (e.g., abrocitinib, baricitinib, seletinib, digotinib, deucravacitinib, fidartinib, filgotinib, gandotinib, lestaurtinib, molotinib, oclacitinib, paclitinib, peftinib, ruxolitinib, tofacitinib or tasocitinib), upadacitinib, ib), CHZ868 or cucurbitacin I (or JSI-124)), neurotrophic tyrosine receptor kinase (NTRK) inhibitors (e.g., entrectinib, larotrectinib, ripretinib, or ceritinib), vascular endothelial growth factor receptor (VEGFR) inhibitors / antagonists (e.g., apatinib or rivoceranib, axitinib, bevacizumab, cabozantinib, cediranib, intedanib, itraconazole, lenvatinib, lucitanib, motesanib, nintedanib, pazopanib, revoceranib, gefenib, semaxanib, sorafenib, sunitinib, vandetanib, or vatalanib), BRAF inhibitors (e.g., dabrafenib, conefactinib, sorafenib, vemurafenib, GDC-0879, or PLX-4720), Bruton's tyrosine kinase (BTK) inhibitors (e.g., acalabrutinib, evobrutinib, fenebrutinib, ibrutinib, pirtobrutinib, spebrutinib, tirabrutinib, tolebrutinib), inib, zanubrutinib, ABBV-105, GS-4059 (or ONO-4059), or HM71224), mitogen-activated protein kinase kinase (MEK) inhibitors (e.g., bemetinib, cobimetinib, selumetinib, trametinib, CI-1040, PD035901, PD-325901, or TAK-733), and / or cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (e.g., abemaciclib, palbociclib, ribociclib, tracerib, voruciclib, or zotiraciclib).

[0374] The antibody or nucleic acid of the present invention (or corresponding pharmaceutical composition or lipid particle) can also be used to treat cancer in combination with cell cancer therapy, for example, in combination with a therapy based on chimeric antigen receptor (CAR) cells, in particular in combination with CAR T cell therapy (for example, using CAR α-β-T cells or CAR γ-δ-T cells) or CAR NK cell therapy. The corresponding example specifically includes Akiren race (axicabtagene ciloleucel), brexucabtagene autoleucel, Cidaquiao race (ciltacabtegene autoleucel), Aijiweiren race (idecabtagene vicleucel), Lijimeiren race (lisocabtagene maraleucel) or Silifuming (tisagenlecleucel).

[0375] In addition, one or more cancer vaccines can also be used in combination with the antibodies or nucleic acids of the present invention (or corresponding pharmaceutical compositions or lipid particles) for the treatment of cancer. Such cancer vaccines can be, for example, cell-based cancer vaccines, protein- or peptide-based cancer vaccines, or nucleic acid-based cancer vaccines. Corresponding examples specifically include AdV-tk, Bacillus Calmette-Guérin (BCG) vaccine, Biovax ID, DC-adenovirus p53 vaccine, GI-6301, GVAX, NeoVax, NeuVax, oncophage (or HSPPC-96), sipuleucel-T, or talimogene laherparepvec.

[0376] The above-mentioned combination can exist in the form of pharmaceutical preparation easily.The individual components of this type of combination can be used successively or simultaneously / with administration in the form of pharmaceutical preparation separated or combined by any convenient approach.When used successively, the antibody of the present invention or nucleic acid (or corresponding compositions or lipid granules) or other therapeutic agents can be first used.When used simultaneously, the combination can be administered in the same pharmaceutical composition or in different pharmaceutical compositions.When combined in the same preparation, it should be understood that two or more activating agents must be stable and compatible with each other and with other components of the preparation.When prepared separately, they can be provided with any convenient preparation, and can be used by any convenient approach.

[0377] The antibodies or nucleic acids of the present invention can also be administered in combination with physical therapy such as radiotherapy. Radiotherapy can be started before, after, or simultaneously with the administration of the antibody or nucleic acid. For example, radiotherapy can be started about 1 to 10 minutes, about 1 to 10 hours, or about 24 to 72 hours after the administration of the antibody or nucleic acid. The subject / patient is exposed to radiation, preferably gamma radiation, which can be provided in a single dose or in multiple doses administered over several hours, days, and / or weeks. Gamma radiation can be delivered using standard doses and protocols according to standard radiotherapy protocols.

[0378] Thus, the present invention relates to antibodies or nucleic acids (as provided herein), or corresponding pharmaceutical compositions or lipid particles, for use in treating cancer, wherein the antibodies or nucleic acids (or pharmaceutical compositions or lipid particles) are combined with one or more anti-cancer drugs (including any one or more of the specific anti-cancer drugs described above) and / or administered in combination with radiation therapy.

[0379] However, the antibodies or nucleic acids of the invention may also be used in monotherapy, in particular monotherapy for cancer (i.e., no further anticancer agents are administered until treatment with the antibody or nucleic acid is terminated). Thus, the present invention also relates to antibodies or nucleic acids (as described herein) for use in monotherapy treatment of cancer.

[0380] The subject or patient to be treated according to the present invention can be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., male or female) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cattle or pig). Most preferably, the subject / patient to be treated according to the present invention is a human.

[0381] As used herein, the term "treatment" (or its various grammatical parts of speech) in relation to a disease or condition (e.g., cancer) refers to the management and care of a patient in order to combat a disease or condition, such as to reverse, alleviate, inhibit, or delay a disease or condition, or one or more symptoms of such a disease or condition. The term also refers to the administration of a substance (e.g., an antibody or nucleic acid) or composition for the purpose of preventing the onset of symptoms of a disease or condition, alleviating such symptoms, or eliminating a disease or condition. Thus, "treatment" can be, for example, curative, ameliorative, palliative, or preventative. However, the present invention also specifically relates to non-preventative treatments for any disease / condition described herein, specifically including non-preventative treatments for cancer. Therefore, preferably, "treatment" is curative, ameliorative, or palliative.

[0382] As used herein, the terms "optional," "optionally," and "may" indicate that the indicated feature may be present but may not be present. Whenever the terms "optional," "optionally," or "may" are used, the invention specifically and solely relates to both possibilities, namely, the presence of the corresponding feature or, alternatively, the absence of the corresponding feature. For example, if a component of a composition is indicated as "optional," the invention specifically relates to both possibilities, namely, the presence of the corresponding component (included in the composition) or the absence of the corresponding component in the composition.

[0383] As used herein, unless expressly stated otherwise or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising "an" excipient can be interpreted to mean a composition comprising "one or more" excipients.

[0384] As used herein, the term "amino acid" refers, inter alia, to any of the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), as well as non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, α-methylalanine (i.e., 2-aminoisobutyric acid), , norvaline, norleucine, tert-leucine (tert-butylleucine), labionin, or alanine or glycine substituted with a cyclic group on the side chain, such as cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isoglutamine, or statins) and / or δ-amino acids and any other compounds comprising at least one carboxylic acid group and at least one amino group. Unless otherwise defined, "amino acid" preferably refers to an α-amino acid, more preferably any one of the 20 standard proteinogenic α-amino acids (which can exist in the form of an L-isomer or a D-isomer, preferably in the form of an L-isomer).

[0385] The terms "peptide", "polypeptide" and "protein" are used interchangeably herein and refer to a polymer of two or more amino acids linked by an amide bond formed between the amino group of one amino acid and the carboxyl group of another amino acid. The amino acids (also referred to as amino acid residues) contained in a peptide or protein can be selected from the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val), but also from non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, Preferably, the amino acid residues contained in the peptide or protein are selected from α-amino acids, more preferably from the 20 standard proteinogenic α-amino acids (which can exist in L-isomers or D-isomers, and preferably all exist in L-isomers). The peptide or protein may be unmodified or may be modified, for example, at its N-terminus, at its C-terminus and / or at the side chain functional groups of any of its amino acid residues (particularly at the side chain functional groups of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu and / or Arg residues). Such modifications may include, for example, post-translational modifications and / or the attachment of any protecting groups described in Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006 for the corresponding functional groups. Such modifications may also include covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide or protein), glycosylation and / or acylation of one or more fatty acids (e.g., one or more C 8-30Alkanoic or alkenoic acids; forming fatty acid acylated peptides or proteins). In addition, such modified peptides or proteins may also include peptide mimetics, provided that they contain at least two amino acids linked by an amide bond (formed between the amino group of one amino acid and the carboxyl group of another amino acid). The amino acid residues contained in the peptide or protein may, for example, exist as a linear molecular chain (forming a linear peptide or protein) or may form one or more rings (corresponding to a cyclic peptide or protein). Peptides or proteins may also form oligomers composed of two or more identical or different molecules.

[0386] All amino acid sequences provided herein are presented in the N→C direction, ie, starting from the N-terminus (the most N-terminal amino acid residue) and ending at the C-terminus (the most C-terminal amino acid residue).

[0387] Furthermore, unless expressly stated otherwise or contradicted by the context, any reference to a sequence (or partial sequence) from a defined nucleotide sequence or a defined amino acid sequence (e.g., as determined by its SEQ ID) is to be understood as relating to a continuous sequence (or continuous partial sequence) from the corresponding defined sequence. Thus, for example, any reference to a partial sequence of amino acid residues X to Y of a larger amino acid sequence defined by its SEQ ID is to be understood as relating to a continuous (uninterrupted) sequence of amino acid residues X to Y of the defined larger amino acid sequence.

[0388] As used herein, the term "% sequence identity" in relation to, for example, the amino acid sequences of proteins / peptides and / or the nucleotide sequences of nucleic acid molecules, describes the number of matches of identical amino acid residues (or nucleotides) of two or more aligned sequences compared to the number of amino acid residues (or nucleotides) that make up the total length of the compared sequences (or all compared portions thereof). Using the alignment of two or more sequences or subsequences, the percentage of identical amino acid residues (or nucleotides) can be determined by comparing and aligning the (sub)sequences for maximum correspondence over a comparison window or designated region (as measured using sequence comparison algorithms known in the art), or by manual alignment and visual inspection. Examples of algorithms that can be used to determine sequence identity include in particular those based on the NCBI BLAST algorithm (Altschul SF et al., Nucleic Acids Res, 1997, 25(17):3389-402, doi:10.1093 / nar / 25.17.3389), CLUSTALW (Thompson JD et al., Nucleic Acids Res, 1994, 22(22):4673-80, doi:10.1093 / nar / 22.22.4673) or FASTA (Pearson WR et al., Proc Natl Acad Sci USA, 1988, 85(8):2444-8, doi:10.1073 / pnas.85.8.2444). Although the FASTA algorithm does not typically consider internal non-matching deletions or additions, i.e. gaps, in the sequence in its calculations, this can be manually corrected to avoid overestimation of the % sequence identity. However, CLUSTALW does consider sequence gaps in its identity calculations.

[0389] In addition, it should be understood that no matter where a numerical range is provided / described herein, all values ​​and subranges encompassed by the corresponding numerical range are specifically provided by the present invention. Therefore, the present invention specifically and individually relates to each value falling within the numerical range described herein, as well as each subrange and any subrange encompassed by the numerical range described herein.

[0390] As used herein, the term "about" preferably refers to ±10% of the numerical value indicated, more preferably ±5% of the numerical value indicated, and in particular refers to the exact numerical value indicated. If the term "about" is used in reference to the endpoints of a range, it preferably refers to the range from -10% of the lower endpoint to +10% of the upper endpoint of the numerical value indicated, more preferably from -5% of the lower endpoint to +5% of the upper endpoint, and even more preferably refers to the range defined by the exact numerical values ​​of the lower and upper endpoints. If the term "about" is used in reference to the endpoints of an open-ended range, it preferably refers to the corresponding range starting from -10% of the lower endpoint or +10% of the upper endpoint, more preferably from -5% of the lower endpoint or +5% of the upper endpoint, and even more preferably refers to the open-ended range defined by the exact numerical values ​​of the corresponding endpoints. If the term "about" is used in reference to a parameter quantified in integers (e.g., the number of nucleotides in a given nucleic acid or the number of amino acid residues in a given peptide or protein), the number corresponding to ±10% or ±5% of the numerical value indicated will be rounded to the nearest integer (using the tie-breaking rule "rounding up"). Thus, for example, the expression "about 25 amino acid residues" preferably refers to the range of 23 to 28 amino acid residues, more preferably to the range of 24 to 26 amino acid residues, and even more preferably to the specific value of 25 amino acid residues.

[0391] As used herein, unless expressly stated otherwise or contradicted by context, the term "comprising" (or its various grammatical parts or "contain" and its various grammatical parts) has the meaning of "comprising, especially", that is, "comprising among other optional elements...". In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprises B and C" has the meaning of "A especially contains B and C", where A may contain other optional elements (e.g., "A contains B, C and D" would also be encompassed), but the term also includes (i.e., provides specific disclosure of) the meaning of "A consists essentially of B and C" and the meaning of "A consists of B and C" (i.e., A does not include other components other than B and C).

[0392] As used herein, the term "having" (or its various grammatical parts of speech), in particular when used in conjunction with an amino acid sequence or a nucleotide sequence, means "comprising". In addition, the term "having" also includes the preferred meaning of "consisting of". Thus, the expression "a VH domain having the sequence..." means that the VH domain "comprising" the indicated sequence, and preferably "consisting of the indicated sequence".

[0393] Unless otherwise specifically indicated or contradicted by the context, all properties and parameters (including functional parameters) mentioned herein are preferably determined under standard conditions (and likewise, all tests and measurements mentioned herein are preferably performed under standard conditions), in particular under standard ambient temperature and pressure conditions, for example at a temperature of 25° C. (298.15 K) and an absolute pressure of 101.325 kPa (1 atm). Tests for determining biological activity (e.g., enzyme activity) can also be performed at a temperature of 37° C.

[0394] In addition, unless otherwise indicated, any reference to a database, industry standard, pharmacopoeia or manufacturer's manual refers to the corresponding latest version available on the filing date of this specification or the earliest priority date (also referred to as the earliest application date), preferably the latest version available on the earliest priority date of this specification.

[0395] All amino acid sequences and all nucleotide sequences mentioned herein are also described in the sequence listing submitted simultaneously, which is incorporated herein by reference in its entirety. In the event of a conflict between any sequence specified in this disclosure and the corresponding sequence specified in the appended sequence listing, the present invention specifically and individually relates to each corresponding sequence.

[0396] It should be understood that the present invention is specifically and individually directed to each combination of features and embodiments described herein, including any combination of typical and / or preferred features / embodiments. Therefore, each such combination is specifically contemplated herein according to the present invention.

[0397] This specification cites numerous references, including patent applications, scientific literature, and manufacturer's manuals. The disclosures of these references, while not considered relevant to the patentability of the present invention, are hereby incorporated by reference in their entirety. More specifically, all references are incorporated by reference to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0398] Reference in this specification to any previous publication (or information derived therefrom) is not and should not be taken as an acknowledgement or approval or any form of implication that the corresponding previous publication (or information derived therefrom) forms part of the common general knowledge in the technical field to which this specification relates.

[0399] The present invention specifically relates to the following projects:

[0400] 1. A monoclonal antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway.

[0401] wherein the antibody or antigen-binding fragment specifically binds to:

[0402] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0403] And further, wherein the antibody or antigen-binding fragment specifically binds to one or more of the following:

[0404] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0405] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0406] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0407] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0408] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0409] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0410] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0411] 2. The antibody or antigen-binding fragment according to item 1, wherein the antibody or antigen-binding fragment specifically binds to:

[0412] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1), having non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0413] And further, wherein the antibody or antigen-binding fragment specifically binds three or more of the following:

[0414] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0415] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0416] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY YPDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0417] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0418] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0419] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0420] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0421] 3. The antibody or antigen-binding fragment according to item 1 or 2, wherein the antibody or antigen-binding fragment specifically binds to all of the following:

[0422] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises or consists of the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1) and has non-sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0423] And further, wherein the antibody or antigen-binding fragment specifically binds to three or more of:

[0424] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17;

[0425] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, having a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17;

[0426] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16;

[0427] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17.

[0428] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16;

[0429] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7), or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17, and a non-sulfated tyrosine residue at position Y15; and

[0430] - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

[0431] 4. The antibody or antigen-binding fragment according to any one of items 1 to 3, wherein the antibody or antigen-binding fragment specifically binds to the extracellular domain of human CCR8.

[0432] 5. The antibody or antigen-binding fragment according to any one of items 1 to 4, wherein the antibody or antigen-binding fragment inhibits the binding of human CCL1 to human CCR8. 50 is about 20 nM or lower, preferably IC 50 About 10 nM or less.

[0433] 6. The antibody or antigen-binding fragment according to any one of items 1 to 5, wherein the antibody or antigen-binding fragment is an antagonist of CCL1-induced CCR8-Gi2 signaling.

[0434] 7. The antibody or antigen-binding fragment according to any one of items 1 to 6, wherein the antibody or antigen-binding fragment has antagonistic activity against the CCL1-CCR8 signaling pathway at pH 6.2 to 6.9, preferably pH 6.5.

[0435] 8. The antibody or antigen-binding fragment according to any one of items 1 to 7, wherein the antibody or antigen-binding fragment has antagonistic activity against CCL1-induced CCR8-Gi2 signaling at pH 6.2 to 6.9, preferably pH 6.5.

[0436] 9. The antibody or antigen-binding fragment according to any one of items 1 to 8, wherein the antibody or antigen-binding fragment is an irreversible antagonist of the CCL1-CCR8 signaling pathway, preferably wherein the antibody or antigen-binding fragment is an irreversible antagonist of CCL1-induced CCR8–Gi2 signaling.

[0437] 10. The antibody or antigen-binding fragment according to any one of items 1 to 9, wherein the antibody or antigen-binding fragment comprises:

[0438] (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence VARFYGISPYAMDY (SEQ ID NO: 12); and

[0439] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15);

[0440] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0441] (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and

[0442] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20);

[0443] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0444] (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and

[0445] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24);

[0446] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0447] (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and

[0448] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15);

[0449] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0450] (5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and

[0451] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15);

[0452] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0453] (6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and

[0454] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31);

[0455] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0456] (7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and

[0457] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36);

[0458] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0459] (8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and

[0460] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36);

[0461] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0462] (9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and

[0463] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46);

[0464] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0465] (10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence SEVRRGYFDV (SEQ ID NO: 49); and

[0466] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52);

[0467] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0468] (11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and

[0469] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76);

[0470] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0471] (12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and

[0472] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91);

[0473] wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or

[0474] (13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence ARVARSSGSGPYAMDY (SEQ ID NO: 94); and

[0475] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence of KVS, and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15);

[0476] wherein in each of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue.

[0477] 11. The antibody or antigen-binding fragment according to any one of items 1 to 10, wherein the antibody or antigen-binding fragment comprises:

[0478] (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence VARFYGISPYAMDY (SEQ ID NO: 12); and

[0479] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0480] (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and

[0481] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); or

[0482] (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and

[0483] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); or

[0484] (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and

[0485] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0486] (5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and

[0487] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0488] (6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and

[0489] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31); or

[0490] (7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and

[0491] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36); or

[0492] (8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and

[0493] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36); or

[0494] (9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and

[0495] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46); or

[0496] (10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence SEVRRGYFDV (SEQ ID NO: 49); and

[0497] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52); or

[0498] (11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and

[0499] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76); or

[0500] (12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and

[0501] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91); or

[0502] (13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence ARVARSSGSGPYAMDY (SEQ ID NO: 94); and

[0503] A light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence SQSTHVPYT (SEQ ID NO: 15).

[0504] 12. The antibody or antigen-binding fragment according to any one of items 1 to 11, wherein the antibody or antigen-binding fragment comprises:

[0505] (1) a heavy chain variable domain (VH) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSKVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVQQIHGKSPEWIGGINPNGDTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARFYGISPYAMDYWGQGTSVTVSS (SEQ ID NO: 53); and

[0506] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPYTFGGGTNLEIK (SEQ ID NO: 54); or

[0507] (2) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55); and

[0508] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTYVPPTFGGGTKLEIK (SEQ ID NO: 56); or

[0509] (3) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELLKPGTSVKISCTTSGYTFSDYTLHWVKQSHGKSLEWIGGITPKNGDTRYDPRFKDKATLTIDKSSSAAYMELRSLTSEDSAVYYCARVARFYGVSPYAMDYWGQGASVTVSS (SEQ ID NO: 57); and

[0510] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSNSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLEITRVEAEDLGVYFCSQTTHVPYTFGGGTKLEIK (SEQ ID NO: 58); or

[0511] (4) a heavy chain variable domain (VH) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 59); and

[0512] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60); or

[0513] (5) a heavy chain variable domain (VH) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGKSLEWVGGINPDNGNTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 61); and

[0514] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60); or

[0515] (6) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55); and

[0516] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of MDFLVQIFSFLLISASVAMSRGENVLTQSPAIMSASPGEKVTMTCRASSSVSSSYLHWYQQKSGASPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQYSGYPYTFGGGTKLEIK (SEQ ID NO: 62); or

[0517] (7) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYRVSWIRQPPGKGLEWLGVIWGGRSTYYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCAKQGDGYYALDYWGQGTSVTVSS (SEQ ID NO: 63); and

[0518] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSYGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFHGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 64); or

[0519] (8) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVSWIRQPPGKGPEWLGVIWGGGNTYYNSVLKSRLSISNDNSKSQVFLRMNSLQTADTAIYYCARPRRDYYALDYWGQGTSVTVAS (SEQ ID NO: 65); and

[0520] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYTNGNTFLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 66); or

[0521] (9) a heavy chain variable domain (VH) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence MGWSSIILFLVATASGVHSQVQLQQPGSELVRPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGNIWPGSASTNYDEKFKNKATLTVDTSSSTAYMQLSSLTSEDSAVYYCIRGGKGAMDYWSQGTSVTVSS (SEQ ID NO: 67); and

[0522] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQIPLSLPVSLGDQASISCRSSQSLENSYGNTYLNWYLQKPGQSPQLLIYRVSNRFSGVLDRFSGSGSGTDFTLKISRVEAEDLGVYFCLQVTHVPPTFGAGTKLELK (SEQ ID NO: 68); or

[0523] (10) a heavy chain variable domain (VH) having an amino acid sequence that is at least 80% identical to the amino acid sequence of MERHWIFLLLLSVTAGVHSQVQVQQSGAELARPGASVKMSCKASGYTFTTYAMHWVKQRPGQGLEWIGHINPSSGYSNYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSEVRRGYFDVWGAGTTVTVSS (SEQ ID NO: 69); and

[0524] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCRTSQDIRNYLNWYQQKPDGTVKLLISYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPPTFGGGTRVEIK (SEQ ID NO: 70); or

[0525] (11) a heavy chain variable domain (VH) having an amino acid sequence having at least 80% sequence identity to the amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKASVYSFTGSYMHWVKQSHVKSLEWIGRINPYNGATSYNQNFKDKASLTVDKSSSTAYMELHSLTSEDSAVYYCATTLLRLLDYWGQGTTLTVSS (SEQ ID NO: 77); and

[0526] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of MRFSAQLLGLLVLWIPGSTADIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPWTFGGGTKLEIK (SEQ ID NO: 78); or

[0527] (12) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSS (SEQ ID NO: 96); and

[0528] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIK (SEQ ID NO: 97); or

[0529] (13) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 98); and

[0530] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99); or

[0531] (14) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 100); and

[0532] a light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99); or

[0533] (15) a heavy chain variable domain (VH) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 101); and

[0534] A light chain variable domain (VL) having an amino acid sequence that has at least 80% sequence identity to the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 102).

[0535] 13. The antibody or antigen-binding fragment according to any one of items 1 to 12, wherein the antibody or antigen-binding fragment comprises:

[0536] (1) Heavy chain (HC) having the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:103); and

[0537] Light chain (LC) having the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:104); or

[0538] (2) Heavy chain (HC) having the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:105); and

[0539] Light chain (LC) having the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:104); or

[0540] (3) Heavy chain (HC) having the amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:106); and

[0541] Light chain (LC) having the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:X); or

[0542] It should be noted that there seems to be a minor error in the original text where "SEQ ID NO:107" in the light chain sequence description is likely a misprint as it is later referred to as "SEQ ID NO:X". I've left it as "SEQ ID NO:X" in the translation for consistency with the original. If this is a known error in the source text, it should be corrected accordingly in the original before translation for a more accurate result.(4) Heavy chain (HC) having the amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:108); and

[0543] Light chain (LC) having the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:107); or

[0544] (5) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:109); and

[0545] Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or

[0546] (6) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:111); and

[0547] Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or

[0548] (7) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:112); and

[0549] Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or

[0550] (8) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:113); and

[0551] Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or

[0552] (9) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVA RSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNWALPAP ISKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:114); and

[0553] A light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFG GGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:110).

[0554] 14. A monoclonal antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8, and wherein the antibody or antigen-binding fragment comprises:

[0555] (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence VARFYGISPYAMDY (SEQ ID NO: 12); and

[0556] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or

[0557] (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and

[0558] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); or

[0559] (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and

[0560] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); or

[0561] (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and

[0562] a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having th...

Claims

1. A monoclonal antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8 and is an antagonist of the CCL1-CCR8 signaling pathway. wherein the antibody or antigen-binding fragment specifically binds to: - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNG (SEQ ID NO: 1) or consisting thereof, There are non-sulfated tyrosine residues at positions Y15, Y16 and Y17. And further, wherein the antibody or antigen-binding fragment specifically binds to one or more of the following: - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y YYPDIFSSPCDAELIQTNG (SEQ ID NO: 2) or consisting thereof, having a sulfated tyrosine residue at position Y15 and non-sulfated tyrosine residues at positions Y16 and Y17; - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY Y YPDIFSSPCDAELIQTNG (SEQ ID NO: 3) or consisting thereof, in a sulfated tyrosine residue at position Y16 and non-sulfated tyrosine residues at positions Y15 and Y17; - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDYY Y PDIFSSPCDAELIQTNG (SEQ ID NO: 4) or consisting thereof, having a sulfated tyrosine residue at position Y17 and non-sulfated tyrosine residues at positions Y15 and Y16; - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YY or consists of YPDIFSSPCDAELIQTNG (SEQ ID NO: 5), having sulfated tyrosine residues at positions Y15 and Y16, and a non-sulfated tyrosine residue at position Y17. - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD Y Y Y PDIFSSPCDAELIQTNG (SEQ ID NO: 6) or consisting thereof, having sulfated tyrosine residues at positions Y15 and Y17 and a non-sulfated tyrosine residue at position Y16; - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTDY YY PDIFSSPCDAELIQTNG (SEQ ID NO: 7) or consisting thereof, having sulfated tyrosine residues at positions Y16 and Y17 and a non-sulfated tyrosine residue at position Y15; and - human CCR8 or a partial sequence thereof, wherein the partial sequence comprises the amino acid sequence MDYTLDLSVTTVTD YYY PDIFSSPCDAELIQTNG (SEQ ID NO: 8) or consists thereof, having sulfated tyrosine residues at positions Y15, Y16 and Y17.

2. The antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment inhibits the binding of human CCL1 to human CCR8. 50 is about 20 nM or lower, preferably IC 50 About 10 nM or less.

3. The antibody or antigen-binding fragment of claim 1 or 2, wherein the antibody or antigen-binding fragment is an antagonist of CCL1-induced CCR8-Gi2 signaling.

4. The antibody or antigen-binding fragment according to any one of claims 1 to 3, wherein the antibody or antigen-binding fragment is an insurmountable antagonist of the CCL1-CCR8 signaling pathway, preferably wherein the antibody or antigen-binding fragment is an insurmountable antagonist of CCL1-induced CCR8-Gi2 signaling.

5. The antibody or antigen-binding fragment according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment comprises: (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence of VARFYGISPYAMDY (SEQ ID NO: 12); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence SEVRRGYFDV (SEQ ID NO: 49); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76); wherein in each of said CDR-H1, said CDR-H2, said CDR-H3, said CDR-L1, said CDR-L2 and said CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue; or (13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence ARVARSSGSGPYAMDY (SEQ ID NO: 94); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence of KVS, and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); wherein in each of the CDR-H1, the CDR-H2, the CDR-H3, the CDR-L1, the CDR-L2 and the CDR-L3, a single amino acid residue is optionally replaced by a different amino acid residue.

6. The antibody or antigen-binding fragment according to any one of claims 1 to 5, wherein the antibody or antigen-binding fragment comprises: (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91); or (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence of VARFYGISPYAMDY (SEQ ID NO: 12); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); or (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); or (5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31); or (8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36); or (9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36); or (10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46); or (11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence SEVRRGYFDV (SEQ ID NO: 49); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52); or (12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76); or (13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence ARVARSSGSGPYAMDY (SEQ ID NO: 94); and A light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence SQSTHVPYT (SEQ ID NO: 15).

7. The antibody or antigen-binding fragment according to any one of claims 1 to 6, wherein the antibody or antigen-binding fragment comprises: (1) a heavy chain variable domain (VH) having an amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSS (SEQ ID NO: 96) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIK (SEQ ID NO: 97) ; or (2) a heavy chain variable domain (VH) having an amino acid sequence similar to MGWSWIFLFLLSGTAGVLSKVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVQQIHGKSPEWIGGINPNGDTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARFYGISPYAMDYWGQGTSVTVSS (SEQ ID NO: 53) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPYTFGGGTNLEIK (SEQ ID NO: 54) an amino acid sequence having at least 80% sequence identity; or (3) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTYVPPTFGGGTKLEIK (SEQ ID NO: 56) an amino acid sequence having at least 80% sequence identity; or (4) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELLKPGTSVKISCTTSGYTFSDYTLHWVKQSHGKSLEWIGGITPKNGDTRYDPRFKDKATLTIDKSSSAAYMELRSLTSEDSAVYYCARVARFYGVSPYAMDYWGQGASVTVSS (SEQ ID NO: 57) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSNSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLEITRVEAEDLGVYFCSQTTHVPYTFGGGTKLEIK (SEQ ID NO: 58) an amino acid sequence having at least 80% sequence identity; or (5) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 59) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60) has an amino acid sequence with at least 80% sequence identity; or (6) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGKSLEWVGGINPDNGNTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 61) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60) has an amino acid sequence with at least 80% sequence identity; or (7) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MDFLVQIFSFLLISASVAMSRGENVLTQSPAIMSASPGEKVTMTCRASSSVSSSYLHWYQQKSGASPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQYSGYPYTFGGGTKLEIK (SEQ ID NO: 62) ; or (8) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYRVSWIRQPPGKGLEWLGVIWGGRSTYYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCAKQGDGYYALDYWGQGTSVTVSS (SEQ ID NO: 63) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSYGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFHGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 64) an amino acid sequence having at least 80% sequence identity; or (9) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVSWIRQPPGKGPEWLGVIWGGGNTYYNSVLKSRLSISNDNSKSQVFLRMNSLQTADTAIYYCARPRRDYYALDYWGQGTSVTVAS (SEQ ID NO: 65) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYTNGNTFLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 66) an amino acid sequence having at least 80% sequence identity; or (10) a heavy chain variable domain (VH) having an amino acid sequence MGWSSIILFLVATASGVHSQVQLQQPGSELVRPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGNIWPGSASTNYDEKFKNKATLTVDTSSSTAYMQLSSLTSEDSAVYYCIRGGKGAMDYWSQGTSVTVSS (SEQ ID NO: 67) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQIPLSLPVSLGDQASISCRSSQSLENSYGNTYLNWYLQKPGQSPQLLIYRVSNRFSGVLDRFSGSGSGTDFTLKISRVEAEDLGVYFCLQVTHVPPTFGAGTKLELK (SEQ ID NO: 68) an amino acid sequence having at least 80% sequence identity; or (11) a heavy chain variable domain (VH) having an amino acid sequence MERHWIFLLLLSVTAGVHSQVQVQQSGAELARPGASVKMSCKASGYTFTTYAMHWVKQRPGQGLEWIGHINPSSGYSNYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSEVRRGYFDVWGAGTTVTVSS (SEQ ID NO: 69) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCRTSQDIRNYLNWYQQKPDGTVKLLISYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPPTFGGGTRVEIK (SEQ ID NO: 70) an amino acid sequence having at least 80% sequence identity; or (12) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKASVYSFTGSYMHWVKQSHVKSLEWIGRINPYNGATSYNQNFKDKASLTVDKSSSTAYMELHSLTSEDSAVYYCATTLLRLLDYWGQGTTLTVSS (SEQ ID NO: 77) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MRFSAQLLGLLVLWIPGSTADIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPWTFGGGTKLEIK (SEQ ID NO: 78) has an amino acid sequence with at least 80% sequence identity; or (13) a heavy chain variable domain (VH) having an amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 98) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99) ; or (14) a heavy chain variable domain (VH) having an amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 100) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99) ; or (15) a heavy chain variable domain (VH) having an amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 101) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 102) has an amino acid sequence with at least 80% sequence identity.

8. The antibody or antigen-binding fragment according to any one of claims 1 to 7, wherein the antibody or antigen-binding fragment comprises: (1) Heavy chain (HC), which has the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:105); and Light chain (LC), which has the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:104); or (2) a heavy chain (HC) having the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:103); and a light chain (LC) having the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:104); or (3) a heavy chain (HC) having the amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:106); and a light chain (LC) having the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:107); or (4) a heavy chain (HC) having the amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:108); and Light chain (LC), which has the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:107); or (5) Heavy chain (HC), which has the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:109); and a light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (6) a heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:111); and Light chain (LC), having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (7) Heavy chain (HC), having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:112); and a light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (8) a heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:113); and Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (9) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWG QGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNWALPAPISKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:114); and Light chain (LC), which has the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:110).

9. A monoclonal antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8, and wherein the antibody or antigen-binding fragment comprises: (1) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of GFTFNAYA (SEQ ID NO: 87), a CDR-H2 having the amino acid sequence of IRSKSNDYAT (SEQ ID NO: 88), and a CDR-H3 having the amino acid sequence of VRGREAYYRYDGGYYAMDV (SEQ ID NO: 89); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of KSLLHSNGNTY (SEQ ID NO: 90), a CDR-L2 having the amino acid sequence of RMS, and a CDR-L3 having the amino acid sequence of MQHREYPFT (SEQ ID NO: 91); or (2) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPNGDTRYDQKFKG (SEQ ID NO: 11), and a CDR-H3 having the amino acid sequence of VARFYGISPYAMDY (SEQ ID NO: 12); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (3) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYSNGNTYLH (SEQ ID NO: 19), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTYVPPT (SEQ ID NO: 20); or (4) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYTLH (SEQ ID NO: 21), a CDR-H2 having the amino acid sequence GITPKNGDTRYDPRFKD (SEQ ID NO: 22), and a CDR-H3 having the amino acid sequence VARFYGVSPYAMDY (SEQ ID NO: 23); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHSNGDTYLH (SEQ ID NO: 13), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQTTHVPYT (SEQ ID NO: 24); or (5) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence GINPNNGNTRYDQKFKG (SEQ ID NO: 25), and a CDR-H3 having the amino acid sequence VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (6) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence of EYTIH (SEQ ID NO: 10), a CDR-H2 having the amino acid sequence of GINPDNGNTRYDQKFKG (SEQ ID NO: 28), and a CDR-H3 having the amino acid sequence of VARSSGSGPYAMDY (SEQ ID NO: 26); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RCTQSLLHTNGDTYLH (SEQ ID NO: 27), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPYT (SEQ ID NO: 15); or (7) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYVVT (SEQ ID NO: 16), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSDLKS (SEQ ID NO: 17), and a CDR-H3 having the amino acid sequence RHRDYALDY (SEQ ID NO: 18); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RASSSVSSSYLH (SEQ ID NO: 29), a CDR-L2 having the amino acid sequence of STSNLAS (SEQ ID NO: 30), and a CDR-L3 having the amino acid sequence of QQYSGYPYT (SEQ ID NO: 31); or (8) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYRVS (SEQ ID NO: 32), a CDR-H2 having the amino acid sequence VIWGGRSTYYNSALKS (SEQ ID NO: 33), and a CDR-H3 having the amino acid sequence QGDGYYALDY (SEQ ID NO: 34); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVHSYGNTYLH (SEQ ID NO: 35), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO: 14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO: 36); or (9) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence DYGVS (SEQ ID NO: 37), a CDR-H2 having the amino acid sequence VIWGGGNTYYNSVLKS (SEQ ID NO: 38), and a CDR-H3 having the amino acid sequence PRRDYYALDY (SEQ ID NO: 39); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLVYTNGNTFLH (SEQ ID NO:40), a CDR-L2 having the amino acid sequence of KVSNRFS (SEQ ID NO:14), and a CDR-L3 having the amino acid sequence of SQSTHVPPT (SEQ ID NO:36); or (10) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence SYWMH (SEQ ID NO: 41), a CDR-H2 having the amino acid sequence NIWPGSASTNYDEKFKN (SEQ ID NO: 42), and a CDR-H3 having the amino acid sequence GGKGAMDY (SEQ ID NO: 43); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSQSLENSYGNTYLN (SEQ ID NO: 44), a CDR-L2 having the amino acid sequence of RVSNRFS (SEQ ID NO: 45), and a CDR-L3 having the amino acid sequence of LQVTHVPPT (SEQ ID NO: 46); or (11) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence TYAMH (SEQ ID NO: 47), a CDR-H2 having the amino acid sequence HINPSSGYSNYNQKFKD (SEQ ID NO: 48), and a CDR-H3 having the amino acid sequence SEVRRGYFDV (SEQ ID NO: 49); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RTSQDIRNYLN (SEQ ID NO: 50), a CDR-L2 having the amino acid sequence of YTSRLHS (SEQ ID NO: 51), and a CDR-L3 having the amino acid sequence of QQGNTLPPT (SEQ ID NO: 52); or (12) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GSYMH (SEQ ID NO: 71), a CDR-H2 having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO: 72), and a CDR-H3 having the amino acid sequence TLLRLLDY (SEQ ID NO: 73); and a light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 74), a CDR-L2 having the amino acid sequence of QMSNLAS (SEQ ID NO: 75), and a CDR-L3 having the amino acid sequence of AQNLELPWT (SEQ ID NO: 76); or (13) a heavy chain variable domain (VH) comprising a CDR-H1 having the amino acid sequence GYTFTEYT (SEQ ID NO: 92), a CDR-H2 having the amino acid sequence INPNNGNT (SEQ ID NO: 93), and a CDR-H3 having the amino acid sequence ARVARSSGSGPYAMDY (SEQ ID NO: 94); and A light chain variable domain (VL) comprising a CDR-L1 having the amino acid sequence QSLLHTNGDTY (SEQ ID NO: 95), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence SQSTHVPYT (SEQ ID NO: 15).

10. A monoclonal antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8, and wherein the antibody or antigen-binding fragment comprises: (1) a heavy chain variable domain (VH) having an amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSS (SEQ ID NO: 96) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIK (SEQ ID NO: 97) ; or (2) a heavy chain variable domain (VH) having an amino acid sequence similar to MGWSWIFLFLLSGTAGVLSKVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVQQIHGKSPEWIGGINPNGDTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARFYGISPYAMDYWGQGTSVTVSS (SEQ ID NO: 53) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPYTFGGGTNLEIK (SEQ ID NO: 54) an amino acid sequence having at least 80% sequence identity; or (3) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTYVPPTFGGGTKLEIK (SEQ ID NO: 56) an amino acid sequence having at least 80% sequence identity; or (4) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELLKPGTSVKISCTTSGYTFSDYTLHWVKQSHGKSLEWIGGITPKNGDTRYDPRFKDKATLTIDKSSSAAYMELRSLTSEDSAVYYCARVARFYGVSPYAMDYWGQGASVTVSS (SEQ ID NO: 57) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSNSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHSNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLEITRVEAEDLGVYFCSQTTHVPYTFGGGTKLEIK (SEQ ID NO: 58) an amino acid sequence having at least 80% sequence identity; or (5) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 59) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60) has an amino acid sequence with at least 80% sequence identity; or (6) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGKSLEWVGGINPDNGNTRYDQKFKGKATLTIDKSSSTAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 61) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 60) has an amino acid sequence with at least 80% sequence identity; or (7) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGLSMNDYVVTWIRQPPGKGLEWLGVIWGGGNTYYNSDLKSRLSITKDNSKSQVFFKMSSLQTDDTAVYYCARRHRDYALDYWGQGISVTVSS (SEQ ID NO: 55) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MDFLVQIFSFLLISASVAMSRGENVLTQSPAIMSASPGEKVTMTCRASSSVSSSYLHWYQQKSGASPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQYSGYPYTFGGGTKLEIK (SEQ ID NO: 62) ; or (8) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYRVSWIRQPPGKGLEWLGVIWGGRSTYYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCAKQGDGYYALDYWGQGTSVTVSS (SEQ ID NO: 63) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSYGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFHGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 64) an amino acid sequence having at least 80% sequence identity; or (9) a heavy chain variable domain (VH) having an amino acid sequence MAVLGLLLCLVTFPSCVLSQVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVSWIRQPPGKGPEWLGVIWGGGNTYYNSVLKSRLSISNDNSKSQVFLRMNSLQTADTAIYYCARPRRDYYALDYWGQGTSVTVAS (SEQ ID NO: 65) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVYTNGNTFLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPTFGGGTKLEIK (SEQ ID NO: 66) an amino acid sequence having at least 80% sequence identity; or (10) a heavy chain variable domain (VH) having an amino acid sequence MGWSSIILFLVATASGVHSQVQLQQPGSELVRPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGNIWPGSASTNYDEKFKNKATLTVDTSSSTAYMQLSSLTSEDSAVYYCIRGGKGAMDYWSQGTSVTVSS (SEQ ID NO: 67) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MKLPVRLLVLMFWIPVSSSDVVMTQIPLSLPVSLGDQASISCRSSQSLENSYGNTYLNWYLQKPGQSPQLLIYRVSNRFSGVLDRFSGSGSGTDFTLKISRVEAEDLGVYFCLQVTHVPPTFGAGTKLELK (SEQ ID NO: 68) an amino acid sequence having at least 80% sequence identity; or (11) a heavy chain variable domain (VH) having an amino acid sequence MERHWIFLLLLSVTAGVHSQVQVQQSGAELARPGASVKMSCKASGYTFTTYAMHWVKQRPGQGLEWIGHINPSSGYSNYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSEVRRGYFDVWGAGTTVTVSS (SEQ ID NO: 69) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCRTSQDIRNYLNWYQQKPDGTVKLLISYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPPTFGGGTRVEIK (SEQ ID NO: 70) an amino acid sequence having at least 80% sequence identity; or (12) a heavy chain variable domain (VH) having an amino acid sequence MGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKASVYSFTGSYMHWVKQSHVKSLEWIGRINPYNGATSYNQNFKDKASLTVDKSSSTAYMELHSLTSEDSAVYYCATTLLRLLDYWGQGTTLTVSS (SEQ ID NO: 77) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence MRFSAQLLGLLVLWIPGSTADIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPWTFGGGTKLEIK (SEQ ID NO: 78) has an amino acid sequence with at least 80% sequence identity; or (13) a heavy chain variable domain (VH) having an amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 98) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99) ; or (14) a heavy chain variable domain (VH) having an amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSS (SEQ ID NO: 100) has an amino acid sequence of at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIK (SEQ ID NO: 99) ; or (15) a heavy chain variable domain (VH) having an amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSS (SEQ ID NO: 101) an amino acid sequence having at least 80% sequence identity; and The light chain variable domain (VL) has an amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 102) has an amino acid sequence with at least 80% sequence identity.

11. A monoclonal antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human CCR8, and wherein the antibody or antigen-binding fragment comprises: (1) Heavy chain (HC), which has the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:105); and Light chain (LC), having the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:104); or (2) Heavy chain (HC), having the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNAYAMNWVRQAPGKGLEWVARIRSKSNDYATYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRGREAYYRYDGGYYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:103); and Light chain (LC), which has the amino acid sequence DIVMTQAAPSLSVTPGESASISCTSSKSLLHSNGNTYLYWFLQKPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHREYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:104); or (3) Heavy chain (HC), which has the amino acid sequence QVQLVQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWVGGINPNNGNTRYDQKFQGRVTITRDKSASTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:106); and Light chain (LC), having the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:107); or (4) Heavy chain (HC), having the amino acid sequence QVQLQQSGPEVVKPGASVKVSCKTSGYTFTEYTIHWVRQSHGQSLEWVGGINPNNGNTRYDQKFKGRVTITIDKSSSTAYMELRSLTSEDTAVYYCARVARSSGSGPYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:108); and Light chain (LC), which has the amino acid sequence DVVMTQSPLSLPVTLGDQASISCRCSQSLLHTNGDTYLHWYLQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:107); or (5) Heavy chain (HC), which has the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:109); and Light chain (LC), having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (6) Heavy chain (HC), having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:111); and Light chain (LC), having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (7) Heavy chain (HC), having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:112); and Light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (8) Heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:113); and a light chain (LC) having the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:110); or (9) a heavy chain (HC) having the amino acid sequence EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTIHWVKQSHGESLEWVGGINPNNGNTRYDQKFKGKATLTIDKSSSPAYMELRSLTSEDSAVYYCARVARSSGSGPYAMDYWG QGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELVGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSVLTVLHQDWLNGKEYKCKVSNWALPAPISKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:114); and Light chain (LC), which has the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRCTQSLLHTNGDTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:110).

12. The antibody or antigen-binding fragment according to any one of claims 1 to 11, wherein the antibody or antigen-binding fragment comprises an Fc region, preferably an IgG1 Fc region.

13. The antibody or antigen-binding fragment according to any one of claims 1 to 12, wherein the antibody or antigen-binding fragment has ADCC, CDC and / or ADCP activity.

14. The antibody or antigen-binding fragment of any one of claims 1 to 13, wherein the antibody or antigen-binding fragment comprises a hypofucosylated or afucosylated Fc region.

15. The antibody or antigen-binding fragment of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment comprises an Fc region having one or more mutations that enhance ADCC and / or CDC and / or ADCP activity. 16 . The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment has an activity of depleting CCR8-positive cells. 17 . The antibody or antigen-binding fragment according to any one of claims 1 to 16 , wherein the antibody or antigen-binding fragment has the activity of depleting CCR8-positive immune cells.

18. The antibody or antigen-binding fragment according to any one of claims 1 to 16, wherein the antibody or antigen-binding fragment has activity in depleting CCR8-positive cancer cells.

19. The antibody or antigen-binding fragment according to any one of claims 1 to 18, wherein the antibody or antigen-binding fragment has an activity of inhibiting CCL1-induced CCR8-positive cell migration.

20. The antibody or antigen-binding fragment according to any one of claims 1 to 19, wherein the antibody or antigen-binding fragment has an activity of inhibiting CCL1-induced activation of CCR8-positive cells.

21. The antibody or antigen-binding fragment of any one of claims 1 to 20, wherein the antibody or antigen-binding fragment does not bind to peripheral immune cells from a healthy donor.

22. A nucleic acid encoding the heavy chain and / or light chain of the antibody or antigen-binding fragment according to any one of claims 1 to 21.

23. A vector comprising the nucleic acid according to claim 22.

24. A host cell comprising the nucleic acid according to claim 22 or the vector according to claim 23.

25. A method of producing the antibody or antigen-binding fragment according to any one of claims 1 to 21, the method comprising culturing the host cell according to claim 24 and isolating the antibody or antigen-binding fragment.

26. The method of claim 25, wherein the host cell is a hypofucosylated or afucosylated host cell.

27. An antibody or antigen-binding fragment as defined in any one of claims 1 to 21, obtainable by the method of any one of claims 25 or 26.

28. The antibody or antigen-binding fragment according to any one of claims 1 to 21, which is obtainable by using a hypofucosylated or afucosylated producer cell line.

29. A composition comprising the antibody or antigen-binding fragment according to any one of claims 1 to 21, 27 or 28 or the nucleic acid according to claim 22, wherein the composition is preferably a pharmaceutical composition.

30. A lipid particle comprising one or more nucleic acids according to claim 22.

31. nucleic acid according to claim 22 or lipid granule according to claim 30, wherein the nucleic acid is mRNA.

32. A chimeric antigen receptor (CAR) comprising an antibody or antigen-binding fragment as defined in any one of claims 1 to 7, 9 or 10, preferably comprising a single-chain variable fragment (scFv) according to any one of claims 1 to 7, 9 or 10.

33. An immune cell expressing the chimeric antigen receptor according to claim 32, wherein the immune cell is preferably a T cell or a natural killer cell, more preferably a T cell, and even more preferably an α-β-T cell or a γ-δ-T cell.

34. The antibody or antigen-binding fragment of any one of claims 1 to 21, 27 or 28, the nucleic acid of claim 22 or 31, the composition of claim 29, the lipid particle of claim 30 or 31 or the immune cell of claim 33 for use in treating cancer.

35. The antibody or antigen-binding fragment for use according to claim 34, the nucleic acid for use according to claim 34, the composition for use according to claim 34, the lipid particle for use according to claim 34, or the immune cell for use according to claim 34, wherein the cancer is a solid cancer.

36. The antibody or antigen-binding fragment for use according to claim 34, the nucleic acid for use according to claim 34, the composition for use according to claim 34, the lipid particle for use according to claim 34, or the immune cell for use according to claim 34, wherein the cancer is a blood cancer.

37. The antibody or antigen-binding fragment for use according to claim 34, the nucleic acid for use according to claim 34, the composition for use according to claim 34, the lipid particle for use according to claim 34, or the immune cell for use according to claim 34, wherein the cancer is selected from ovarian cancer, colorectal cancer, colon cancer, gastric cancer, esophageal cancer, breast cancer, lung cancer, bladder cancer, uterine cancer, urothelial cancer, Kaposi's sarcoma, skin cancer, head and / or neck cancer, kidney cancer, and lymphoma.

38. An antibody or antigen-binding fragment for use according to any one of claims 34 to 37, a nucleic acid for use according to any one of claims 34 to 37, a composition for use according to any one of claims 34 to 37, a lipid particle for use according to any one of claims 34 to 37, or an immune cell for use according to any one of claims 34 to 37, wherein the treatment comprises administering one or more immune checkpoint inhibitors in combination; preferably, wherein the one or more immune checkpoint inhibitors are selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti-OX40 antibodies, and anti-ICOS antibodies. More preferably, the one or more immune checkpoint inhibitors are selected from ipilimumab, tesimumab, nivolumab, pembrolizumab, pidilizumab, cemiplizumab, dustalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalizumab, zimbelimab, AMP-224, AMP-514, JTX-4014, INCMGA00012, APE02058, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI93 9. M6223, cobolimab, sabatolimab, BMS-986258, Sym023, TQB2618, LY3321367, SHR-1702, relatlimab, ieramilimab, encelimab, tebo telimab, REGN3767, FS118, IMP701, IMP731, ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A44 5. YH-002, BMS986178, INBRX-106, IBI101, MOXR0916, alomfilimab, feladilimab, vopratelimab, BMS-986226, MEDI-570 and XmAb23104.

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