Methods of treating cancer with anti-CC motif chemokine receptor 8 (CCR8) antibodies

Abstract

The present disclosure provides, inter alia, methods of treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof by administering an anti-CCR8 antibody to the subject, and related therapeutic uses.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, and is incorporated herein by reference in its entirety. Said XML copy, created on October 5, 2023, is titled 50474-310WO3_Sequence_Listing_10_05_23 and is 161,635 bytes in size.

[0002] The present invention relates to methods of treating cancer (eg, locally advanced, recurrent, or metastatic solid tumor malignancies) in a patient and compositions for use in treating cancer. [Background technology]

[0003] Regulatory T (Treg) cells, which express the transcription factor Foxp3, are important for maintaining peripheral immune tolerance and preventing autoimmunity. Treg cells also constitute a major component of the immune infiltrate in solid tumors, promoting tumor initiation and progression by establishing an immunosuppressive tumor microenvironment and attenuating antitumor immune responses. Treg cells also hinder the effectiveness of immunotherapy. An increased proportion of Treg cells among tumor-infiltrating lymphocytes is associated with poorer outcomes in several cancer indications.

[0004] Although checkpoint blockade has resulted in improved overall survival in some patients, there remains a subset of patients whose cancer is refractory to treatment (primary resistance) or progresses after treatment (secondary resistance).

[0005] Therefore, there is a need for improved methods for treating cancer. Summary of the Invention

[0006] The present disclosure provides, inter alia, methods of treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, anti-CCR8 antibodies (e.g., monoclonal antibodies that bind to CCR8) for use in treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, and related uses and kits.

[0007] In one aspect, the invention features a method of treating locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CC motif chemokine receptor 8 (CCR8).

[0008] In another aspect, the invention features a monoclonal antibody that binds to CCR8 for use in treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof.

[0009] In some embodiments, (i) the subject has progressed after at least one available standard treatment; and / or (ii) the subject is one for whom all available standard treatments have proven ineffective or intolerable or are contraindicated.

[0010] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor is incurable.

[0011] In some embodiments, the subject is 18 years of age or older.

[0012] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UC), esophageal cancer, gastric cancer, cervical cancer, renal cell carcinoma (RCC), or hepatocellular carcinoma (HCC).

[0013] In some embodiments, the RCC is clear cell RCC.

[0014] In some embodiments, the HNSCC is an HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

[0015] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC.

[0016] In some embodiments, the subject's tumor contains a targetable somatic alteration and the subject is experiencing disease progression during or after treatment with, or intolerance to, treatment with a targeted agent.

[0017] In some embodiments, targetable somatic alterations include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

[0018] In some embodiments, the melanoma is cutaneous melanoma.

[0019] In some embodiments, the subject's tumor comprises a BRAFV600 mutation and the subject is experiencing disease progression during or after treatment with, or intolerance to, one or more serine / threonine-protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase (MEK) inhibitors.

[0020] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is UC.

[0021] In some embodiments, the subject has (i) histologically confirmed, incurable, advanced transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, bladder, and urethra); and / or the subject's tumor has mixed histology with a predominant transitional cell pattern.

[0022] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is TNBC.

[0023] In some embodiments, TNBC is defined by the American Society of Clinical Oncology-College of American Pathologists guidelines: (i) less than 1% of tumor cell nuclei are immunoreactive for estrogen receptors and less than 1% of tumor cell nuclei are immunoreactive for progesterone receptors; and / or (ii) is HER2 negative based on immunohistochemistry (IHC) and / or in situ hybridization.

[0024] In some embodiments, the subject is checkpoint inhibitor (CPI) naive.

[0025] In some embodiments, the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC or UC.

[0026] In some embodiments, the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is UC, the subject is eligible for treatment with cisplatin, and the subject experiences disease progression during or after treatment with or intolerance to treatment with cisplatin.

[0027] In some embodiments, the subject has not received previous treatment with a CPI, or the subject has received adjuvant treatment with a CPI that was discontinued at least 6 months prior to the subject's first administration of a monoclonal antibody that binds CCR8.

[0028] In some embodiments, the subject is experiencing CPI.

[0029] In some embodiments, the subject locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC, HNSCC, melanoma, UC, TNBC, esophageal cancer, gastric cancer, cervical cancer, clear cell RCC, or HCC.

[0030] In some embodiments, the subject derives clinical benefit from treatment comprising a PD-1 axis-binding antagonist prior to disease progression.

[0031] In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody.

[0032] In some embodiments, the subject had a treatment duration with a treatment comprising a PD-1 axis-binding antagonist of 6 months or greater and / or had a partial response or a complete response as the best objective response.

[0033] In some embodiments, (i) the subject has not been treated with a CPI, an immunomodulatory monoclonal antibody, or an immunomodulatory monoclonal antibody induction therapy within 6 weeks prior to the subject's first administration of a monoclonal antibody that binds CCR8; or (ii) the subject has been previously treated with a PD-1 axis-binding antagonist, and the subject's last administration of the PD-1 axis-binding antagonist was at least 3 weeks prior to the subject's first administration of a monoclonal antibody that binds CCR8.

[0034] In some embodiments, the CPI is a PD-1 axis binding antagonist or a CTLA4 antagonist.

[0035] In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody.

[0036] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject in a dosing regimen comprising one or more dosing cycles.

[0037] In some embodiments, the one or more administration cycles comprise a 21 day administration cycle.

[0038] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject on day 1 of each 21-day administration cycle.

[0039] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject until disease progression or unacceptable toxicity occurs.

[0040] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject at a dose of 2 mg.

[0041] In some embodiments, the monoclonal antibody that binds to CCR8 is administered intravenously to the subject.

[0042] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject intravenously by infusion.

[0043] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject as a monotherapy.

[0044] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject in combination with one or more additional therapeutic agents.

[0045] In some embodiments, the one or more additional therapeutic agents comprises atezolizumab.

[0046] In some embodiments, atezolizumab is administered to a subject in a dosing regimen comprising one or more dosing cycles.

[0047] In some embodiments, the one or more administration cycles comprise a 21 day administration cycle.

[0048] In some embodiments, atezolizumab is administered to the subject on day 1 of each 21-day administration cycle.

[0049] In some embodiments, atezolizumab is administered to a subject at a dose of 1200 mg.

[0050] In some embodiments, atezolizumab is administered to the subject intravenously.

[0051] In some embodiments, atezolizumab is administered to a subject intravenously by infusion.

[0052] In some embodiments, a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.

[0053] In some embodiments, a tumor sample from a subject has 1% or more tumor cells (TC), immune cells (IC), combined positive score (CPS), or tumor proportion score (TPS).

[0054] In some embodiments, the subject received at least two cycles of a monoclonal antibody that binds to CCR8 prior to administration of atezolizumab to the subject.

[0055] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0056] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0057] In some embodiments, the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO:106.

[0058] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35-47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48-52; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0059] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52.

[0060] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 48; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0061] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:47, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:48.

[0062] In some aspects, the VL comprises a V4M mutation, a P43A mutation, a F46L mutation, a C90Q mutation, or a combination thereof. In some embodiments, the V4M mutation, the P43A mutation, the F46L mutation, or the C90Q mutation is according to Kabat numbering.

[0063] In some aspects, the VH comprises a G49S mutation, a K71R mutation, an S73N mutation, or a combination thereof. In some embodiments, the G49S mutation, the K71R mutation, or the S73N mutation is according to Kabat numbering.

[0064] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:55 and the light chain amino acid sequence of SEQ ID NO:56.

[0065] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:60 and the light chain amino acid sequence of SEQ ID NO:56.

[0066] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:111 and the light chain amino acid sequence of SEQ ID NO:56.

[0067] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:113 and the light chain amino acid sequence of SEQ ID NO:56.

[0068] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52.

[0069] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:47 and the VL sequence of SEQ ID NO:48.

[0070] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0071] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0072] In some embodiments, the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:106.

[0073] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0074] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 10-21 and a VL sequence selected from the group consisting of SEQ ID NOs: 22-25.

[0075] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 24; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0076] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:21, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:24.

[0077] In some aspects, the VL comprises a Y2I mutation. In some embodiments, the Y2I mutation is according to Kabat numbering.

[0078] In some aspects, the VH comprises a S73N mutation, a V78L mutation, a T76N mutation, a F91Y mutation, and a P105Q mutation, or a combination thereof. In some embodiments, the S73N mutation, the V78L mutation, the T76N mutation, the F91Y mutation, or the P105Q mutation is according to Kabat numbering.

[0079] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:57 and the light chain amino acid sequence of SEQ ID NO:58.

[0080] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:61 and the light chain amino acid sequence of SEQ ID NO:58.

[0081] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:112 and the light chain amino acid sequence of SEQ ID NO:58.

[0082] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:114 and the light chain amino acid sequence of SEQ ID NO:58.

[0083] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:21 and the VL sequence of SEQ ID NO:24.

[0084] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75.

[0085] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 95; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 94; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0086] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:95 and the VL sequence of SEQ ID NO:94.

[0087] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:101 and the light chain amino acid sequence of SEQ ID NO:100.

[0088] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:115 and the light chain amino acid sequence of SEQ ID NO:100.

[0089] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0090] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 97; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 96; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0091] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:97 and the VL sequence of SEQ ID NO:96.

[0092] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:103 and the light chain amino acid sequence of SEQ ID NO:102.

[0093] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:116 and the light chain amino acid sequence of SEQ ID NO:102.

[0094] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81.

[0095] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 99; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 98; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0096] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:99 and the VL sequence of SEQ ID NO:98.

[0097] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:105 and the light chain amino acid sequence of SEQ ID NO:104.

[0098] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:117 and the light chain amino acid sequence of SEQ ID NO:104.

[0099] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0100] In some embodiments, the antibody binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO:106.

[0101] In some embodiments, the antibody binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:106.

[0102] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0103] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 70; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 69; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0104] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:70 and the VL sequence of SEQ ID NO:69.

[0105] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:72 and the light chain amino acid sequence of SEQ ID NO:71.

[0106] In some embodiments, the monoclonal antibody that binds to CCR8 is a human antibody.

[0107] In some embodiments, the monoclonal antibody that binds to CCR8 is a humanized antibody.

[0108] In some embodiments, the monoclonal antibody that binds to CCR8 is a chimeric antibody.

[0109] In some embodiments, the monoclonal antibody that binds to CCR8 is an antibody fragment that binds to CCR8.

[0110] In some embodiments, the monoclonal antibody that binds to CCR8 is a full-length antibody.

[0111] In some embodiments, the monoclonal antibody that binds to CCR8 is a full-length IgG1 antibody.

[0112] In some embodiments, the monoclonal antibody that binds to CCR8 comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:59.

[0113] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO:54.

[0114] In some embodiments, the monoclonal antibody that binds to CCR8 is about 1 x 10 -12 M ~ approx. 1×10 -11 Binding affinity (K d ) binds to CCR8.

[0115] In some embodiments, the CCR8 is human CCR8.

[0116] In some embodiments, the monoclonal antibody that binds to CCR8 is defucosylated.

[0117] In some embodiments, the defucosylation rate is about 80% to about 95%.

[0118] In some embodiments, regulatory T cells present in the tumor microenvironment of locally advanced, recurrent, or metastatic solid tumor malignancies are depleted.

[0119] In some embodiments, regulatory T cells outside the tumor microenvironment of locally advanced, recurrent, or metastatic solid tumor malignancies are depleted.

[0120] In some embodiments, the subject is a human. [Brief explanation of the drawings]

[0121] [Figure 1] Screening results for anti-CCR8 monoclonal antibodies (mAbs) that selectively bind to Treg cells (Tregs) from human dissociated colorectal carcinoma tumor cells (DTCs) (obtained from Discovery Life Sciences) are shown. Mean fluorescence intensity (MFI) values ​​are shown for CD8 T cells (defined as CD45+CD14-CD3+CD8-CD4-) (circles, circles), conventional CD4 T cells (defined as CD45+CD14-CD3+CD8-CD4+FOXP3-) (squares, squares), and Treg cells (defined as CD45+CD14-CD3+CD8-CD4+FOXP3+) (triangles, triangles). Three of the five anti-CCR8 mAb clones, Ab1–Ab5, specifically stained intratumoral Treg cells but not conventional CD4 or CD8 T cells, ranked based on CCR8 MFI: hu.Ab4.H1L1 > hu.Ab5.H1L1 > hu.Ab3.H1L1. [Figure 2A-2B]The proposed mechanism of action of natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), which results in the depletion of tumor-infiltrating CCR8-expressing Tregs (Figure 2A), and the ADCC activity of human / cyno cross-reactive anti-CCR8 mAbs brought forward for further study (Figure 2B) are shown. EC50 values ​​were determined to be 0.02 nM, 0.02 nM, and 0.08 nM for the anti-CCR8 mAbs hu.Ab3.H1L1, hu.Ab5.H1L1, and hu.Ab4.H1L1, respectively. [Figures 3A-3D]Figure 3 shows the agonist and antagonist activities of the human / cyno cross-reactive anti-CCR8 mAbs hu.Ab4.H1L1, hu.Ab5.H1L1, and hu.Ab3.H1L1, as well as comparator anti-CCR8 mAbs (humanized anti-human Yoshida anti-CCR8 antibody, mouse anti-human CCR8 mAb 433H (BD Biosciences), and mouse anti-human CCR8 mAb L263G8 (Biolegend)). As shown in Figure 3A, CCL1, a known ligand for CCR8, exhibits agonist activity, whereas none of the anti-CCR8 mAbs tested exhibited agonist effects. The data in Figure 3B show that the anti-CCR8 mAb hu.Ab4.H1L1 exhibits antagonist (neutralizing / ligand-blocking) activity against the CCR8 ligand CCL1 (20 nM ligand), whereas the anti-CCR8 mAbs hu.Ab5.H1L1 and hu.Ab3.H1L1 exhibit no ligand-blocking activity (non-neutralizing) at the concentrations studied. The data in Figure 3C show that the comparator anti-CCR8 mAbs (humanized anti-human Yoshida anti-CCR8 antibody, mouse anti-human CCR8 mAb 433H (BD Biosciences), and mouse anti-human CCR8 mAb L263G8 (Biolegend)) do not exhibit agonistic effects, whereas the CCR8 ligand CCL1 does. The data in Figure 3D show that comparator anti-CCR8 mAbs (humanized anti-human Yoshida anti-CCR8 antibody, mouse anti-human CCR8 mAb 433H (BD Biosciences), and mouse anti-human Biolegend L263G8 (Biolegend)) exhibit antagonist (neutralizing / ligand-blocking) activity against the CCR8 ligand CCL1. IC50 values ​​for ligand-blocking activity are provided in the Examples. [Figures 4A-4F]Figure 4A shows the binding of hu.Ab3.H1L1 (Figure 4A), hu.Ab4.H1L1 (Figure 4B), and hu.Ab5.H1L1 (Figure 4C), as well as the commercially available anti-CCR8 mAbs mouse anti-human CCR8 mAb 433H (BD Biosciences) (Figure 4D), and mouse anti-human CCR8 mAb L263G8 (Biolegend) (Figure 4E), to HEK293 cells transiently transfected with N-terminal FLAG® (DYKDDDDK, SEQ ID NO: 118)-tagged plasmids encoding human GPCRs (CCR2, CCR3, CCR4, CCR5, CCR8, CXCR4, ACKR2, and ACKR4), hCCR8 constructs, or mock constructs using TransIT-X2® (reagent:DNA=3:1). Binding data for the mAbs (Figure 4F) are shown. Cell surface expression of each GPCR was confirmed by staining with an anti-FLAG® antibody control (5 μg / mL). mAbs hu.Ab4.H1L1 and hu.Ab5.H1L1 stained only hCCR8-containing cells, confirming their specificity for hCCR8. mAb hu.Ab3.H1L1 stained multiple other GPCRs, indicating a lack of specificity. The CCR8-selective hu.Ab4.H1L1 and hu.Ab5.H1L1 mAbs (shown in Figures 2A and 2B) that showed the best ADCC activity were carried forward for further study. [Figures 5A-5D] Alignment of the light chain variable region (Figure 5A) and heavy chain variable region (Figures 5B-5D) sequences of the rabbit (rb.Ab4) and humanized Ab4 (L1-L4 and H1-H12) CCR8 mAbs studied is shown. Y2 on the light chain (L3) and S73, T76, V78, F91, and P105 on the heavy chain (H12) were determined to be important rabbit Vernier residues based on binding evaluation of the variant antibodies. The CDRs, variable region, constant region, and full-length sequences are provided in the Examples. [Figures 6A-6D]Alignment of the light chain variable region (Figure 6A) and heavy chain variable region (Figures 6B-6D) sequences of the rabbit (rb.Ab5) and humanized Ab5 (L1-L5 and H1-H13) CCR8 mAbs studied is shown. The C90Q mutation in CDR L3 was introduced to remove an unpaired cysteine ​​that could be a cause of problems during manufacturing. V4, P43, and F46 on the light chain (L1) and G49, K71, and S73 on the heavy chain (H13) were determined to be critical rabbit Vernier residues based on binding evaluation of the variant antibodies. The CDRs, variable regions, constant regions, and full-length sequences are provided in the Examples. [Figures 7A-7D] Figure 7 shows the results of cell-based affinity measurements of the hu.Ab5.H13L1 and hu.Ab4.H12L3 mAbs using radiolabeled IgG and CHO cell lines stably expressing human CCR8 or cynomolgus monkey ("cyno") CCR8. The data demonstrate that the hu.Ab4.H12L3 and hu.Ab5.H13L1 mAbs have similar affinities for both human and cyno CCR8 and exhibit desirable cross-reactivity (compare Figure 7A with Figure 7B and Figure 7C with Figure 7D). Kd (nM) affinity data from these studies are provided in the Examples. [Figure 8A-8B] Binding data for the hu.Ab4.H12L3 (FIG. 8A) and hu.Ab5.H13L1 (FIG. 8B) mAbs to a panel of sulfated GPCRs are shown, reaffirming that these Ab4 and Ab5 variants exhibit selectivity for CCR8, similar to the Ab4 and Ab5 data provided in FIG. 4B and FIG. 4C. Due to weaker binding to the N-terminal FLAG® tag of hCCR8 (which affects binding of Ab5 to the N-terminal epitope; see FIG. 16A and FIG. 16B), a CCR8 construct with a C-terminal FLAG® is also provided in FIG. 4C. [Figure 9A-9B]Figure 9A shows the effects of anti-CCR8 mAbs hu.Ab4.H12L3 and hu.Ab5.H13L1 on CCR8 activation as determined by Ca influx assay (Figure 9A) and CCR8 CCL1 ligand binding (Figure 9B). Similar to the data in Figure 3A, Figure 9A reaffirms that neither the Ab4 nor the Ab5 anti-CCR8 mAb variants exhibit agonistic effects in the absence of the CCR8 ligand CCL1. Similar to the data in Figure 3B, Figure 9B reaffirms that the Ab4 variants exhibit antagonistic effects on the CCR8 ligand CCL1 (20 nM ligand), whereas the Ab5 variants exhibit no ligand-blocking activity at the concentrations tested. IC50 values ​​for ligand-blocking activity are provided in the Examples. [Figures 10A-10E] Figure 1 shows the difference in staining of hu.Ab4.H12L3 and hu.Ab5.H13L1 compared to the humanized anti-human Yoshida CCR8 mAb and the commercially available antibodies mouse anti-human CCR8 mAb 433H (BD Biosciences) and mouse anti-human CCR8 mAb L263G8 (Biolegend) on CCR8+ HEK293 cells with (hCCR8.TPST1 / 2 NTC) and without (hCCR8.TPST1 / 2 KO) tyrosylprotein sulfotransferase (TPST)1 and tyrosylprotein sulfotransferase (TPST)2. hu.Ab4.H12L3 (Figure 10A) and hu.Ab5.H13L1 (Figure 10B) showed similar binding / staining to both cell lines (hCCR8.TPST1 / 2 NTC and hCCR8.TPST1 / 2 KO), indicating that they bind to CCR8 regardless of tyrosine sulfation ("sulfation-independent"). In contrast, the humanized anti-human Yoshida CCR8 antibody (Figure 10C) and the commercially available antibodies mouse anti-human CCR8 mAb 433H (BD Biosciences) (Figure 10D) and mouse anti-human CCR8 mAb L263G8 (Biolegend) (Figure 10E) failed to bind to TPST1 / 2 KO cells, indicating that they require tyrosine sulfation of CCR8 for binding and are therefore considered "sulfation-dependent." [Figures 11A-11D]Using NK-92 F158 (Figure 11A) and NK-92 V158 (Figure 11B) as effector cells, against CHO cells stably expressing hCCR8, the defucosylated CCR8 mAbs Afuc.hu.Ab5.H13L1 and Afuc.hu.Ab4.H12L3 showed enhanced ADCC activity (>10-fold improvement) compared to their fucosylated CCR8 counterparts, hu.Ab5.H13L1 and hu.Ab4.H12L3, and 10- to 20-fold improved ADCC activity compared to the humanized anti-human Yoshida anti-CCR8 antibody (Figure 11C). The commercially available anti-CCR8 mAbs mouse anti-human CCR8 mAb 433H (BD Biosciences) and mouse anti-human CCR8 mAb L263G8 (Biolegend) did not demonstrate ADCC activity (as expected) because the assay used is primarily relevant to antibodies containing human Fc regions (Figure 11C). Figure 11D shows that mouse anti-human CCR8 mAb 433H (BD Biosciences) and mouse anti-human CCR8 mAb L263G8 (Biolegend) have ADCC activity using an assay specific for antibodies containing mouse Fc regions and human anti-CCR8 activity. Activity data are also provided in the Examples. [Figures 12A-12D]Figure 1 shows the selective ADCC activity against human Treg cells compared to conventional human CD4 T cells from peripheral blood mononuclear cells (PBMCs) recovered after transfer into NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ (NSG™) mice to induce CCR8 expression, when incubated with defucosylated, fucosylated (hIgG1), and defucosylated isotype control mAb ("gD.afuc") and primary NK cells as effector cells. ADCC activity against Treg cells was measured by calculating the ratio of recovered Treg cells to recovered CD8 cells (Treg / CD8) or conventional CD4 T cells to recovered CD8 T cells (CD4conv / CD8). The CCR8 mAbs Afuc.hu.Ab4.H12L3 and hu.Ab4.H12L3 selectively mediated ADCC activity against Treg cells (Figure 12A) compared to conventional CD4 T cells (Figure 12B), with the defucosylated variants exhibiting increased ADCC activity. Similarly, the CCR8 mAbs Afuc.hu.Ab5.H13L1 and hu.Ab5.H13L1 selectively mediated ADCC activity against Treg cells (Figure 12C) compared to conventional CD4 T cells (Figure 12D), with the defucosylated variants exhibiting increased ADCC activity. [Figures 13A-13D]Figure 13 shows the selective ADCC activity against Treg cells compared to conventional CD4 T cells when human dissociated renal cell carcinoma (RCC) cells were incubated with defucosylated, fucosylated (hIgG1), and defucosylated isotype control mAb ("gD.afuc") and primary NK cells as effector cells. ADCC activity against Treg cells was measured by calculating the ratio of recovered Treg cells to recovered CD8 cells (Treg / CD8) or conventional CD4 T cells to recovered CD8 T cells (CD4conv / CD8). The CCR8 mAbs Afuc.hu.Ab4.H12L3 and hu.Ab4.H12L3 selectively mediated ADCC activity against Treg cells (Figure 13A) compared to conventional CD4 T cells (Figure 13B), with the defucosylated variants showing increased ADCC activity. Similarly, CCR8 mAbs Afuc.hu.Ab5.H13L1 and hu.Ab5.H13L1 selectively mediated ADCC activity against Treg cells (Figure 13C) compared to conventional CD4 T cells (Figure 13D), with the defucosylated variants exhibiting increased ADCC activity. [Figures 14A-14E] In CD14+ monocyte-derived macrophages from four different donors with the FcgRIIa(H131R) / FcgRIIIa(V158F) genotypes HR / FF (Figure 14A), RR / FF (Figure 14B), HR / VF (Figure 14C), and RR / VF (Figure 14D), the defucosylated anti-CCR8 mAbs Afuc.hu.Ab5.H13L1 and Afuc.hu.Ab4.H12L3 exhibit enhanced ADCP activity compared to the fucosylated mAbs hu.Ab5.H13L1 and hu.Ab4.H12L3, and also show a 3-4 fold improvement in ADCP activity compared to the humanized anti-human Yoshida anti-CCR8 antibody (Figure 14E). Activity data are also provided in the Examples. [Figures 15A-15D]Figure 15A shows that the defucosylated anti-CCR8 mAb Afuc.hu.Ab5.H13L1 exhibits similar improved ADCP activity compared to the FcgRIIa-enhancing G236A.I332E variant Afuc.hu.Ab5.H13L1.G236A.I332E in CD14+ monocyte-derived macrophages from four different donors with the FcgRIIa(H131R) / FcgRIIIa(V158F) genotype: HR / FF (Figure 15A), RR / FF (Figure 15B), HR / VF (Figure 15C), and RR / VF (Figure 15D). [Figures 16A-16B] Epitope maps of hu.Ab5.H13L1 (Figure 16A) and hu.Ab4.H12L3 (Figure 16B) mAbs. As shown in Figure 16A, constructs encoding individual alanine point mutations at positions 2-24 of hCCR8 with a C-terminal FLAG® tag were generated; hu.Ab5.H13L1 did not bind to D2A, Y3A, L5A, or D6A, indicating that the epitope includes at least the DYTLD region of the human CCR8 N-terminus. As shown in Figure 16B, constructs were generated encoding human CCR8.CCR5 chimeras (N-term1, N-term2, ECL1, ECL2, and ECL3) in which different extracellular regions of hCCR8 were replaced with the corresponding regions from CCR5 with a C-terminal FLAG® tag. hu.Ab4.H12L3 did not bind to the ECL1 and ECL2 chimeras, indicating that the epitope of this antibody includes at least the ECL1 and ECL2 regions of CCR8. huCCR8 N-term: MDYTLDLSVTTVTDYYYPDIFSSP (SEQ ID NO: 110). [Figures 17A-17I]Figure 17A shows progressive depletion of Treg cells (measured as the percentage of Treg cells with CD45+ leukocytes) in the tumor (Figure 17A), but not in the spleen (Figure 17B) or tumor-draining lymph nodes (Figure 17C) in CT26 tumor-bearing mice 3 days after injection of a single dose of increasing concentrations of murine surrogate anti-CCR8 mAb from 0.003 to 5 mg / kg. Anti-CCR8 mAb treatment did not result in depletion of CD4 conventional T cells (Figures 17D-17F) or CD8 T cells (Figures 17G-17I). An isotype control antibody (anti-gp120) was used. [Figure 17J] Figure 1 shows depletion of Treg cells (measured as the percentage of Treg cells with CD45+ leukocytes) in the tumor, but not in the spleen, draining lymph nodes (dLN), or blood, of E0771 syngeneic tumor-bearing mice 3 days after injection of increasing concentrations of anti-CCR8 antibody between 0.01 and 1 mg / kg. [Figures 17K-17O] Figure 17 shows the minimal physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model used to simulate the pharmacokinetic (PK) / receptor occupancy (RO) relationship and pharmacodynamics (PD) and efficacy of a murine surrogate anti-CCR8 antibody. The minimal PBPK model structure is shown in Figure 17K. This model predicts the PK (Figure 17L), RO (Figure 17M), Treg depletion (Figure 17N), and anti-tumor efficacy (Figure 17O) of the anti-CCR8 antibody. [Figures 18A-18D] Figure 18B shows tumor growth inhibition after treatment with a single dose (Figure 18B) or twice-weekly administration (Figure 18C) of murine surrogate anti-CCR8 mAb in mice bearing established CT26 syngeneic tumors, compared with treatment with anti-CD25 mAb (Figure 18D) or isotype control mAb (anti-gp120) (Figure 18A). Treatment began when tumors reached a volume of 150-250 mm. Tumor volume was measured over time. Gray lines represent individual mice, and black lines represent group fits. [Figures 19A-19E]Figure 19B shows the growth inhibition of CT26 tumors observed with an effector-competent mouse surrogate anti-CCR8 mAb administered at the time of tumor inoculation (Figure 19B) or tumors reaching 150-250 mm3 (Figure 19D). No tumor growth inhibition is observed with an effector-incompetent LALAPG variant of the same ligand-blocking anti-CCR8 mAb (Figures 19C and 19E). Tumor volume is measured over time. Gray lines represent individual mice, and black lines represent group fits. An isotype control mAb (anti-gp120) was used (Figure 19A). [Figures 20A-20D] We show that the combination of a murine surrogate anti-CCR8 mAb and an anti-PDL1 mAb (Figure 20D) is unexpectedly more effective at inhibiting EMT6 tumor growth than either anti-CCR8 mAb (Figure 20B) or anti-PDL1 mAb (Figure 20C). Treatment began when tumors reached 150-250 mm. Tumor volume was measured over time. Gray lines represent individual mice, and black lines represent group fits. An isotype control mAb (anti-gp120) was used (Figure 20A). [Figure 21] Serum pharmacokinetic profiles (mean ± SD) of the anti-gD (control) and test anti-CCR8 mAbs Afuc.hu.Ab5.H13L1 and Afuc.hu.Ab4.H12L3 in cynomolgus monkeys after a single 10 mg / kg IV bolus injection are shown. Afuc.hu.Ab5.H13L1 demonstrated desirable sustained serum concentration levels over 35 days post-dose, which is expected to elicit more sustained target engagement, potentially leading to better anti-cancer activity and reduced dosing frequency. [Figures 22A-22C]Figure 22 shows the results of whole blood flow cytometry analysis of total Treg cell numbers from nine male cynos administered 10 mg / kg by intravenous injection of defucosylated anti-gD (control; group 1, designated 1001, 1002, 1003; Figure 22A), Afuc.hu.Ab5.H13L1 (group 2, designated 2001, 2002, 2003; Figure 22B), or Afuc.hu.Ab4.H12L3 (group 3, designated 3001, 3002, 3003; Figure 22C). Both test anti-CCR8 mAbs did not substantially reduce absolute total Treg cell numbers in whole blood up to 840 hours post-administration. [Figures 23A-23I]Figure 23 shows the results of whole blood flow cytometry analysis for the depletion of CCR8+FoxP3+ Treg cells in nine male cynos administered defucosylated anti-gD (control; Group 1, designated 1001 (Figure 23A), 1002 (Figure 23B), 1003 (Figure 23C)), Afuc.hu.Ab4.H12L3 (Group 3, designated 3001 (Figure 23D), 3002 (Figure 23E), 3003 (Figure 23F)), or Afuc.hu.Ab5.H13L1 (Group 2, designated 2001 (Figure 23G), 2002 (Figure 23H), 2003 (Figure 23I)). Blood was collected from each animal prior to dosing ("Pre-Study") and at time 0 on Day 1 ("Pre-Dose"). Each animal then received a single dose of 10 mg / kg of defucosylated anti-gD (control group), Afuc.hu.Ab5.H13L1 (group 2), or Afuc.hu.Ab4.H12L3 (group 3) via intravenous injection. Blood was then collected from the animals and subjected to the following treatments before flow cytometry analysis: (i) a blood sample not spiked with any of the test CCR8 mAbs ("non-spiked"), (ii) a blood sample further spiked with a saturating concentration of Afuc.hu.Ab5.H13L1, and (iii) a blood sample further spiked with a saturating concentration of Afuc.hu.Ab4.H12L3. Each of the non-spiked and spiked samples was then treated with labeled goat anti-human IgG antibody and analyzed by flow cytometry. As seen in Figures 23A-23C, flow cytometry of blood initially treated with control (Group 1) but not spiked showed no modulation of total CCR8+ T-reg cells. Furthermore, flow cytometry of spiked blood also had little effect on total CCR8+ T-reg cell numbers. For Group 3, as seen in Figures 23D-23F, flow cytometry of blood analyzed from each of three animals showed a decrease in CCR8+ T-reg cells by 168 hours post-dose. For Group 2, as seen in Figures 23G-23I, flow cytometry of blood analyzed showed a decrease in CCR8+ T-reg cells in animals 2002 and 2003.Both Group 2 and Group 3 animals showed little or no effect on total Treg cell numbers (Figures 22A-22C), but showed a decrease in the number of peripheral blood CCR8+ T-reg cells after spiked or unspiked dosing (Figures 23D-23I), consistent with the proposed mechanism of action (see Figure 2A). [Figure 24] FIG. 1 is a schematic showing the study design for the Phase 1a portion of the GO43860 study (RO7502175 as a single agent). DL = dose level; DLT = dose-limiting toxicity; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; MAD = maximum dose; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; PD = pharmacodynamics; PK = pharmacokinetics; Q3W = every 3 weeks; RCC = renal cell carcinoma; TNBC = triple-negative breast cancer; UC = urothelial carcinoma. Actual patient numbers may vary. [Figure 25] FIG. 1 is a schematic showing the study design for the Phase Ib portion of the GO43860 study (RO7502175 in combination with atezolizumab). TBD = not yet determined. [Figure 26] Schematic showing the criteria for continuing treatment beyond disease progression in the GO43860 study. ECOG = Eastern Cooperative Oncology Group; RECIST = Response Evaluation Criteria in Solid Tumors. [Figures 27A-27B] Schematic showing the criteria for crossover from Phase Ia to Phase Ib for Phase Ia patients in the GO43860 study. AE = adverse event; PD = progressive disease. [Figures 28A-28C] Figure 28A shows the in vitro pharmacology of RO7502175. RO7502175 binds to CCR8 only from human and cynomolgus monkeys among the species evaluated. Defucosylated RO7502175 shows enhanced binding to FcγRIIIA-F158 (Figure 28B) and FcγRIIIA-V158 (Figure 28C) compared to the trastuzumab control antibody. [Figure 29]Figure 1 shows the in vitro ADCC activity of RO7502175 against human Treg cells derived from pre-activated PBMCs. The plot shows the ADCC activity of RO7502175, a fucosylated (wild-type) anti-CCR8 control, and a defucosylated anti-gD (isotype) control against human Treg cells derived from pre-activated PBMCs isolated from three different donors. [Figure 30A-30B] Figure 30 shows the in vitro ADCC activity of RO7502175 against dissociated tumor cells and CCR8-expressing CHO cells. (Figure 30A) The plot shows the ADCC activity of RO7502175 against human regulatory conventional CD4+ and CD8+ T cells from dissociated renal cell carcinoma tumors. (Figure 30B) The plot shows the percent cytotoxicity (mean ± SD) of RO7502175 in an ADCC assay with CCR8-expressing CHO cells using PBMCs isolated from eight different healthy donors. The geometric mean EC50 values ​​are listed. [Figures 31A-31F] Figure 31 shows in vitro cytokine release of RO7502175 in PBMC assays using soluble and fixed formats. (Figure 31A) Graphical representations of the soluble assay format and (Figure 31B) the fixed assay format combining PBMCs with test articles are shown. (Figures 31C-31F) Cytokine concentrations (pg / mL) after 18 hours of incubation of the indicated test articles in soluble or fixed formats with PBMCs (n=8), (Figure 31C) IFNγ, (Figure 31D) IL-2, (Figure 31E) IL-6, and (Figure 31F) TNFα. [Figures 32A-32E] Figure 32 shows the in vivo activity of anti-mouse CCR8 antibodies in a syngeneic mouse tumor model. (Figure 32A) Study design, (Figure 32B) Treg cell and (Figure 32C) CD8+ T cell frequencies in tumors and blood, and (Figure 32D) serum antibody concentrations (mean ± SD) after a single IV administration of anti-mouse CCR8 antibodies in C57BL / 6 mice bearing E0771 tumors. (Figure 32E) Anti-tumor activity in C57BL / 6 mice bearing E0771 tumors after a single IV administration of anti-mouse CCR8 antibodies in an efficacy study. dLN, draining lymph node; MQC, lowest quantifiable concentration. [Figure 33A-33B] Figure 33 shows the in vivo activity of anti-mouse CCR8 antibodies in a syngeneic mouse tumor model (additional data from the PD study described in Figures 32A-32D). Figure 33 shows the frequency of (Figure 33A) Treg cells and (Figure 33B) CD8+ T cells in the spleen and draining lymph nodes. [Figure 34] Figure 32E shows anti-mouse CCR8 antibody PK in C57BL / 6 mice from the efficacy study described in Figure 32E. Serum concentrations (mean ± SD) of pharmacokinetic parameter estimates from non-compartmental analysis after a single IV dose of anti-mouse CCR8 antibody in C57BL / 6 mice are shown. [Figures 35A-35D]

[0071] Figure 35 shows the PK, PD, and safety profile of RO7502175 in cynomolgus monkeys. (Figure 35A) Serum concentration-time profile (mean ± SD) after a single IV administration of 10 mg / kg anti-gD (control) or RO7502175 to male cynomolgus monkeys, and (Figure 35B) plasma MCP-1 and IL-6 cytokine concentrations (mean ± SD). (Figure 35C) Serum concentration-time profile (mean ± SD) of blood CCR8+ Treg cells in cynomolgus monkeys after IV administration of vehicle control or RO7502175 in a repeat-dose study, and (Figure 35D) fold change from baseline (mean ± SD). [Figure 36A-36B] Figure 36 shows the PD profile of RO7502175 in a single-dose study in cynomolgus monkeys. The relative percentage of CCR8+ Treg cells (mean ± SEM; n = duplicates) in the blood of individual male cynomolgus monkeys after IV administration of 10 mg / kg (Figure 36A) anti-gD (control) or (Figure 36B) RO7502175 is shown. [Figures 37A-37H]The mPBPK-PD model reproduced preclinical PK, PD, and anti-tumor efficacy data. (Figure 37A) A schematic diagram of the mPBPK-PD model structure is shown. (Figure 37B) The model captured anti-mouse CCR8 antibody PK in mice after single dose administration of 0.01, 0.03, 0.1, and 1 mg / kg IV. (Figure 37C) The model predicted receptor occupancy (RO) over time for anti-mouse CCR8 antibody. (Figure 37D) The model is calibrated to tumor CCR8+ Treg cell numbers. (Figure 37E) The model captured CD8+ T cell expansion and (Figure 37F) mean tumor kill. (Figure 37G) The model is calibrated and validated for RO7502175 PK from single-dose and repeat-dose studies in cynomolgus monkeys. (Figure 37H) RO predictions in cynomolgus monkeys at a single dose of 10 mg / kg and qw doses of 30 and 100 mg / kg are shown. Symbols represent individual data points and lines represent model fits or predictions. [Figures 38A-38D] Predicted clinical PK profiles and receptor occupancy (RO) of RO7502175 in patient plasma and tumors are shown. Clinical PK and RO predictions are shown in the blood (Figures 38A and 38B) and tumor compartments (Figures 38C and 38D) following administration of RO7502175 at dose levels of 0.2, 0.6, 2, 6, and 20 mg IV q3w. [Figure 39] Predicted RO7502175 receptor occupancy (RO) in patient tumors is shown. Clinical mean RO predictions in the tumor compartment over Cycle 1 (21 days) after administration of RO7502175 at dose levels of 0.2, 0.6, 2, 6, and 20 mg IV q3w are shown. Ranges indicate mean RO in the tumor, taking into account uncertainty in PK parameters (Vplasma = 37.1 mL / kg + / - 20%, CL = 0.12 mL / h / kg + / - 20%, sig_tumor = 0.91-0.95 (for 5-10% tumor / plasma AUC), KD = 0.032-0.060 nM). Vplasma, plasma volume; CL, clearance; sig_tumor, tumor reflection coefficient; KD, antibody binding affinity for CCR8. [Figure 40A-40B]First-in-human dose selection for RO7502175 is shown. (Figure 40A) For RO7502175 FiH dose selection, a MABEL-based approach, an mPAD-based approach, and an integrated approach based on overall preclinical data were considered. The schematic workflow shows the in vitro and in vivo datasets utilized as input and the criteria used to generate results from each evaluated methodology. (Figure 40B) The plot shows the resulting FiH dose for RO7502175 based on each investigated method. RO, receptor occupancy; KD, antibody binding affinity to CCR8; ADCC, antibody-dependent cell-mediated cytotoxicity; MABEL, minimum expected biological effect level; Cmax, maximum observed concentration; mPAD, minimum pharmacologically active dose; Cavg, average concentration over a specified period after administration; NOAEL, no-observed-adverse-effect level; CRA, in vitro cytokine release assay. DETAILED DESCRIPTION OF THE INVENTION

[0122] I. Definition For purposes herein, an "acceptor human framework" is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0123] "Affinity" refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the specific binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative, exemplary methods for measuring binding affinity are also described herein.

[0124] An "affinity matured" antibody refers to an antibody with one or more modifications in one or more complementarity determining regions (CDRs) that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody that does not possess such modifications.

[0125] The terms "anti-CCR8 antibody" and "antibody that binds to CCR8" refer to an antibody that can bind to CCR8 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CCR8. In one embodiment, the extent of binding of an anti-CCR8 antibody to an unrelated, non-CCR8 protein is less than about 10% of the binding of the antibody to CCR8, as measured, for example, by surface plasmon resonance (SPR). In certain embodiments, an antibody that binds to CCR8 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g., 10 -13 M~10 -8 M, e.g., 10 -13 M~10 -9 Dissociation constant (K D In certain embodiments, the antibody that binds to CCR8 has a concentration of about 1 x 10 ~12 M ~ approx. 1×10 ~10 M, about 1 x 10 ~12 M ~ approx. 1×10 ~11 M, or approximately 1 x 10 ~11 M ~ approx. 5×10 ~11 K of MD In certain embodiments, the antibody that binds to CCR8 has about 2 x 10 -11 K of M D In certain embodiments, the antibody that binds to CCR8 has about 5 x 10 -12 K of M D The antibody has a K D In certain embodiments, an anti-CCR8 antibody binds to epitopes of CCR8 of at least two different species (e.g., human and cyno).

[0126] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0127] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. For a review of specific antibody fragments, see Holliger and Hudson, Nature Biotechnology (2005) 23:1126-1136.

[0128] The term "epitope" refers to a site on an antigen, either proteinaceous or non-proteinaceous, to which an anti-CCR8 antibody binds. An epitope can be formed from a continuous stretch of amino acids (linear epitope) or can include non-contiguous amino acids (conformational epitope), and is formed in close spatial proximity, for example, due to antigen folding (i.e., tertiary folding of a proteinaceous antigen). A linear epitope is typically still bound by an anti-CCR8 antibody after exposing a proteinaceous antigen to a denaturing agent, while a conformational epitope is typically destroyed by treatment with a denaturing agent. An epitope includes at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 10, at least 15, at least 20, at least 30, or at least 35, or 3-25, 3-20, 3-15, 3-10, 3-5, 30-40, 35-40, or 5-10 amino acids in a unique spatial conformation.

[0129] Screening for antibodies that bind to a specific epitope (i.e., antibodies that bind to the same epitope) can be performed using methods routine in the art, such as, but not limited to, alanine scanning, peptide blotting (see, e.g., Kobeissy et al., Meth. Mol. Biol. (2004) 248:443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see Hochleitner et al., Prot. Sci. 9 (2000) 487-496), and cross-blocking (see "Antibodies," Harlow and Lane, Cold Spring Harbor Press, Cold Spring Harb., NY).

[0130] Antigen Structure-based Antibody Profiling (ASAP), also known as Modification-Assisted Profiling (MAP), allows multiple monoclonal antibodies that specifically bind to CCR8 to be classified based on their respective binding profiles to chemically or enzymatically modified antigen surfaces (see, e.g., U.S. Patent Application Publication No. 2004 / 0101920). Each classified antibody binds to the same epitope, which may be distinct from epitopes represented by other classifications or may be a unique epitope that overlaps.

[0131] Competitive binding can also be used to easily determine whether an antibody binds to the same epitope of CCR8 as a reference anti-CCR8 antibody or competes for binding with the reference anti-CCR8 antibody. For example, an "antibody that binds to the same epitope" as a reference anti-CCR8 antibody refers to an antibody that inhibits the binding of the reference anti-CCR8 antibody to the antigen by 50% or more in a competitive assay; conversely, the reference antibody inhibits the binding of the antibody to the antigen by 50% or more in a competitive assay. For example, to determine whether an antibody binds to the same epitope as a reference anti-CCR8 antibody, the reference antibody can be bound to CCR8 at saturation. After removing excess reference anti-CCR8 antibody, the ability of the anti-CCR8 antibody in question to bind to CCR8 is evaluated. If the anti-CCR8 antibody can bind to CCR8 after saturation binding of the reference anti-CCR8 antibody, it can be concluded that the anti-CCR8 antibody binds to a different epitope than the reference anti-CCR8 antibody. However, if the anti-CCR8 antibody cannot bind to CCR8 after the saturation binding of the reference anti-CCR8 antibody, this anti-CCR8 antibody may bind to the same epitope as the reference anti-CCR8 antibody.To determine whether the antibodies in question bind to the same epitope or whether binding is simply hindered by steric reasons, routine experiments can be used (e.g., peptide mutation and binding analysis using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art).This assay should be performed in two settings, i.e., when both antibodies are saturating antibodies.In both settings, if only the first (saturating) antibody can bind to CCR8, it can be concluded that the anti-CCR8 antibody in question and the reference anti-CCR8 antibody compete for binding to CCR8.

[0132] In some embodiments, two antibodies are considered to bind to the same or overlapping epitope if a 1-, 5-, 10-, 20-, or 100-fold excess of one antibody inhibits binding of the other by at least 50%, at least 75%, at least 90%, or even 99% or more, as measured in competitive binding assays (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).

[0133] In some embodiments, two antibodies are considered to bind to the same epitope if substantially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other antibody. Two antibodies are considered to have "overlapping epitopes" if only a subset of amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody.

[0134] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, and the remainder of the heavy and / or light chain is derived from a different source or species.

[0135] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In certain embodiments, the antibody is of the IgG1 isotype. In certain embodiments, the antibody is of the IgG1 isotype with P329G, L234A, and L235A mutations to reduce Fc region effector function. In other embodiments, the antibody is of the IgG2 isotype. In certain embodiments, the antibody is of the IgG4 isotype with an S228P mutation in the hinge region to improve the stability of IgG4 antibodies. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0136] The term "constant region of human origin" or "human constant region" as used herein refers to the constant heavy chain region and / or the constant light chain kappa or lambda region of a human antibody of the subclass IgG1, IgG2, IgG3, or IgG4. Such constant regions are known in the art and are described, for example, in Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, e.g., Johnson, G., and Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218; Kabat, E.A., et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). Unless otherwise specified herein, the numbering of amino acid residues in the constant region is according to the EU numbering system (also known as Kabat's EU index) as described in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0137] "Effector function" refers to the biological activities attributable to the Fc region of an antibody, which vary depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0138] For example, an "effective amount" of an agent in a pharmaceutical composition refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

[0139] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational truncation of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, antibodies produced by host cells by expression of a particular nucleic acid molecule encoding a full-length heavy chain may contain a full-length heavy chain or a truncated variant of the full-length heavy chain. This may be the case when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering system). Thus, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. In one embodiment, the heavy chain comprising the Fc region designated herein comprised in an antibody according to the invention comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447, EU numbering system). In one embodiment, the heavy chain comprising the Fc region designated herein comprised in an antibody according to the invention comprises an additional C-terminal glycine residue (G446, EU index numbering). Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as the EU index) as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0140] "Framework" or "FR" refers to variable domain residues other than the complementarity-determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences generally have the following sequence in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0141] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to a native antibody structure, or an antibody having a heavy chain containing an Fc region as defined herein. A full-length antibody is understood to include heavy and light chain variable domains as defined herein, as well as an Fc region as defined herein.

[0142] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0143] A "human antibody" is one having an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or derived from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0144] A "human consensus framework" is a framework representing the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is derived from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I, as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III, as in Kabat et al., supra.

[0145] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues derived from non-human CDRs and human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, with all or substantially all of the CDRs corresponding to those of a non-human antibody and all or substantially all of the FRs corresponding to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0146] As used herein, the term "hypervariable region" or "HVR" refers to each region of an antibody variable domain that is hypervariable in sequence and determines antigen-binding specificity, e.g., the "complementarity-determining region" (CDR).

[0147] In certain embodiments, an antibody comprises six CDRs, three in the VH (CDR-H1, CDR-H2, CDR-H3) and three in the VL (CDR-L1, CDR-L2, CDR-L3). In certain embodiments, an antibody comprising six CDRs is a full-length antibody. In certain embodiments, an antibody comprising six CDRs is an antibody fragment.

[0148] Exemplary CDRs herein include the following: (a) Hypervariable loops present at amino acid residues 26–32 (L1), 50–52 (L2), 91–96 (L3), 26–32 (H1), 53–55 (H2), and 96–101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901–917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)).

[0149] Unless otherwise indicated, CDRs are determined according to Kabat et al., supra and Chothia, supra. Those skilled in the art will understand that the designations of CDRs can also be determined according to McCallum, supra, or any other scientifically accepted nomenclature system.

[0150] In one embodiment, the CDR residues include those identified in Figures 5A-5D and 6A-6D and Tables C1, C2, D1 and D2. In another embodiment, the CDR residues include those identified in Tables N1, N2, O1 and O2.

[0151] A "subject" is a mammal. Mammals include, but are not limited to, livestock (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject is a human. In some embodiments, the subject is a patient.

[0152] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, the antibody is purified to greater than 95% or 99% purity, as measured, for example, by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0153] The terms "nucleic acid molecule" or "polynucleotide" include any compound and / or substance comprising a polymer of nucleotides. Each nucleotide consists of a base, specifically a purine or pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T), or uracil (U)), a sugar (i.e., deoxyribose or ribose), and a phosphate group. Nucleic acid molecules are often described by the sequence of bases, which thereby represent the primary (linear) structure of the nucleic acid molecule. The sequence of bases is typically presented from 5' to 3'. As used herein, the term nucleic acid molecule encompasses, for example, deoxyribonucleic acid (DNA), including complementary DNA (cDNA) and genomic DNA; ribonucleic acid (RNA), particularly messenger RNA (mRNA); synthetic forms of DNA or RNA; and mixed polymers comprising two or more of these molecules. Nucleic acid molecules can be linear or circular. Furthermore, the term nucleic acid molecule includes both sense and antisense strands, as well as single-stranded and double-stranded forms. Furthermore, the nucleic acid molecules described herein can contain naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugar or phosphate backbone linkages or chemically modified residues. Nucleic acid molecules also encompass DNA and RNA molecules suitable as vectors for directly expressing the antibodies described herein in vitro and / or in vivo, for example, in a host or subject. Such DNA vectors (e.g., cDNA) or RNA vectors (e.g., mRNA) can be unmodified or modified. For example, the mRNA may be chemically modified to increase the stability of the RNA vector and / or the expression of the encoded molecule, such that the mRNA can be injected into a subject to produce antibodies in vivo (see, e.g., Stadler et al., Nature Medicine 2017, published online 12 June 2017, doi:10.1038 / nm.4356 or EP 2101823 B1).

[0154] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from components of its natural environment. Isolated nucleic acid includes a nucleic acid molecule that is contained within a cell that ordinarily contains the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0155] "Isolated nucleic acid encoding an anti-CCR8 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an anti-CCR8 antibody, including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present in one or more locations within a host cell.

[0156] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for variant antibodies that contain, for example, naturally occurring mutations or that may arise during production of the monoclonal antibody preparation, in which such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies according to the present disclosure may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods, as well as other exemplary methods for producing monoclonal antibodies, are described herein.

[0157] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

[0158] "Native antibody" refers to naturally occurring immunoglobulin molecules with various structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical light chains and two identical heavy chains disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy chain domain or heavy chain variable region, followed by three constant heavy chain domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable domain (VL), also called a variable light chain domain or light chain variable region, followed by a constant light chain (CL) domain.

[0159] The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for use of such therapeutic product.

[0160] "Amino acid sequence identity percentage (%)" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps if necessary to achieve the maximum sequence identity percentage, without considering any conservative substitutions as part of the sequence identity for alignment.The alignment for determining amino acid sequence identity percentage can be achieved in various ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or FASTA program package.Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to obtain the maximum alignment over the entire length of the sequences to be compared.Alternatively, identity percentage values ​​can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code is on file in the user documentation at the U.S. Copyright Office, Washington, DC, 20559, registered under U.S. Copyright Registration No. TXU510087, and described in WO 2001 / 007611.

[0161] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values ​​are generated using the ggsearch program in the FASTA package version 36.3.8c, or subsequent BLOSUM50 comparison matrices. The FASTA program package was developed by W.R. Pearson and D.J. Lipman (1988), "Improved Tools for Biological Sequence Analysis," PNAS 85:2444-2448; W.R. Pearson (1996), "Effective protein sequence comparison," Meth. Enzymol. 266:227-258; and Pearson et al. (1997) Genomics 46:24-36, and is publicly available at fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi using the ggsearch(globalprotein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup=2), ensuring a global rather than local alignment. The percent amino acid identity is shown in the output alignment header.

[0162] The terms "pharmaceutical composition" and "pharmaceutical formulation" are used interchangeably herein and refer to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the pharmaceutical composition is administered.

[0163] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0164] The term "CCR8," as used herein, unless otherwise specified, refers to any native CCR8 from any vertebrate source, including mammals such as primates (e.g., humans, monkeys (cyno)) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed CCR8 and any form of CCR8 resulting from processing within a cell. The term also encompasses naturally occurring variants of CCR8, such as splice variants or allelic variants. In certain embodiments, the CCR8 is human CCR8 ("hCCR8" or "huCCR8"). The amino acid sequence of an exemplary human CCR8 is set forth in SEQ ID NO: 106, as shown in the table below. In certain embodiments, the CCR8 is cynomolgus monkey ("cyno") CCR8. The amino acid sequence of an exemplary cyno CCR8 is set forth in SEQ ID NO: 107, as shown in the table below. In certain embodiments, the CCR8 is mouse CCR8 ("mCCR8"). The amino acid sequence of an exemplary mouse CCR8 is shown in SEQ ID NO: 108, as shown in the table below. [Table 1]

[0165] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis-binding partner with one or more of its binding partners in order to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis-binding antagonists include PD-L1-binding antagonists, PD-1-binding antagonists, and PD-L2-binding antagonists. In some cases, the PD-1 axis-binding antagonist includes a PD-L1-binding antagonist or a PD-1-binding antagonist. In a preferred embodiment, the PD-1 axis-binding antagonist is a PD-L1-binding antagonist.

[0166] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, e.g., PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In particular embodiments, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1 and / or B7-1. In one case, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-L1, such that dysfunctional T cells are rendered non-dysfunctional (e.g., enhance effector responses to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one particular embodiment, the PD-L1 binding antagonist is MDX-1105. In another particular embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another particular embodiment, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1 binding antagonist may be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, and in some cases may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS- 003. In one embodiment, the PD-L1 binding antagonist is atezolizumab.

[0167] For purposes herein, "atezolizumab" refers to an Fc-engineered, humanized, aglycosylated IgG1 kappa immunoglobulin that binds to PD-L1. Atezolizumab contains a single amino acid substitution (asparagine to alanine) (N297A) at position 297 on the heavy chain using the EU numbering of Fc region amino acid residues, resulting in an aglycosylated antibody with minimal binding to Fc receptors. Atezolizumab is also listed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 112, Vol. 28, No. 4, 2014, p. 488.

[0168] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary human PD-1 is set forth in UniProtKB / Swiss-Prot Accession No. Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one example, the PD-1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-1, so as to prevent dysfunctional T cells from becoming dysfunctional (e.g., enhancing effector responses to antigen recognition). In some cases, the PD-1 binding antagonist binds to PD-1. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prorugolimab, canrelizumab, sintilimab, tislelizumab, toripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimuzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In a specific embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another specific embodiment, the PD-1 binding antagonist is MED1-0680. In another specific embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another specific embodiment, the PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is prorugolimab. In another specific embodiment, the PD-1 binding antagonist is canrelizumab. In another specific embodiment, the PD-1 binding antagonist is sintilimab. In another specific embodiment, the PD-1 binding antagonist is tislelizumab. In another specific embodiment, the PD-1 binding antagonist is toripalimab. Other exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0169] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural history of a disease (e.g., a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor malignancy)) in the subject being treated, and can be carried out for prevention ("prophylactic treatment" or "prophylactically treating") or during the course of clinical pathology ("therapeutic treatment" or "therapeutic treating"). Desirable effects of therapeutic treatment include, but are not limited to, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, prevention of cancer metastasis, reduction in the rate of disease progression, amelioration or remission of the disease, and remission or improvement in prognosis. Desirable effects of preventative treatment include, but are not limited to, prevention of disease onset or recurrence. In some embodiments, the antibodies described herein are used to delay the onset of disease or to slow the progression of the disease.

[0170] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of a natural antibody generally have similar structures, and each domain contains four conserved framework regions (FR) and three complementarity-determining regions (CDR). (See, e.g., Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated using the VH or VL domain from an antibody that binds the antigen and then screening a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0171] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This term includes vectors that integrate into the genome of a host cell into which they are introduced, as well as vectors that act as self-replicating nucleic acid structures. Certain vectors are capable of directing the expression of a nucleic acid to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0172] II. METHODS AND COMPOSITIONS In one aspect, the present disclosure is based, in part, on the development of therapeutic methods and dosing regimens for treating locally advanced, recurrent, or metastatic solid tumor malignancies using anti-CCR8 antibodies, such as the anti-CCR8 antibodies disclosed herein.

[0173] A. Methods of Treatment and Compositions for Use The present disclosure provides therapeutic methods and compositions for use in treating cancer (e.g., locally advanced, recurrent, or metastatic solid tumor malignancies) in a subject in need thereof, which may include administering to the subject an anti-CCR8 antibody disclosed herein, alone or in combination with one or more additional therapeutic agents (e.g., a PD-1 axis-binding antagonist, e.g., an anti-PD-L1 antibody such as atezolizumab). Any anti-CCR8 antibody (e.g., a monoclonal antibody that binds to CCR8) may be used.

[0174] In one aspect, a method of treating locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof comprises administering to the subject a monoclonal antibody that binds to CCR8.

[0175] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof.

[0176] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof.

[0177] In one aspect, provided herein is a method for depleting regulatory T cells ("Tregs") in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8.

[0178] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof.

[0179] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof.

[0180] In some embodiments, (i) the subject has progressed after at least one available standard treatment; and / or (ii) the subject is one for whom all available standard treatments have proven ineffective or intolerable or are contraindicated.

[0181] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor is incurable.

[0182] In some embodiments, the subject is over the age of 18. For example, the subject can be an adult.

[0183] Any suitable locally advanced, recurrent or metastatic solid tumor malignancy can be treated.For example, in some embodiments, the locally advanced, recurrent or metastatic solid tumor malignancy is non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UC), esophageal cancer, gastric cancer, cervical cancer, renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC).

[0184] In some embodiments, the RCC is clear cell RCC.

[0185] In some embodiments, the HNSCC is an HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

[0186] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC.

[0187] In some embodiments, the subject's tumor contains a targetable somatic alteration and the subject is experiencing disease progression during or after treatment with, or intolerance to, treatment with a targeted agent.

[0188] In some embodiments, targetable somatic alterations include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

[0189] In some embodiments, the melanoma is cutaneous melanoma.

[0190] In some embodiments, the subject's tumor comprises a BRAFV600 mutation and the subject is experiencing disease progression during or after treatment with, or intolerance to, one or more serine / threonine-protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase (MEK) inhibitors.

[0191] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is UC.

[0192] In some embodiments, the subject has (i) histologically confirmed, incurable, advanced transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, bladder, and urethra); and / or the subject's tumor has mixed histology with a predominant transitional cell pattern.

[0193] In some embodiments, the locally advanced, recurrent, or metastatic solid tumor malignancy is TNBC.

[0194] In some embodiments, TNBC is defined by the American Society of Clinical Oncology-College of American Pathologists guidelines: (i) less than 1% of tumor cell nuclei are immunoreactive for estrogen receptors and less than 1% of tumor cell nuclei are immunoreactive for progesterone receptors; and / or (ii) is HER2 negative based on immunohistochemistry (IHC) and / or in situ hybridization.

[0195] In some embodiments, the subject is checkpoint inhibitor (CPI) naive.

[0196] In some embodiments, the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC or UC.

[0197] In some embodiments, the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is UC, the subject is eligible for treatment with cisplatin, and the subject experiences disease progression during or after treatment with or intolerance to treatment with cisplatin.

[0198] In some embodiments, the subject has not received previous treatment with a CPI, or the subject has received adjuvant treatment with a CPI that was discontinued at least 6 months prior to the subject's first administration of a monoclonal antibody that binds CCR8.

[0199] In some embodiments, the subject is experiencing CPI.

[0200] In some embodiments, the subject locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC, HNSCC, melanoma, UC, TNBC, esophageal cancer, gastric cancer, cervical cancer, clear cell RCC, or HCC.

[0201] In some embodiments, the subject derives clinical benefit from treatment comprising a PD-1 axis-binding antagonist prior to disease progression.

[0202] In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody.

[0203] In some embodiments, the subject had a treatment duration with a treatment comprising a PD-1 axis-binding antagonist of 6 months or greater and / or had a partial response or a complete response as the best objective response.

[0204] In some embodiments, (i) the subject has not been treated with a CPI, an immunomodulatory monoclonal antibody, or an immunomodulatory monoclonal antibody induction therapy within 6 weeks prior to the subject's first administration of a monoclonal antibody that binds CCR8; or (ii) the subject has been previously treated with a PD-1 axis-binding antagonist, and the subject's last administration of the PD-1 axis-binding antagonist was at least 3 weeks prior to the subject's first administration of a monoclonal antibody that binds CCR8.

[0205] In some embodiments, the CPI is a PD-1 axis binding antagonist or a CTLA4 antagonist (eg, an anti-CTLA4 antibody such as ipilimumab (Yervoy®)).

[0206] In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody (e.g., any anti-PD-L1 antibody disclosed herein, e.g., atezolizumab or avelumab) or an anti-PD-1 antibody (e.g., any anti-PD-1 antibody disclosed herein, e.g., pembrolizumab).

[0207] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject in a dosing regimen comprising one or more dosing cycles.

[0208] In some embodiments, the one or more administration cycles comprise a 21 day administration cycle.

[0209] For example, in one aspect, provided herein is a method of treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 in a dosing regimen comprising one or more 21-day dosing cycles.

[0210] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, in a dosing regimen comprising one or more 21-day dosing cycles.

[0211] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, in a dosing regimen comprising one or more 21-day dosing cycles.

[0212] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject on day 1 of each 21-day administration cycle.

[0213] In one aspect, provided herein is a method of treating locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 every three weeks (Q3W).

[0214] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in the treatment of locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof every three weeks (Q3W).

[0215] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof every three weeks (Q3W).

[0216] In one aspect, provided herein is a method of depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 every three weeks (Q3W).

[0217] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy every three weeks (Q3W) in a subject in need thereof.

[0218] In one aspect, provided herein is a method of treating locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg.

[0219] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, at a dose of 2 mg.

[0220] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, at a dose of 2 mg.

[0221] In one aspect, provided herein is a method of depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg.

[0222] In another aspect, provided herein is a monoclonal antibody that binds to CCR8, at a dose of 2 mg, for use in depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof.

[0223] In one aspect, provided herein is a method of treating locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg every three weeks (Q3W).

[0224] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in the treatment of locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, at a dose of 2 mg every three weeks (Q3W).

[0225] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof at a dose of 2 mg every three weeks (Q3W).

[0226] In one aspect, provided herein is a method of depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg every three weeks (Q3W).

[0227] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a locally advanced, recurrent, or metastatic solid tumor malignancy in a subject in need thereof, at a dose of 2 mg every three weeks (Q3W).

[0228] In some examples of any of the preceding embodiments, the monoclonal antibody that binds to CCR8 may be administered to the subject until disease progression or unacceptable toxicity occurs.

[0229] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject at a dose of 2 mg.

[0230] Any suitable route of administration can be used in the methods and compositions for use disclosed herein. In some embodiments, the monoclonal antibody that binds to CCR8 is administered intravenously to the subject.

[0231] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject intravenously by infusion.

[0232] In some embodiments, the monoclonal antibody that binds to CCR8 is administered to the subject as a monotherapy.

[0233] In other embodiments, the monoclonal antibody that binds to CCR8 is administered to a subject as a combination therapy. For example, the combination therapy can include administering an antibody described herein and administering at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents).

[0234] The one or more additional therapeutic agents include any agent that can be administered for treatment. In certain embodiments, the additional therapeutic agent is an additional anti-cancer agent. Exemplary anti-cancer agents include, but are not limited to, microtubule-disrupting agents, antimetabolites, topoisomerase inhibitors, DNA intercalators, alkylating agents, hormone therapy, kinase inhibitors, receptor antagonists, tumor cell apoptosis activators, anti-angiogenic agents, immunomodulatory agents, cell adhesion inhibitors, cytotoxic or cytostatic agents, cell apoptosis activators, agents that increase cell sensitivity to apoptosis inducers, cytokines, anti-cancer vaccines or oncolytic viruses, Toll-like receptor (TLR) agents, bispecific antibodies, cell therapy, and immune cell engagers. In certain embodiments, the additional therapeutic agent is an immunomodulatory anti-cancer agent, e.g., a checkpoint inhibitor (CPI) such as an anti-CTLA4 antibody (e.g., ipilimumab) or a PD-1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab or avelumab), a PD-1 binding antagonist (e.g., pembrolizumab), or a PD-L2 binding antagonist).

[0235] In some embodiments, the one or more additional therapeutic agents comprises an anti-PD-L1 antibody, for example, in some embodiments, the one or more additional therapeutic agents comprises atezolizumab.

[0236] In some embodiments, atezolizumab is administered to a subject in a dosing regimen comprising one or more dosing cycles. In some embodiments, the one or more dosing cycles comprise a 14-day, 21-day, or 28-day dosing cycle.

[0237] In some embodiments, the one or more administration cycles comprise a 21-day administration cycle, hi some embodiments, atezolizumab is administered to the subject on day 1 of each 21-day administration cycle.

[0238] Any suitable dose of atezolizumab can be administered to the subject. In some embodiments, atezolizumab is administered to the subject at a dose of 1200 mg. For example, in some embodiments, atezolizumab is administered to the subject at a dose of 1200 mg every three weeks (Q3W). In other examples, atezolizumab is administered to the subject at a dose of 840 mg, for example, every two weeks (Q2W). In yet other examples, atezolizumab is administered to the subject at a dose of 1680 mg, for example, every four weeks (Q4W).

[0239] In some embodiments, atezolizumab is administered to the subject intravenously. In some embodiments, atezolizumab is administered to the subject intravenously by infusion.

[0240] In some embodiments, a tumor sample from a subject has been determined to have a detectable level of PD-L1 expression. For example, in some embodiments, a tumor sample from a subject has 1% or more tumor cells (TC), immune cells (IC), combined positive score (CPS), or tumor proportion score (TPS). The presence or expression level of PD-L1 can be determined using any suitable approach, such as immunohistochemistry using an anti-PD-L1 diagnostic antibody. Any suitable anti-PD-L1 diagnostic antibody can be used, such as SP142 (VENTANA), SP263 (VENTANA), 22C3 (Dako), 28-8 (Dako), E1L3N, 4059, h5H1, 9A11, etc.

[0241] In some embodiments, the subject has received at least two cycles (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles) of a monoclonal antibody that binds CCR8 prior to administration of atezolizumab to the subject.

[0242] Such combination therapy as described above encompasses combined administration (when two or more therapeutic agents are contained in the same or separate pharmaceutical compositions) and separate administration, in which case administration of the antibody described herein can occur before, simultaneously with, and / or after administration of the additional therapeutic agent. In one embodiment, administration of the anti-CCR8 antibody and administration of the additional therapeutic agent occur within about 1 month, or within about 1, 2, or 3 weeks, or within about 1, 2, 3, 4, 5, or 6 days of each other. In one embodiment, the antibody and the additional therapeutic agent are administered to the subject on the first day of treatment. The antibodies described herein can also be used in combination with radiation therapy.

[0243] In one embodiment, an anti-CCR8 antibody is provided for use as a pharmaceutical. In a further embodiment, an anti-CCR8 antibody is provided for use in the treatment of cancer. In certain embodiments, an anti-CCR8 antibody is provided for use in a treatment method. In certain embodiments, the present disclosure provides an anti-CCR8 antibody for use in a method of treating a subject (e.g., a human subject) in need of treatment, comprising administering to the subject an effective amount of an anti-CCR8 antibody. In one such embodiment, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents), e.g., as described below. In a further embodiment, the present disclosure provides an anti-CCR8 antibody for use in depleting Tregs in a tumor microenvironment. In certain embodiments, the present disclosure provides an anti-CCR8 antibody for use in a method of depleting Tregs in a tumor microenvironment of a subject, the method comprising administering to the subject an amount of an anti-CCR8 antibody effective for depleting Tregs in the tumor microenvironment.

[0244] In a further aspect, the present disclosure provides use of an anti-CCR8 antibody in the manufacture or preparation of a medicament. In one aspect, the medicament is for the treatment of cancer. In a further aspect, the medicament is for use in a method of treating cancer, comprising administering an effective amount of the medicament to a subject (e.g., a human subject) in need thereof. In one such aspect, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent, such as those described below. In a further aspect, the medicament is for depleting Tregs in the tumor microenvironment. In a further aspect, the medicament is for use in a method of depleting Tregs in the tumor microenvironment of a subject, comprising administering to the subject an effective amount of the medicament to deplete Tregs in the tumor microenvironment.

[0245] In a further aspect, the present disclosure provides a method for treating cancer. In one aspect, the method comprises administering an effective amount of an anti-CCR8 antibody to a subject (e.g., a human subject) in need thereof to treat the cancer. In one such aspect, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent, as described below.

[0246] In a further aspect, the present disclosure provides anti-CCR8 antibodies for use in depleting Treg cells, e.g., outside or within a tumor microenvironment. For example, in certain embodiments, the present disclosure provides a method for depleting Treg cells in the tumor microenvironment of a subject (e.g., a human subject) with cancer in need of depletion of Treg cells, comprising administering to the subject an effective amount of an anti-CCR8 antibody sufficient to deplete Treg cells in the tumor microenvironment, thereby treating the cancer. In certain aspects, the present disclosure provides a method for depleting Treg cells outside the tumor microenvironment (e.g., in the circulation) of a subject (e.g., a human subject) with cancer in need of depletion of Treg cells, comprising administering to the subject an effective amount of an anti-CCR8 antibody sufficient to deplete Treg cells outside the tumor microenvironment, thereby treating the cancer. Without wishing to be bound by any particular theory, reducing the number of Treg cells outside the tumor microenvironment treats cancer as the number of Treg cells infiltrating the tumor microenvironment is reduced, thereby reducing the number of Treg cells in the tumor microenvironment.

[0247] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 every three weeks (Q3W).

[0248] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating cancer in a subject in need thereof every three weeks (Q3W).

[0249] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating cancer in a subject in need thereof every three weeks (Q3W).

[0250] In one aspect, provided herein is a method of depleting Tregs in a cancer tumor microenvironment in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 every three weeks (Q3W).

[0251] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a cancer every three weeks (Q3W) in a subject in need thereof.

[0252] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg.

[0253] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating cancer in a subject in need thereof, at a dose of 2 mg.

[0254] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating cancer in a subject in need thereof, at a dose of 2 mg.

[0255] In one aspect, provided herein is a method of depleting Tregs in a cancer tumor microenvironment in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg.

[0256] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a cancer in a subject in need thereof, at a dose of 2 mg.

[0257] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg every three weeks (Q3W).

[0258] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in treating cancer in a subject in need thereof, at a dose of 2 mg every three weeks (Q3W).

[0259] In another aspect, provided herein is the use of a monoclonal antibody that binds to CCR8 in the manufacture of a medicament for treating cancer in a subject in need thereof, at a dose of 2 mg every three weeks (Q3W).

[0260] In one aspect, provided herein is a method of depleting Tregs in a cancer tumor microenvironment in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody that binds to CCR8 at a dose of 2 mg every three weeks (Q3W).

[0261] In another aspect, provided herein is a monoclonal antibody that binds to CCR8 for use in depleting Tregs in the tumor microenvironment of a cancer in a subject in need thereof, at a dose of 2 mg every three weeks (Q3W).

[0262] Exemplary cancers include, but are not limited to, bladder cancer (e.g., urothelial cancer), blastoma, blood cancer (lymphoma, e.g., non-Hodgkin's lymphoma, leukemia), bone cancer, brain cancer, breast cancer (e.g., triple-negative breast cancer), cervical cancer, colorectal cancer (e.g., colon cancer, rectal cancer), endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), kidney cancer (e.g., renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma), ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer (e.g., melanoma, squamous cell carcinoma), testicular cancer, and uterine cancer.

[0263] In certain embodiments, the cancer is bladder cancer, blood cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, and skin cancer.

[0264] In particular embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, or skin cancer.

[0265] In certain embodiments, the cancer is a solid tumor, such as a locally advanced or metastatic solid tumor.

[0266] In certain embodiments, the cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor malignancy) expresses CCR8.

[0267] In certain embodiments, the cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor malignancy) is a T-cell inflammatory tumor or comprises a T-cell inflammatory tumor microenvironment.

[0268] In certain embodiments, cancers (e.g., locally advanced, recurrent, or metastatic solid tumor malignancies) contain regulatory T cells in the tumor microenvironment, and exposure of the cancer to a CCR8 antibody described herein results in depletion of regulatory T cells in the tumor microenvironment. In further embodiments, the present disclosure provides pharmaceutical compositions comprising any of the anti-CCR8 antibodies described herein, e.g., for use in any of the above-described therapeutic methods. In one embodiment, the pharmaceutical composition comprises any of the anti-CCR8 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises any of the anti-CCR8 antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.

[0269] Any of the anti-CCR8 antibodies provided herein (e.g., in section B below) can be used in the therapeutic methods and compositions for use (e.g., anti-CCR8 antibodies for use (e.g., monoclonal antibodies that bind to CCR8 for use)) disclosed herein.

[0270] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0271] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0272] In some embodiments, the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO:106.

[0273] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35-47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48-52; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0274] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52.

[0275] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 48; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0276] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:47, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:48.

[0277] In some embodiments, the VL comprises a V4M mutation, a P43A mutation, a F46L mutation, a C90Q mutation, or a combination thereof. In some cases, the V4M mutation, the P43A mutation, the F46L mutation, or the C90Q mutation is according to Kabat numbering.

[0278] In some embodiments, the VH comprises a G49S mutation, a K71R mutation, an S73N mutation, or a combination thereof. In some cases, the G49S mutation, the K71R mutation, or the S73N mutation is according to Kabat numbering.

[0279] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:55 and the light chain amino acid sequence of SEQ ID NO:56.

[0280] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:60 and the light chain amino acid sequence of SEQ ID NO:56.

[0281] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:111 and the light chain amino acid sequence of SEQ ID NO:56.

[0282] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:113 and the light chain amino acid sequence of SEQ ID NO:56.

[0283] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52.

[0284] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:47 and the VL sequence of SEQ ID NO:48.

[0285] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0286] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0287] In some embodiments, the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:106.

[0288] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0289] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 10-21 and a VL sequence selected from the group consisting of SEQ ID NOs: 22-25.

[0290] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 24; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0291] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:21, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:24.

[0292] In some embodiments, the VL comprises a Y2I mutation. In some cases, the Y2I mutation is according to Kabat numbering.

[0293] In some embodiments, the VH comprises a S73N mutation, a V78L mutation, a T76N mutation, a F91Y mutation, and a P105Q mutation, or a combination thereof. In some cases, the S73N mutation, the V78L mutation, the T76N mutation, the F91Y mutation, or the P105Q mutation is according to Kabat numbering.

[0294] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:57 and the light chain amino acid sequence of SEQ ID NO:58.

[0295] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:61 and the light chain amino acid sequence of SEQ ID NO:58.

[0296] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:112 and the light chain amino acid sequence of SEQ ID NO:58.

[0297] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:114 and the light chain amino acid sequence of SEQ ID NO:58.

[0298] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:21 and the VL sequence of SEQ ID NO:24.

[0299] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75.

[0300] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 95; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 94; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0301] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:95 and the VL sequence of SEQ ID NO:94.

[0302] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:101 and the light chain amino acid sequence of SEQ ID NO:100.

[0303] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:115 and the light chain amino acid sequence of SEQ ID NO:100.

[0304] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0305] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 97; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 96; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0306] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:97 and the VL sequence of SEQ ID NO:96.

[0307] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:103 and the light chain amino acid sequence of SEQ ID NO:102.

[0308] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:116 and the light chain amino acid sequence of SEQ ID NO:102.

[0309] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81.

[0310] In some embodiments, the monoclonal antibody that binds to CCR8 comprises: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 99; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 98; and (c) a sequence selected from the group consisting of the VH sequence defined in (a) and the VL sequence defined in (b).

[0311] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:99 and the VL sequence of SEQ ID NO:98.

[0312] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:105 and the light chain amino acid sequence of SEQ ID NO:104.

[0313] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:117 and the light chain amino acid sequence of SEQ ID NO:104.

[0314] In some embodiments, the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of sulfation of CCR8.

[0315] In some embodiments, the antibody binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO:106.

[0316] In some embodiments, the antibody binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:106.

[0317] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0318] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a sequence selected from the group consisting of: (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 70; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 69; and (c) a VH sequence defined in (a) and a VL sequence defined in (b).

[0319] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:70 and the VL sequence of SEQ ID NO:69.

[0320] In some embodiments, the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO:72 and the light chain amino acid sequence of SEQ ID NO:71.

[0321] In some embodiments, the monoclonal antibody that binds to CCR8 is a human antibody.

[0322] In some embodiments, the monoclonal antibody that binds to CCR8 is a humanized antibody.

[0323] In some embodiments, the monoclonal antibody that binds to CCR8 is a chimeric antibody.

[0324] In some embodiments, the monoclonal antibody that binds to CCR8 is an antibody fragment that binds to CCR8.

[0325] In some embodiments, the monoclonal antibody that binds to CCR8 is a full-length antibody.

[0326] In some embodiments, the monoclonal antibody that binds to CCR8 is a full-length IgG1 antibody.

[0327] In some embodiments, the monoclonal antibody that binds to CCR8 comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:59.

[0328] In some embodiments, the monoclonal antibody that binds to CCR8 comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO:54.

[0329] In some embodiments, the monoclonal antibody that binds to CCR8 is about 1 x 10 -12 M ~ approx. 1×10 -11 Binding affinity (K d ) binds to CCR8.

[0330] In some embodiments, the CCR8 is human CCR8.

[0331] In some embodiments, the monoclonal antibody that binds to CCR8 is defucosylated.

[0332] In some embodiments, the defucosylation rate is about 80% to about 95%.

[0333] In some embodiments, regulatory T cells present in the tumor microenvironment of locally advanced, recurrent, or metastatic solid tumor malignancies are depleted.

[0334] In some embodiments, regulatory T cells outside the tumor microenvironment of locally advanced, recurrent, or metastatic solid tumor malignancies are depleted.

[0335] In some embodiments, the subject is a human.

[0336] The antibodies (and any additional therapeutic agents) described herein can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is brief or chronic. Various administration schedules are contemplated herein, including, but not limited to, a single administration or multiple administrations over various time periods, bolus administration, and pulse infusion.

[0337] The antibodies described herein will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the specific disorder being treated, the specific subject species being treated, the subject's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals. The antibodies are optionally, but not necessarily, formulated with one or more agents currently used to treat the disorder in question. The effective amount of such other agents will depend on the amount of antibody present in the pharmaceutical composition, the type of disorder or treatment, and other factors discussed above. These will generally be administered in the same dosages and via the same routes of administration as those described herein, or at about 1-99% of the dosages described herein, or at any dosage and via any route empirically / clinically determined to be appropriate.

[0338] Antibodies of the invention are preferably administered to a subject at one time or over a series of treatments. With repeated administrations over several days or longer, depending on the symptoms, treatment is usually continued until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy can be monitored by conventional techniques and assays.

[0339] B. Exemplary Anti-CCR8 Antibodies Any of the anti-CCR8 antibodies may be used in any of the methods and compositions for use disclosed herein, for example, as described above in Section A.

[0340] In one embodiment, the present disclosure provides an antibody that binds to CCR8. In one embodiment, the provided antibody is an isolated antibody that binds to CCR8. In one embodiment, the present disclosure provides an antibody that specifically binds to CCR8. In certain embodiments, the anti-CCR8 antibody binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO: 106. In certain embodiments, the anti-CCR8 antibody binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO: 106. In certain embodiments, the CCR8 is human CCR8, mouse CCR8, or cyno CCR8. In certain embodiments, the CCR8 is human CCR8. In one embodiment, the present disclosure provides an antibody that binds to CCR8 regardless of tyrosine sulfation of CCR8 ("sulfation-independent"). Exemplary antibodies disclosed herein that are sulfation-independent include Ab4 and Ab5, and are further described in more detail below.

[0341] In certain embodiments, the antibodies provided herein have a cytotoxicity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the antibody that binds to CCR8 has a concentration of about 1 x 10 -12 M ~ approx. 1×10 -10 M, about 1 x 10 -12 M ~ approx. 1×10 -11 M, or approximately 1 x 10 -11 M ~ approx. 5×10 -11 K of M D In certain embodiments, the antibody that binds to CCR8 has about 2 x 10 -11 K of M D In certain embodiments, the antibody that binds to CCR8 has about 5 x 10 -12 K of M D In one embodiment, K Dis measured using radiolabeled IgG and a CHO cell line stably expressing the antigen. Stable CHO cells expressing the antigen are seeded at 50,000 cells / well in cold binding buffer (Opti-MEM + 2% fetal bovine serum (FBS) + 50 mM HEPES, pH 7.2 + 0.1% sodium azide). Binding of the desired antibody at a fixed concentration is performed using the NEX244 IODOGEN® method (Perkin Elmer). 125 Radiolabeled antigen is mixed with serially diluted antibodies of interest, starting at 20 nM or 50 nM. The antibody mixture is added to the cells and incubated at room temperature for 12 hours with gentle agitation. The cells and antibodies are then transferred to a Millipore multiscreen filter plate. The filter plate is washed four times with 250 μL of cold binding buffer, allowed to dry for at least 30 minutes, and the filters are punched into 5 mL polystyrene tubes. Radioactivity is measured using a Perkin Elmer Wallac Wizard® 2470 Gamma Counter set at 1 count / min with a counting efficiency of 0.8. Data are analyzed using GraphPad Prism. (登録商標) The K i is fitted using a heterogeneous one-site competitive binding model.

[0342] In certain embodiments, the antibodies provided herein exhibit a mean clearance of about 3 to about 5 mL / day / kg over 35 days after a single 10 mg / kg dose administered intravenously on day 1. For example, but not limited to, such administration can include a single 10 mg / kg IV bolus of mAb. Blood samples for analysis can be collected, for example, at 0.25, 2, and 6 hours; and at 1, 2, 7, 14, 21, 28, and 35 days after administration; serum can be assayed for mAb concentration using various means, for example, a qualified ELISA assay. In certain embodiments, administration is to a mammal. In certain embodiments, administration is to a primate. In certain embodiments, administration is to a non-human primate, e.g., a cyno. In certain embodiments, administration is to a human.

[0343] (i) Embodiments of Ab5 and Fragments Thereof In one embodiment, the present disclosure provides an anti-CCR8 antibody comprising at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to both human CCR8 and cyno CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0344] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32.

[0345] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0346] In another embodiment, the antibody described herein comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to both human CCR8 and cyno CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0347] In another aspect, the present disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0348] In another aspect, the anti-CCR8 antibody comprises one or more CDR sequences of a VH sequence selected from the group consisting of SEQ ID NOs: 35 to 47. In another embodiment, the anti-CCR8 antibody comprises one or more CDR sequences of a VL sequence selected from the group consisting of SEQ ID NOs: 48 to 52. In another embodiment, the anti-CCR8 antibody comprises a CDR sequence of a VH sequence selected from the group consisting of SEQ ID NOs: 35 to 47 and a CDR sequence of a VL sequence selected from the group consisting of SEQ ID NOs: 48 to 52.

[0349] In another aspect, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 47. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 48. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 47. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 48.

[0350] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of the VH domain selected from the group consisting of SEQ ID NOs: 35 to 47, and the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of the VL domain selected from the group consisting of SEQ ID NOs: 48 to 52.

[0351] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 47 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 48.

[0352] In one embodiment, the anti-CCR8 antibody comprises one or more heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47. In one embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47. In one embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47, and a framework having at least 95% sequence identity to the framework amino acid sequence of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47. In another embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47, and a framework having at least 98% sequence identity to the framework amino acid sequence of a VH domain selected from the group consisting of SEQ ID NOs: 35 to 47.

[0353] In one embodiment, an anti-CCR8 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 47 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 47. In one embodiment, an anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 47 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 47. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 47 and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 47. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 47 and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 47.

[0354] In one embodiment, the anti-CCR8 antibody comprises one or more light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52, and a framework having at least 95% sequence identity to a framework amino acid sequence of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52. In another embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52, and a framework having at least, particularly at least 98% sequence identity to a framework amino acid sequence of a VL domain selected from the group consisting of SEQ ID NOs: 48 to 52.

[0355] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 48 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 48. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 48 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 48. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 48 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 48. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 48 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 48.

[0356] In one embodiment, the anti-CCR8 antibody comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28, and the CDRs of SEQ ID NOs: 35 to 47. and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 52. In one embodiment, the VH domain has at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35 to 47. In one embodiment, the VL domain has at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 52. In one embodiment, the dissociation constant (K D ) compared to the dissociation constant (K D ) binds to CCR8.

[0357] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 47, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 47. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to mouse CCR8.

[0358] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35 to 47. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35 to 47. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from the group consisting of SEQ ID NOs: 35 to 47. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35 to 47, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, or (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32. In another aspect, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 52. In one aspect, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 52.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from the group consisting of SEQ ID NOs: 48-52. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 48-52, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0359] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 47. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 47. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 47. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 47, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, or (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48. In one embodiment, an anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 48.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 48, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

[0360] In another aspect, an anti-CCR8 antibody is provided, comprising a VH sequence as in any of the aspects provided above and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52, including post-translational modifications of these sequences. In one aspect, the antibody comprises the VH sequence of SEQ ID NO: 47 and the VL sequence of SEQ ID NO: 48, including post-translational modifications of these sequences.

[0361] In one embodiment, the VL sequence comprises a V4M mutation, a P43A mutation, a F46L mutation, a C90Q mutation, or a combination thereof (e.g., according to Kabat numbering). In one embodiment, the VH comprises a G49S mutation, a K71R mutation, a S73N mutation, or a combination thereof (e.g., according to Kabat numbering).

[0362] In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59. In one aspect, the antibody comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54. In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises (a) an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59, and (b) a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54.

[0363] In another embodiment, an anti-CCR8 antibody is provided, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In one embodiment, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 47 and the VL sequence of SEQ ID NO: 48.

[0364] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:55 and a light chain of SEQ ID NO:56.

[0365] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:60 and a light chain of SEQ ID NO:56.

[0366] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the heavy chain of the antibody comprises a truncated C-terminus in which one or two C-terminal amino acid residues have been removed. In one aspect, the C-terminus of the heavy chain is PG terminating in the truncated C-terminus. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 111 and a light chain of SEQ ID NO: 56. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 113 and a light chain of SEQ ID NO: 56.

[0367] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, which does not bind to a CCR8 ligand. In one aspect, the anti-CCR8 antibody does not have CCR8 ligand blocking activity. In one aspect, the anti-CCR8 antibody is a non-neutralizing antibody. In one aspect, the CCR8 ligand is CCL1.

[0368] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided that binds to CCR8 independently of tyrosine sulfation of CCR8 for binding (i.e., sulfation-independent).

[0369] In another aspect of any of the above embodiments, there is provided an anti-CCR8 antibody, wherein the anti-CCR8 antibody is a defucosylated antibody variant. In one aspect, the defucosylated antibody variant has enhanced FcγRIIIa receptor binding. In one aspect, the defucosylated anti-CCR8 antibody variant has enhanced antibody-dependent cellular cytotoxicity (ADCC). In one aspect, the defucosylated anti-CCR8 antibody variant has antibody-dependent cellular phagocytosis (ADCP) activity.

[0370] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the antibody stability is improved. In one aspect, the anti-CCR8 antibody has low aggregation, good solubility, and / or low viscosity. In a specific aspect of any of the above embodiments, the anti-CCR8 antibody is at about 1×10 -12 M ~ approx. 1×10 -11 K of M D In certain embodiments, an anti-CCR8 antibody that binds to CCR8 has a CCR8-binding domain of about 5×10 -12 K of M D In certain embodiments, the antibody that binds to CCR8 has about 4 x 10 -12 K of M D In certain embodiments, the antibody that binds to CCR8 has about 3 x 10 -12 K of M D It has.

[0371] In one aspect, the anti-CCR8 antibody is designated in the present disclosure as "hu.Ab5.H13L1," which can be fucosylated or defucosylated, optionally contains one or more heavy chain mutations at G236A and I331E, and optionally includes a truncated C-terminus of the heavy chain in which one or two of the C-terminal amino acid residues are removed. In some embodiments, the heavy chain mutations are numbered according to the EU index.

[0372] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0373] (ii) Embodiments of Ab4 and Fragments Thereof In one embodiment, the present disclosure provides an anti-CCR8 antibody comprising at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to both human CCR8 and cyno CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0374] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:6, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:7. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:7. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:3. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:3, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:6. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:6, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:7.

[0375] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0376] In another embodiment, the antibody described herein comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to both human CCR8 and cyno CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0377] In another aspect, the present disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0378] In another embodiment, the anti-CCR8 antibody comprises one or more CDR sequences of a VH sequence selected from the group consisting of SEQ ID NOs: 10 to 21. In another embodiment, the anti-CCR8 antibody comprises one or more CDR sequences of a VL sequence selected from the group consisting of SEQ ID NOs: 22 to 25. In another embodiment, the anti-CCR8 antibody comprises a CDR sequence of a VH sequence selected from the group consisting of SEQ ID NOs: 10 to 21 and a CDR sequence of a VL sequence selected from the group consisting of SEQ ID NOs: 22 to 25.

[0379] In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 21. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 24. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 21. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 24.

[0380] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of the VH domain selected from the group consisting of SEQ ID NOs: 10 to 21, and the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of the VL domain selected from the group consisting of SEQ ID NOs: 22 to 25.

[0381] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 21 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 24.

[0382] In one embodiment, the anti-CCR8 antibody comprises one or more heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21. In one embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the framework amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21. In one embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21, and a framework having at least 95% sequence identity to the framework amino acid sequence of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21. In another embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21, and a framework having at least 98% sequence identity to the framework amino acid sequence of a VH domain selected from the group consisting of SEQ ID NOs: 10 to 21.

[0383] In one embodiment, an anti-CCR8 antibody comprises one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 21 and frameworks of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 21. In one embodiment, an anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 21 and frameworks of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 21. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 21 and a framework with at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 21. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 21 and a framework with at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 21.

[0384] In one embodiment, the anti-CCR8 antibody comprises one or more light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25, and a framework having at least 95% sequence identity to a framework amino acid sequence of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25. In another embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25, and a framework having at least, particularly at least 98% sequence identity to a framework amino acid sequence of a VL domain selected from the group consisting of SEQ ID NOs: 22 to 25.

[0385] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 24 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 24. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 24 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 24. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 24 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 24. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 24 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 24.

[0386] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 25. In one embodiment, the VH domain has at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21. In one embodiment, the VL domain has at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 25. In one embodiment, the dissociation constant (K D ) compared to the dissociation constants (K D ) binds to CCR8.

[0387] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 21, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 21. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 24. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to mouse CCR8.

[0388] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 10 to 21, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7. In another aspect, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 25. In one aspect, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 25.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 22-25, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0389] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 21. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 21. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 21. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 21, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24. In one embodiment, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 24. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 24.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 24, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[0390] In another aspect, an anti-CCR8 antibody is provided, comprising a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 10-21 and a VL sequence selected from the group consisting of SEQ ID NOs: 22-25, including post-translational modifications of these sequences. In one aspect, the antibody comprises a VH sequence of SEQ ID NO: 21 and a VL sequence of SEQ ID NO: 24, including post-translational modifications of these sequences.

[0391] In one embodiment, the VL sequence comprises a Y2I mutation. In one embodiment, the VH sequence comprises a S73N mutation, a V78L mutation, a T76N mutation, a F91Y mutation, and a P105Q mutation, or a combination thereof (according to Kabat numbering).

[0392] In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59. In one aspect, the antibody comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54. In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises (a) an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59, and (b) a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54.

[0393] In another embodiment, an anti-CCR8 antibody is provided, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In one embodiment, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 21 and the VL sequence of SEQ ID NO: 24.

[0394] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:57 and a light chain of SEQ ID NO:58.

[0395] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:61 and a light chain of SEQ ID NO:58.

[0396] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the heavy chain of the antibody comprises a truncated C-terminus in which one or two C-terminal amino acid residues have been removed. In one aspect, the C-terminus of the heavy chain is PG terminating in the truncated C-terminus. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 112 and a light chain of SEQ ID NO: 58. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 114 and a light chain of SEQ ID NO: 58.

[0397] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody binds to a CCR8 ligand. In one aspect, the anti-CCR8 antibody has an antagonistic effect on the CCR8 ligand. In one aspect, the anti-CCR8 antibody has CCR8 ligand blocking activity. In one aspect, the anti-CCR8 antibody is a neutralizing antibody. In one aspect, the CCR8 ligand is CCL1.

[0398] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided that binds to CCR8 independently of tyrosine sulfation of CCR8 for binding (i.e., sulfation-independent).

[0399] In another aspect of any of the above embodiments, there is provided an anti-CCR8 antibody, wherein the anti-CCR8 antibody is a defucosylated antibody variant. In one aspect, the defucosylated antibody variant has enhanced FcγRIIIa receptor binding. In one aspect, the defucosylated anti-CCR8 antibody variant has enhanced antibody-dependent cellular cytotoxicity (ADCC). In one aspect, the defucosylated anti-CCR8 antibody variant has antibody-dependent cellular phagocytosis (ADCP) activity.

[0400] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the antibody stability is improved. In one aspect, the anti-CCR8 antibody has low aggregation, good solubility, and / or low viscosity. In a specific aspect of any of the above embodiments, the anti-CCR8 antibody is at about 1×10 -11 M ~ approx. 5×10 -11 K of M D In certain embodiments, an anti-CCR8 antibody that binds to CCR8 has a CCR8 concentration of about 2 x 10 -11 K of M D It has.

[0401] In one embodiment, the anti-CCR8 antibody is designated in the present disclosure as "hu.Ab4.H12L3," which can be fucosylated or defucosylated, optionally contains one or more heavy chain mutations at G236A and I331E, and optionally includes a truncated C-terminus of the heavy chain in which one or two of the C-terminal amino acid residues are removed. In some cases, the heavy chain mutations are numbered according to the EU index.

[0402] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0403] (iii) Embodiments of Ab1 and Fragments Thereof In one aspect, the present disclosure provides an anti-CCR8 antibody comprising at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75. In certain aspects, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain aspects, the anti-CCR8 antibody is a full-length antibody. In certain aspects, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain aspects, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0404] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85.

[0405] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75.

[0406] In another embodiment, the antibody described herein comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0407] In another aspect, the disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75.

[0408] In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 95. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 94. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 95. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 94.

[0409] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 95 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 94.

[0410] In one embodiment, the anti-CCR8 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 95 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 95. In one embodiment, the anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 95 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 95. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 95 and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 95. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 95 and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 95.

[0411] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 94 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 94. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 94 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 94. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 94 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 94. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 94 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 94.

[0412] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 95, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 94. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 95. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 94. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to mouse CCR8.

[0413] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 95. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 95. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 95. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 95, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 94. In one embodiment, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 94. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 94.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 94, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75.

[0414] In another embodiment, an anti-CCR8 antibody is provided, comprising the VH sequence of any of the embodiments provided above and the VL sequence of any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence of SEQ ID NO: 95 and the VL sequence of SEQ ID NO: 94, including post-translational modifications of these sequences.

[0415] In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59. In one aspect, the antibody comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54. In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises (a) an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59, and (b) a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54.

[0416] In another aspect, an anti-CCR8 antibody is provided, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 75. In one aspect, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 95 and the VL sequence of SEQ ID NO: 94.

[0417] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:101 and a light chain of SEQ ID NO:100.

[0418] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the heavy chain of the antibody comprises a truncated C-terminus in which one or two C-terminal amino acid residues are removed. In one aspect, the C-terminus of the heavy chain is PG, terminating in the truncated C-terminus. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 115 and a light chain of SEQ ID NO: 100.

[0419] In one embodiment, the anti-CCR8 antibody is designated in the present disclosure as "hu.Ab1.H1L1," which can be fucosylated or defucosylated, optionally contains one or more heavy chain mutations at G236A and I331E, and optionally includes a truncated C-terminus of the heavy chain in which one or two of the C-terminal amino acid residues are removed. In some cases, the heavy chain mutations are numbered according to the EU index.

[0420] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0421] (iv) Embodiments of Ab2 and Fragments Thereof In one embodiment, the present disclosure provides an anti-CCR8 antibody comprising at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0422] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89.

[0423] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0424] In another embodiment, the antibody described herein comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0425] In another aspect, the present disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0426] In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 97. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 96. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 97. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 96.

[0427] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:97 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:96.

[0428] In one embodiment, an anti-CCR8 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 97 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 97. In one embodiment, an anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 97 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 97. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 97 and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 97. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 97 and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 97.

[0429] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 96 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 96. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 96 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 96. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 96 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 96. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 96 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 96.

[0430] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 97, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 96. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 97. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 96. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to mouse CCR8.

[0431] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 97. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 97. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 97. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 97, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, or (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 96. In one embodiment, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 96. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 96.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 96, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 75, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0432] In another embodiment, an anti-CCR8 antibody is provided, comprising the VH sequence of any of the embodiments provided above and the VL sequence of any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence of SEQ ID NO: 97 and the VL sequence of SEQ ID NO: 96, including post-translational modifications of these sequences.

[0433] In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59. In one aspect, the antibody comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54. In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises (a) an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59, and (b) a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54.

[0434] In another aspect, an anti-CCR8 antibody is provided, comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78.

[0435] In one embodiment, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO:97 and the VL sequence of SEQ ID NO:96.

[0436] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:103 and a light chain of SEQ ID NO:102.

[0437] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the heavy chain of the antibody comprises a truncated C-terminus in which one or two C-terminal amino acid residues are removed. In one aspect, the C-terminus of the heavy chain is PG, terminating in the truncated C-terminus. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 116 and a light chain of SEQ ID NO: 102.

[0438] In one embodiment, the anti-CCR8 antibody is designated in the present disclosure as "hu.Ab2.H1L1," which can be fucosylated or defucosylated, optionally contains one or more heavy chain mutations at G236A and I331E, and optionally includes a truncated C-terminus of the heavy chain in which one or two of the C-terminal amino acid residues are removed. In some cases, the heavy chain mutations are numbered according to the EU index.

[0439] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0440] (v) Embodiments of Ab3 and Fragments Thereof In one embodiment, the present disclosure provides an anti-CCR8 antibody comprising at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:91; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:92; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:93; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:79; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:80; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:81. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0441] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:91, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:92, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:93. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:93. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:93, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:81. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:93, a CDR-L3 comprising the amino acid sequence of SEQ ID NO:81, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:92. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93.

[0442] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81.

[0443] In another embodiment, the antibody described herein comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a human antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a humanized antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to human CCR8 and is a chimeric antibody.

[0444] In another aspect, the present disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81.

[0445] In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 99. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 98. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 99. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 98.

[0446] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:99 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:98.

[0447] In one embodiment, an anti-CCR8 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 99 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 99. In one embodiment, an anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 99 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 99. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 99 and a framework with at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 99. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 99 and a framework with at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 99.

[0448] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 98 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 98. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 98 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 98. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 98 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 98. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 98 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 98.

[0449] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 99, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 98. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 99. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 98. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to CCR8.

[0450] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 99. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 99. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 99. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 99, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from: SEQ ID NO: 90 or SEQ ID NO: 91; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92; or (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 98. In one embodiment, the anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 98. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 98.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 98, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81.

[0451] In another embodiment, an anti-CCR8 antibody is provided, comprising the VH sequence of any of the embodiments provided above and the VL sequence of any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence of SEQ ID NO: 99 and the VL sequence of SEQ ID NO: 98, including post-translational modifications of these sequences.

[0452] In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59. In one aspect, the antibody comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54. In another aspect, an anti-CCR8 antibody is provided, wherein the anti-CCR8 antibody comprises (a) an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 53 or SEQ ID NO: 59, and (b) a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 54.

[0453] In another aspect, an anti-CCR8 antibody is provided, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 81. In one aspect, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 99 and the VL sequence of SEQ ID NO: 98.

[0454] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:105 and a light chain of SEQ ID NO:104.

[0455] In another aspect of any of the above embodiments, an anti-CCR8 antibody is provided, wherein the heavy chain of the antibody comprises a truncated C-terminus in which one or two C-terminal amino acid residues are removed. In one aspect, the C-terminus of the heavy chain is PG, terminating in the truncated C-terminus. In one aspect, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO: 117 and a light chain of SEQ ID NO: 104.

[0456] In one embodiment, the anti-CCR8 antibody is designated in the present disclosure as "hu.Ab3.H1L1," which can be fucosylated or defucosylated, optionally contains one or more heavy chain mutations at G236A and I331E, and optionally includes a truncated C-terminus of the heavy chain in which one or two of the C-terminal amino acid residues are removed. In some cases, the heavy chain mutations are numbered according to the EU index.

[0457] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0458] (vi) Mouse Surrogate Embodiments In one embodiment, the present disclosure provides an anti-CCR8 antibody that binds to mouse CCR8 and comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64. In certain embodiments, the anti-CCR8 antibody comprises all six of the aforementioned CDRs. In certain embodiments, the anti-CCR8 antibody is a full-length antibody. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to mouse CCR8. In certain embodiments, the anti-CCR8 antibody is a full-length antibody that binds to mouse CCR8 and is a chimeric antibody (eg, a rabbit-mouse chimera).

[0459] In one aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6. In a further aspect, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68.

[0460] In another aspect, the disclosure provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64. In one aspect, the antibody comprises (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0461] In another aspect, the antibodies described herein comprise: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from the group consisting of: (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from the group consisting of: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0462] In another aspect, the present disclosure provides an antibody comprising a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68; and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0463] In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VH sequence of SEQ ID NO: 70. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 69. In another embodiment, the anti-CCR8 antibody comprises the CDR sequences of the VH sequence of SEQ ID NO: 70. In another embodiment, the anti-CCR8 antibody comprises one or more of the CDR sequences of the VL sequence of SEQ ID NO: 69.

[0464] In a further embodiment, the anti-CCR8 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 70 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 69.

[0465] In one embodiment, an anti-CCR8 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 70 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 70. In one embodiment, an anti-CCR8 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 70 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VH domain of SEQ ID NO: 70. In one embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 70 and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 70. In another embodiment, the anti-CCR8 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 70 and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 70.

[0466] In one embodiment, the anti-CCR8 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 69 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 69. In one embodiment, the anti-CCR8 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 69 and a framework of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequences of the VL domain of SEQ ID NO: 69. In one embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 69 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 69. In another embodiment, the anti-CCR8 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 69 and a framework of at least 98% sequence identity, in particular, to the framework amino acid sequence of the VL domain of SEQ ID NO: 69.

[0467] In one embodiment, the anti-CCR8 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64, as well as a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 70, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 70. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 69. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constant (K D ) binds to mouse CCR8.

[0468] In another embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 70. In one embodiment, the anti-CCR8 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 70. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-CCR8 antibody comprising that sequence retains the ability to bind to murine CCR8. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 70. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 70, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three CDRs selected from the following: SEQ ID NO: 65 or SEQ ID NO: 66, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, or (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68. In another embodiment, an anti-CCR8 antibody is provided, comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69. In one embodiment, an anti-CCR8 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 69. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 antibody comprising that sequence retains the ability to bind to CCR8. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 69.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-CCR8 antibody comprises the VL sequence of SEQ ID NO: 69, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64.

[0469] In another embodiment, an anti-CCR8 antibody is provided, comprising the VH sequence of any of the embodiments provided above and the VL sequence of any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO: 69, including post-translational modifications of these sequences.

[0470] In another aspect, an anti-CCR8 antibody is provided that binds to mouse CCR8 and comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 64. In one aspect, the anti-CCR8 antibody comprises the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO: 69.

[0471] In one embodiment, the anti-CCR8 antibody comprises a heavy chain of SEQ ID NO:72 and a light chain of SEQ ID NO:71.

[0472] In a further embodiment, the anti-CCR8 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody. In one embodiment, the anti-CCR8 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.

[0473] (vii) Other embodiments In further embodiments, anti-CCR8 antibodies according to any of the above embodiments may incorporate any of the features described in sections 1-5 below, either alone or in combination.

[0474] 1. Antibody fragments In certain aspects, the antibodies provided herein are antibody fragments.

[0475] In one embodiment, the antibody fragment is a Fab, Fab', Fab'-SH, or F(ab')2 fragment, particularly a Fab fragment. Papain digestion of an intact antibody generates two identical antigen-binding fragments (so-called "Fab" fragments), each containing the heavy and light chain variable domains (VH and VL, respectively) as well as the light chain constant domain (CL) and the first heavy chain constant domain (CH1). Thus, the term "Fab fragment" refers to an antibody fragment containing a light chain containing the VL and CL domains, and a heavy chain fragment containing the VH and CH1 domains. "Fab' fragments" differ from Fab fragments by the addition of residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is a Fab' fragment in which the cysteine ​​residues (multivalent) of the constant domains retain a free thiol group. Pepsin treatment yields a F(ab')2 fragment containing two antigen-binding sites (two Fab fragments) and part of the Fc region. See US Pat. No. 5,869,046 for a description of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased in vivo half-lives.

[0476] In another embodiment, the antibody fragment is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. Diabodies are antibody fragments with two antigen-binding sites, which may be bivalent or bispecific. See, for example, EP 404,097, WO 1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0477] In a further embodiment, the antibody fragment is a single-chain Fab fragment. A "single-chain Fab fragment" or "scFab" is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL), and a linker, where the antibody domains and the linker have one of the following orders from N- to C-terminus: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL. In particular, the linker is a polypeptide of at least 30 amino acids, preferably 32-50 amino acids. The single-chain Fab fragment is stabilized by a native disulfide bond between the CL and CH1 domains. In addition, these single-chain Fab fragments can be further stabilized by the creation of interchain disulfide bonds through the insertion of cysteine ​​residues (e.g., at position 44 of the variable heavy chain and position 100 of the variable light chain according to the Kabat numbering).

[0478] In another embodiment, the antibody fragment is a single-chain variable fragment (scFv). A "single-chain variable fragment" or "scFv" is a fusion protein of the variable domains of an antibody's heavy chain (VH) and light chain (VL) linked by a linker. In particular, the linker is a short polypeptide of 10 to 25 amino acids, typically rich in glycine for flexibility and serine or threonine for solubility, which can link the N-terminus of the VH to the C-terminus of the VL, or vice versa. This protein retains the specificity of the original antibody despite the removal of the constant region and the introduction of the linker. For a review of scFv fragments, see, for example, Pluckthun, in *The Pharmacology of Monoclonal Antibodies*, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994). See also WO 93 / 16185 and U.S. Patent Nos. 5,571,894 and 5,587,458.

[0479] In another embodiment, the antibody fragment is a single-domain antibody. A "single-domain antibody" is an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1).

[0480] Antibody fragments can be produced by a variety of techniques, including but not limited to, proteolytic digestion of intact antibodies and recombinant production in recombinant host cells (e.g., E. coli), as described herein.

[0481] 2. Chimeric and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Specific chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. The chimeric antibody includes an antigen-binding fragment thereof.

[0482] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the CDRs (or portions thereof) are derived from a non-human antibody and the FRs (or portions thereof) are derived from a human antibody sequence. Optionally, the humanized antibody also comprises at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0483] Humanized antibodies and methods for producing them are described, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing grafting of specificity-determining regions (SDRs)); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

[0484] Human framework regions that can be used for humanization include, but are not limited to, the following: Framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al. al., J. Biol. Chem. 271:22611-22618 (1996).

[0485] 3. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0486] Human antibodies can be prepared by administering immunogens to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge.Such animals typically contain all or part of the human immunoglobulin loci that replace the endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the animal's chromosomes.In such transgenic mice, the endogenous immunoglobulin loci are generally inactivated.For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat.Biotech.23:1117-1125(2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Patent No. 5,770,429, which describes HuMab® technology; U.S. Patent No. 7,041,870, which describes KM MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VelociMouse® technology. The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining with different human constant regions.

[0487] Human antibodies can also be produced by hybridoma-based methods.Human myeloma cell lines and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described.(See, for example, Kozbor J.Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J.Immunol., 147:86 (1991)).Human antibodies produced through human B cell hybridoma technology are also described in Li et al., Proc.Natl.Acad.Sci.USA, 103:3557-3562 (2006). Further methods include, for example, U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268(2006) (which describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937(2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91(2005).

[0488] Human antibodies can also be generated by isolating variable domain sequences selected from human-derived phage display libraries. These variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0489] 4. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. A "multispecific antibody" is a monoclonal antibody that has binding specificities for at least two different sites, i.e., different epitopes on different antigens or different epitopes on the same antigen. In certain embodiments, a multispecific antibody has three or more binding specificities. In certain embodiments, one binding specificity is for CCR8 and another specificity is for any other antigen. In certain embodiments, a bispecific antibody can bind to two (or more) different epitopes of CCR8. Multispecific (e.g., bispecific) antibodies can also be used to localize cytotoxic agents or cells to cells expressing CCR8. Multispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0490] Techniques for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983)) and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168 and Atwell et al., J. Mol. Biol. 270:26 (1997)). Multispecific antibodies can also be produced by manipulating electrostatic steering effects to create antibody Fc heterodimeric molecules (see, e.g., WO 2009 / 089004); cross-linking two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al., Science, 229:81 (1985)); producing bispecific antibodies using leucine zippers (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992) and WO 2011 / 034605); using conventional light chain technology to circumvent light chain mispairing issues (see, e.g., WO 98 / 50431); using "diabody" technology to create bispecific antibody fragments (see, e.g., Hollinger et al., J. Immunol., 148(5):1547-1553 (1992) and WO 2011 / 034605)); al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and by the use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and by the preparation of triabodies as described, for example, in Tutt et al. J. Immunol. 147:60 (1991).

[0491] 5. Antibody Variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to change the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to arrive at the final construct, provided that the final construct possesses the desired properties, e.g., antigen binding.

[0492] a) Substitution, insertion and deletion variants In certain embodiments, antibody variants with one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and FRs.

[0493] In one embodiment, the VL sequence of an antibody disclosed herein comprises a V4M mutation, a P43A mutation, an F46L mutation, a C90Q mutation, or a combination thereof. In one embodiment, the VH sequence of an antibody disclosed herein comprises a G49S mutation, a K71R mutation, an S73N mutation, or a combination thereof. In one embodiment, the VL sequence of an antibody disclosed herein comprises a Y2I mutation. In one embodiment, the VH sequence of an antibody disclosed herein comprises an S73N mutation, a V78L mutation, a T76N mutation, an F91Y mutation, and a P105Q mutation, or a combination thereof. In some cases, any of the foregoing mutations are numbered according to Kabat. [Table 2]

[0494] Conservative substitutions are shown in Table 2 under the heading "Conservative Substitutions." More substantial changes are provided in Table 2 under the heading "Exemplary Substitutions," and are as further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the products screened for a desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

[0495] Amino acids can be grouped according to common side chain properties. (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0496] Non-conservative substitutions will involve exchanging a member of one of these classes for a member of another class.

[0497] Certain substitutional variants involve substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., an improvement) in a particular biological property (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will have substantially retained a particular biological property of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage display-based affinity maturation techniques as described herein. Briefly, one or more CDR residues are mutated, and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0498] For example, to improve antibody affinity, changes (e.g., substitutions) can be made in the CDRs. Such changes can be made in CDR "hot spots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or within residues that contact the antigen, and the resulting variants VH or VL are tested for binding affinity. Affinity maturation by constructing and then reselecting from a secondary library is described, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. This library is then screened to identify antibody variants with the desired affinity. Another method for introducing diversity involves CDR-directed approaches, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0499] In certain embodiments, substitutions, insertions, or deletions may occur within one or more CDRs, as long as such changes do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in the CDRs. Such modifications may, for example, be outside the antigen-contacting residues in the CDRs. In the specific variant VH and variant VL sequences provided above, each CDR is unchanged or contains no more than one, two, or three amino acid substitutions.

[0500] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues, such as Arg, Asp, His, Lys, and Glu) is identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Further substitutions may be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of an antigen-antibody complex may be used to identify contact points between the antibody and the antigen. Such contact residues and adjacent residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they possess desired properties.

[0501] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the N- or C-terminal fusion of the antibody to an enzyme (e.g., ADEPT (for antibody-directed enzyme prodrug therapy) or a polypeptide which increases the serum half-life of the antibody.

[0502] b) Glycosylation variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0503] If the antibody contains an Fc region, the oligosaccharides attached to the antibody may be altered. Native antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides, which are generally linked to Asn297 in the CH2 domain of the Fc region via an N-linkage. See, for example, Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharides may contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the bisected oligosaccharide structure. In some embodiments, modifications of the oligosaccharides in the antibodies described herein may be made to generate antibody variants with specific improved properties.

[0504] In one embodiment, antibody variants are provided that have nonfucosylated oligosaccharides, i.e., oligosaccharide structures lacking fucose linkages (direct or indirect) to the Fc region. Such nonfucosylated oligosaccharides (also referred to as "defucosylated" oligosaccharides) are particularly N-linked oligosaccharides lacking the first GlcNAc-linked fucose residue at the stem of the biantennary oligosaccharide structure; such antibodies are further referred to herein as "defucosylated antibodies." In one embodiment, antibody variants are provided that have an increased proportion of nonfucosylated oligosaccharides in the Fc region compared to the native or parent antibody. For example, the proportion of nonfucosylated oligosaccharides can be at least about 20%, at least about 40%, at least about 60%, at least about 80%, or even about 100% (i.e., no fucosylated oligosaccharides are present). In certain embodiments, the defucosylation rate is about 65% to about 100%, about 80% to about 100%, or about 80% to about 95%. The percentage of nonfucosylated oligosaccharides is the (average) amount of oligosaccharides lacking a fucose residue relative to the sum of all oligosaccharides attached to Asn297 (e.g., complex, hybrid, and high mannose structures), as measured, for example, by MALDI-TOF mass spectrometry as described in WO 2006 / 082515. Asn297 refers to an asparagine residue located at approximately position 297 (Fc region residues in EU numbering) within the Fc region; however, due to slight sequence variations in antibodies, Asn297 may also be located ±3 amino acids upstream or downstream from position 297, i.e., between positions 294 and 300 (e.g., Asn299). Such antibodies with an increased proportion of nonfucosylated oligosaccharides in the Fc region may have improved FcγRIIIa receptor binding and / or improved effector function, particularly improved ADCC function (see, e.g., U.S. Patent Application Publication Nos. 2003 / 0157108; 2004 / 0093621).

[0505] In one aspect, the present disclosure provides defucosylated antibody variants with enhanced FcγRIIIa receptor binding. In one aspect, the present disclosure provides defucosylated antibody variants with enhanced antibody-dependent cellular cytotoxicity (ADCC). In one aspect, the present disclosure provides defucosylated antibody variants with antibody-dependent cellular phagocytosis (ADCP) activity.

[0506] Examples of cell lines capable of producing antibodies with reduced fucosylation include Lec13 CHO cells, which lack protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108; and WO 2004 / 056312, particularly Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614-622 (2004); Kanda, Y. et al. al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003 / 085107), or cells with reduced or eliminated GDP-fucose synthesis or transport proteins (see, e.g., U.S. Patent Publications 2004259150, 2005031613, 2004132140, and 2004110282). See also Pereira et al., MABS (2018) 693-711.

[0507] In a further embodiment, antibody variants having bisected oligosaccharides are provided, for example, antibody variants in which the biantennary oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function, as described above. Examples of such antibody variants are described, for example, in Umana et al., Nat Biotechnol 17, 176-180 (1999); Ferrara et al., Biotechn Bioeng 93, 851-861 (2006); WO 99 / 54342, WO 2004 / 065540, and WO 2003 / 011878.

[0508] Also provided are antibody variants that have at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants can have improved CDC function. Examples of such antibody variants are described in, for example, WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.

[0509] c) Fc region variants In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid alteration (e.g., substitution) at one or more amino acid positions.

[0510] In certain embodiments, the present invention contemplates antibody variants that possess some, but not all, effector functions, making them desirable candidates for applications where in vivo antibody half-life is important, but where certain effector functions (e.g., complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / absent CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and thus potentially lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. Expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (see, e.g., Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA) and CytoTox 96 (登録商標)See non-radioactive cytotoxicity assays (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or in addition, the desired ADCC activity can be assessed in vivo in an animal model, such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, CDC assays can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929).

[0511] Antibodies with reduced effector function include those with substitutions at one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant with substitutions of residues 265 and 297 to alanine (U.S. Patent No. 7,332,581).

[0512] Certain antibody variants have been described with improved or diminished binding to FcRs (see, e.g., U.S. Pat. No. 6,737,056, WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0513] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0514] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcγR binding, e.g., at positions 234 and 235 of the Fc region (residues EU numbering). In one embodiment, the substitutions are L234A and L235A (LALA). In certain embodiments, the antibody variant further comprises D265A and / or P329G in an Fc region derived from a human IgG1 Fc region. In one embodiment, the substitutions are L234A, L235A, and P329G (LALA-PG) in an Fc region derived from a human IgG1 Fc region. (See, e.g., WO 2012 / 130831). In another embodiment, the substitutions are L234A, L235A, and D265A (LALA-DA) in an Fc region derived from a human IgG1 Fc region.

[0515] In certain embodiments, the antibody variants comprise an Fc region with one or more amino acid substitutions, e.g., substitutions at positions, that improve FcγR binding (and thereby improve effector function). In certain embodiments, the antibody variants comprise an Fc region with at least one amino acid substitution of G236A, I332E, S298A, E333A, K334A, S239D, A330L, F243L, R292P, Y300L, V305I, P396L, L235V, L234Y, L235Q, G236W, S239M, H268D, D270E, K326D, A330M, or K334E (see, e.g., Liu et al., Antibodies (Basel) (2020); 9(4): 64).

[0516] In some embodiments, modifications are made in the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as disclosed in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0517] Antibodies with extended half-lives and improved binding to the neonatal Fc receptor (FcRn) responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in U.S. Patent Publication No. 2005 / 0014934 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having a substitution at one or more of Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., a substitution at Fc region residue 434 (see, e.g., U.S. Patent No. 7,371,826; Dall'Acqua, WF, et al. J. Biol. Chem. 281 (2006) 23514-23524).

[0518] The Fc region residues critical for mouse Fc-mouse FcRn interaction have been identified by site-directed mutagenesis (see, e.g., Dall'Acqua, WF, et al. J. Immunol 169 (2002) 5171-5180). Residues I253, H310, H433, N434, and H435 (EU numbering of residues) are involved in the interaction (Medesan, C., et al., Eur. J. Immunol. 26 (1996) 2533; Firan, M., et al., Int. Immunol. 13 (2001) 993; Kim, JK, et al., Eur. J. Immunol. 24 (1994) 542). Residues I253, H310, and H435 were found to be important for the interaction between human Fc and mouse FcRn (Kim, JK, et al., Eur. J. Immunol. 29 (1999) 2819). Studies of the human Fc-human FcRn complex have shown that residues I253, S254, H435, and Y436 are important for this interaction (Firan, M., et al., Int. Immunol. 13 (2001) 993; Shields, RL, et al., J. Biol. Chem. 276 (2001) 6591-6604). Yeung, YA, et al. (J. Immunol. 182 (2009) 7667-7671) reported and investigated various mutants of residues 248-259, 301-317, 376-382, and 424-437.

[0519] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that reduce FcRn binding, e.g., substitutions at positions 253, 310, and / or 435 (EU numbering of residues) of the Fc region. In certain embodiments, the antibody variant comprises an Fc region with amino acid substitutions at positions 253, 310, and 435. In one embodiment, the substitutions are I253A, H310A, and H435A in the Fc region derived from a human IgG1 Fc region. See, e.g., Grevys, A., et al., J. Immunol. 194 (2015) 5497-5508.

[0520] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcRn binding, e.g., mutations at positions 310, and / or 433, and / or 436 (EU numbering of residues) of the Fc region. In certain embodiments, the antibody variant comprises an Fc region having amino acid substitutions at positions 310, 433, and 436. In one embodiment, the substitutions are H310A, H433A, and Y436A in the Fc region derived from a human IgG1 Fc region. (See, e.g., WO 2014 / 177460).

[0521] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that increase FcRn binding, e.g., mutations at positions 252, 254, and / or 256 (EU numbering of residues) of the Fc region. In certain embodiments, the antibody variant comprises an Fc region with amino acid substitutions at positions 252, 254, and 256. In one embodiment, the substitutions are M252Y, S254T, and T256E in the Fc region derived from a human IgG1 Fc region. For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988), U.S. Patent No. 5,648,260, U.S. Patent No. 5,624,821, and WO 94 / 29351.

[0522] The C-terminus of the heavy chain of an antibody as reported herein may be a complete C-terminus ending in amino acid residue PGK. The C-terminus of the heavy chain may be a truncated C-terminus in which one or two of the C-terminal amino acid residues are removed. In one embodiment, the C-terminus of the heavy chain is a truncated C-terminus ending in PG. In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain comprising a C-terminal CH3 domain as specified herein comprises a C-terminal glycine-lysine dipeptide (G446 and K447, EU index numbering of amino acid positions). In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain comprising a C-terminal CH3 domain as specified herein comprises a C-terminal glycine residue (G446, EU index numbering of amino acid positions). In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain comprising a C-terminal CH3 domain as specified herein comprises a C-terminal proline residue (P445, EU index numbering of amino acid positions).

[0523] d) Cysteine ​​Engineered Antibody Variants In certain embodiments, cysteine ​​engineered antibodies, e.g., THIOMAB, in which one or more residues of the antibody are substituted with a cysteine ​​residue are used. (商標) In certain embodiments, the substituted residues occur at accessible sites on the antibody. By replacing these residues with cysteine, a reactive thiol group is placed at an accessible site on the antibody, which can be used to conjugate the antibody to other moieties, such as a drug moiety or a linker-drug moiety, to create an immunoconjugate, as further described herein. Cysteine ​​engineered antibodies are described, for example, in U.S. Pat. Nos. 7,521,541, 8,30,930, 7,855,275, 9,000,130, or WO2016040856.

[0524] e) Antibody derivative In certain embodiments, the antibodies provided herein can be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. Suitable sites for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propropylene glycol homopolymer, prolypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde can be advantageous during manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody may vary, and when multiple polymers are attached, they may be the same or different molecules. In general, the number and / or type of polymers used for derivatization may be determined based on considerations such as, but not limited to, the particular properties or functions of the antibody to be improved and whether the antibody derivative will be used therapeutically under defined conditions.

[0525] C. Recombinant Methods and Compositions The antibodies disclosed herein can be produced using, for example, the recombinant methods and compositions described in U.S. Patent No. 4,816,567. For these methods, one or more isolated nucleic acids encoding the antibody are provided.

[0526] In the case of a natural antibody or natural antibody fragment, two nucleic acids are required: one for the light chain or fragment thereof, and the other for the heavy chain or fragment thereof. Such nucleic acid(s) encode an amino acid sequence comprising the VL and / or VH of the antibody (e.g., the light and / or heavy chain(s) of the antibody). These nucleic acids may be on the same or different expression vectors.

[0527] For bispecific antibodies with heterodimeric heavy chains, four nucleic acids are required: one for the first light chain, one for the first heavy chain comprising the first heteromonomeric Fc region polypeptide, one for the second light chain, and one for the second heavy chain comprising the second heteromonomeric Fc region polypeptide. The four nucleic acids may be contained in one or more nucleic acid molecules or expression vectors. Such nucleic acids encode an amino acid sequence comprising a first VL and / or an amino acid sequence comprising a first VH comprising the first heteromonomeric Fc region and / or an amino acid sequence comprising a second VL and / or an amino acid sequence comprising a second VH comprising the second heteromonomeric Fc region of the antibody (e.g., the first and / or second light chains and / or the first and / or second heavy chains of the antibody). These nucleic acids may be on the same or different expression vectors; typically, these nucleic acids are located on two or three expression vectors; i.e., one vector may contain two or more of these nucleic acids. An example of these bispecific antibodies is CROSSMAB® (see, e.g., Schaefer, W. et al., PNAS, 108 (2011) 11187-1191). For example, one of the heteromonomer heavy chains contains a so-called "knob mutation" (T366W and, optionally, one of S354C or Y349C) according to EU index numbering, and the other contains a so-called "hole mutation" (T366S, L368A, and Y407V and, optionally, Y349C or S354C) (see, e.g., Carter, P. et al., Immunotechnol. 2 (1996) 73).

[0528] In one aspect, an isolated nucleic acid encoding an antibody for use in the methods reported herein is provided.

[0529] In one aspect, a method of making an anti-CCR8 antibody is provided, comprising culturing a host cell comprising nucleic acid encoding the antibody under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture).

[0530] For recombinant production of anti-CCR8 antibodies, for example, nucleic acids encoding the above-described antibodies are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be easily isolated and sequenced using standard procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody), or can be produced by recombinant methods or obtained by chemical synthesis.

[0531] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly if glycosylation and effector functions are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, KA, In: Methods in Molecular Biology, Vol. 248, Lo, BKC (ed.), Humana Press, Totowa, NJ (2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibody can be isolated from the bacterial cell paste in appropriate fractions and further purified.

[0532] In addition to prokaryotes, useful eukaryotic microorganisms such as filamentous fungi or yeast, including fungal and yeast strains whose glycosylation pathways have been "humanized" to result in the production of antibodies with partial or fully human glycosylation patterns, are also suitable cloning or expression hosts for antibody-encoding vectors. See Gerngross, TU, Nat. Biotech. 22 (2004) 1409-1414; and Li, H. et al., Nat. Biotech. 24 (2006) 210-215.

[0533] Suitable host cells for the expression of (glycosylated) antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified and can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0534] Plant cell cultures can also be used as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0535] Vertebrate cells may also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7), human embryonic kidney lines (e.g., 293 cells or 293T cells as described in Graham, FL et al., J. Gen. Virol. 36 (1977) 59-74), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells as described in Mather, JP, Biol. Reprod. 23 (1980) 243-252), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical carcinoma cells (HELA), canine kidney cells (MDCK), buffalo rat liver cells (BRL3A), human lung cells (W138), human liver cells (Hep G2), mouse mammary tumor (MMT060562), TRI cells (e.g., Mather, JP et al., Annals NY Acad. Sci. 383 (1982) 44-68), MRC5 cells, and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub, G. et al., Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220), and myeloma cell lines, such as Y0, NS0, and Sp2 / 0. For a review of specific mammalian host cells suitable for antibody production, see, for example, Yazak...

Claims

1. 1. A method of treating locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof, comprising administering to the subject a monoclonal antibody that binds to C-C motif chemokine receptor 8 (CCR8).

2. (i) the subject has progressed after at least one available standard of care; and / or (ii) the subject is a subject for whom all available standard treatments have proven ineffective or intolerable or for whom treatment is contraindicated; The method of claim 1.

3. 3. The method of claim 1 or 2, wherein the locally advanced, recurrent, or metastatic solid tumor is incurable.

4. The method of any one of claims 1 to 3, wherein the subject is 18 years of age or older.

5. 5. The method of any one of claims 1 to 4, wherein the locally advanced, recurrent, or metastatic solid tumor malignancy is non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UC), esophageal cancer, gastric cancer, cervical cancer, renal cell carcinoma (RCC), or hepatocellular carcinoma (HCC).

6. 6. The method of claim 5, wherein the RCC is clear cell RCC.

7. 6. The method of claim 5, wherein the HNSCC is HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

8. 6. The method of claim 5, wherein the locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC.

9. 10. The method of claim 8, wherein the subject's tumor contains a targetable somatic alteration and the subject is experiencing disease progression during or after treatment with, or intolerance to, treatment with a targeted agent.

10. 10. The method of claim 9, wherein the targetable somatic alteration comprises a somatic alteration comprising epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

11. 6. The method of claim 5, wherein the melanoma is cutaneous melanoma.

12. 12. The method of claim 11, wherein the subject's tumor comprises a BRAFV600 mutation and the subject is experiencing disease progression during or after treatment with, or intolerance to treatment with, one or more serine / threonine-protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase (MEK) inhibitors.

13. 6. The method of claim 5, wherein the locally advanced, recurrent, or metastatic solid tumor malignancy is UC.

14. The object is (i) histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, bladder, and urethra); and / or (ii) the subject's tumor has mixed histology with a predominant transitional cell pattern 14. The method of claim 13, comprising:

15. 6. The method of claim 5, wherein the locally advanced, recurrent, or metastatic solid tumor malignancy is TNBC.

16. TNBC has adopted the American Society of Clinical Oncology-College of American Pathologists guidelines: (i) less than 1% of tumor cell nuclei are immunoreactive for estrogen receptors and less than 1% of tumor cell nuclei are immunoreactive for progesterone receptors; and / or (ii) is HER2 negative based on immunohistochemistry (IHC) and / or in situ hybridization; 16. The method of claim 15, wherein:

17. The method of any one of claims 1 to 16, wherein the subject is checkpoint inhibitor (CPI) naive.

18. 18. The method of claim 17, wherein the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC or UC.

19. 19. The method of claim 18, wherein the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is UC, the subject is eligible for treatment with cisplatin, and the subject experiences disease progression during or after treatment with or intolerance to treatment with cisplatin.

20. 20. The method of any one of claims 17-19, wherein the subject has not received previous treatment with a CPI or the subject has received adjuvant treatment with a CPI that was discontinued at least 6 months prior to the subject's first administration of the monoclonal antibody that binds to CCR8.

21. The method of any one of claims 1 to 16, wherein the subject is experiencing CPI.

22. 22. The method of claim 21, wherein the subject's locally advanced, recurrent, or metastatic solid tumor malignancy is NSCLC, HNSCC, melanoma, UC, TNBC, esophageal cancer, gastric cancer, cervical cancer, clear cell RCC, or HCC.

23. 23. The method of claim 21 or 22, wherein the subject derives clinical benefit from treatment comprising a PD-1 axis binding antagonist prior to disease progression.

24. 24. The method of claim 23, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody.

25. 25. The method of claim 23 or 24, wherein the subject has had a treatment duration with the treatment comprising the PD-1 axis binding antagonist of 6 months or more and / or had a partial response or a complete response as a best objective response.

26. (i) the subject has not received treatment with a CPI, an immunomodulatory monoclonal antibody, or an immunomodulatory monoclonal antibody induction therapy within 6 weeks prior to first administering to the subject the monoclonal antibody that binds CCR8; or (ii) the subject has been previously treated with a PD-1 axis binding antagonist, and the subject's last administration of the PD-1 axis binding antagonist was at least 3 weeks prior to the subject's first administration of the monoclonal antibody that binds CCR8; The method according to any one of claims 21 to 25.

27. The method of any one of claims 17 to 26, wherein the CPI is a PD-1 axis binding antagonist or a CTLA4 antagonist.

28. 28. The method of claim 27, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody.

29. The method of any one of claims 1 to 28, wherein the monoclonal antibody that binds to CCR8 is administered to the subject in a dosing regimen comprising one or more dosing cycles.

30. 30. The method of claim 29, wherein the one or more administration cycles comprises a 21 day administration cycle.

31. 31. The method of claim 30, wherein the monoclonal antibody that binds to CCR8 is administered to the subject on day 1 of each 21-day administration cycle.

32. 32. The method of any one of claims 29 to 31, wherein the monoclonal antibody that binds to CCR8 is administered to the subject until disease progression or unacceptable toxicity occurs.

33. 33. The method of any one of claims 1 to 32, wherein the monoclonal antibody that binds to CCR8 is administered to the subject at a dose of 2 mg.

34. The method of any one of claims 1 to 33, wherein the monoclonal antibody that binds to CCR8 is administered intravenously to the subject.

35. 35. The method of claim 34, wherein the monoclonal antibody that binds to CCR8 is administered to the subject intravenously by infusion.

36. The method of any one of claims 1 to 35, wherein the monoclonal antibody that binds to CCR8 is administered to the subject as a monotherapy.

37. The method of any one of claims 1 to 35, wherein the monoclonal antibody that binds to CCR8 is administered to the subject in combination with one or more additional therapeutic agents.

38. 38. The method of claim 37, wherein the one or more additional therapeutic agents comprises atezolizumab.

39. 39. The method of claim 38, wherein the atezolizumab is administered to the subject in a dosing regimen comprising one or more dosing cycles.

40. 40. The method of claim 39, wherein the one or more administration cycles comprises a 21 day administration cycle.

41. 41. The method of claim 40, wherein the atezolizumab is administered to the subject on day 1 of each 21-day administration cycle.

42. 42. The method of any one of claims 38-41, wherein the atezolizumab is administered to the subject at a dose of 1200 mg.

43. 43. The method of any one of claims 38-42, wherein the atezolizumab is administered to the subject intravenously.

44. 44. The method of claim 43, wherein the atezolizumab is administered to the subject intravenously by infusion.

45. 45. The method of any one of claims 1 to 44, wherein the subject-derived tumor sample has been determined to have a detectable level of PD-L1 expression.

46. 46. ​​The method of claim 45, wherein the tumor sample from the subject has 1% or more tumor cells (TC), immune cells (IC), combined positive score (CPS), or tumor proportion score (TPS).

47. 47. The method of any one of claims 38-46, wherein the subject has received at least two cycles of the monoclonal antibody that binds to CCR8 prior to administration of atezolizumab to the subject.

48. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

28.

49. The method of claim 48, wherein the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of CCR8 sulfation.

50. 50. The method of claim 48 or 49, wherein the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 2 to 6 of SEQ ID NO:

106.

51. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 35-47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48-52; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

51. The method of any one of claims 48 to 50, comprising a sequence selected from the group consisting of:

52. 52. The method of any one of claims 48 to 51, wherein the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35 to 47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48 to 52.

53. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 47; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 48; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

53. The method of any one of claims 48 to 52, comprising a sequence selected from the group consisting of:

54. 54. The method of any one of claims 48 to 53, wherein the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 47, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:

48.

55. 55. The method of any one of claims 48-54, wherein the VL comprises a V4M mutation, a P43A mutation, a F46L mutation, a C90Q mutation, or a combination thereof (numbering according to Kabat).

56. 56. The method of any one of claims 48 to 55, wherein the VH comprises a G49S mutation, a K71R mutation, an S73N mutation, or a combination thereof (numbering according to Kabat).

57. The method of any one of claims 48 to 56, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 55 and the light chain amino acid sequence of SEQ ID NO:

56.

58. The method of any one of claims 48 to 56, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 60 and the light chain amino acid sequence of SEQ ID NO:

56.

59. The method of any one of claims 48 to 56, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 111 and the light chain amino acid sequence of SEQ ID NO:

56.

60. The method of any one of claims 48 to 56, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 113 and the light chain amino acid sequence of SEQ ID NO:

56.

61. 48. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 35-47 and a VL sequence selected from the group consisting of SEQ ID NOs: 48-52.

62. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO: 47 and the VL sequence of SEQ ID NO:

48.

63. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

3.

64. The method of claim 63, wherein the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of CCR8 sulfation.

65. The method of claim 63 or 64, wherein the monoclonal antibody that binds to CCR8 binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:

106.

66. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

66. The method of any one of claims 63 to 65, comprising a sequence selected from the group consisting of:

67. 67. The method of any one of claims 63 to 66, wherein the monoclonal antibody that binds to CCR8 comprises a VH sequence selected from the group consisting of SEQ ID NOs: 10-21 and a VL sequence selected from the group consisting of SEQ ID NOs: 22-25.

68. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 21; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 24; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

68. The method of any one of claims 63 to 67, comprising a sequence selected from the group consisting of:

69. 69. The method of any one of claims 63 to 68, wherein the monoclonal antibody that binds to CCR8 comprises a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:21, and a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO:

24.

70. 70. The method of any one of claims 63 to 69, wherein the VL comprises a Y2I mutation (numbering according to Kabat).

71. 71. The method of any one of claims 63 to 70, wherein the VH comprises an S73N mutation, a V78L mutation, a T76N mutation, an F91Y mutation, and a P105Q mutation, or a combination thereof (numbering according to Kabat).

72. The method of any one of claims 63 to 71, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 57 and the light chain amino acid sequence of SEQ ID NO:

58.

73. The method of any one of claims 63 to 71, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 61 and the light chain amino acid sequence of SEQ ID NO:

58.

74. The method of any one of claims 63 to 71, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 112 and the light chain amino acid sequence of SEQ ID NO:

58.

75. The method of any one of claims 63 to 71, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 114 and the light chain amino acid sequence of SEQ ID NO:

58.

76. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO:21 and the VL sequence of SEQ ID NO:

24.

77. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 84, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

75.

78. The monoclonal antibody that binds to CCR8 (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 95; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 94; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

78. The method of claim 77, comprising a sequence selected from the group consisting of:

79. 79. The method of claim 77 or 78, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO: 95 and the VL sequence of SEQ ID NO:

94.

80. 80. The method of any one of claims 77 to 79, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 101 and the light chain amino acid sequence of SEQ ID NO:

100.

81. 80. The method of any one of claims 77 to 79, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 115 and the light chain amino acid sequence of SEQ ID NO:

100.

82. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 88, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 89, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

78.

83. The monoclonal antibody that binds to CCR8 (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 97; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 96; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

83. The method of claim 82, comprising a sequence selected from the group consisting of:

84. The method of claim 82 or 83, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO: 97 and the VL sequence of SEQ ID NO:

96.

85. The method of any one of claims 82 to 84, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 103 and the light chain amino acid sequence of SEQ ID NO:

102.

86. The method of any one of claims 82 to 84, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 116 and the light chain amino acid sequence of SEQ ID NO:

102.

87. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 93, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 80, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

81.

88. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 99; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 98; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

88. The method of claim 87, comprising a sequence selected from the group consisting of:

89. The method of claim 87 or 88, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO: 99 and the VL sequence of SEQ ID NO:

98.

90. 90. The method of any one of claims 87 to 89, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 105 and the light chain amino acid sequence of SEQ ID NO:

104.

91. The method of any one of claims 87 to 90, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 117 and the light chain amino acid sequence of SEQ ID NO:

104.

92. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 binds to CCR8 regardless of CCR8 sulfation.

93. 93. The method of claim 92, wherein the antibody binds to an epitope consisting of one or more of amino acid residues 2-6 of SEQ ID NO:

106.

94. 93. The method of claim 92, wherein the antibody binds to an epitope consisting of one or more of amino acid residues 91-104 and 172-193 of SEQ ID NO:

106.

95. The method of any one of claims 1 to 47, wherein the monoclonal antibody that binds to CCR8 comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 65 or SEQ ID NO: 66, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 63, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

64.

96. The monoclonal antibody that binds to CCR8 is (a) a VH sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 70; (b) a VL sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to the amino acid sequence of SEQ ID NO: 69; and (c) a VH sequence as defined in (a) and a VL sequence as defined in (b).

96. The method of claim 95, comprising a sequence selected from the group consisting of:

97. 97. The method of claim 95 or 96, wherein the monoclonal antibody that binds to CCR8 comprises the VH sequence of SEQ ID NO: 70 and the VL sequence of SEQ ID NO:

69.

98. 98. The method of any one of claims 95 to 97, wherein the monoclonal antibody that binds to CCR8 comprises the heavy chain amino acid sequence of SEQ ID NO: 72 and the light chain amino acid sequence of SEQ ID NO:

71.

99. The method of any one of claims 1 to 98, wherein the monoclonal antibody that binds to CCR8 is a human antibody.

100. The method of any one of claims 1 to 98, wherein the monoclonal antibody that binds to CCR8 is a humanized antibody.

101. The method of any one of claims 1 to 100, wherein the monoclonal antibody that binds to CCR8 is a chimeric antibody.

102. The method of any one of claims 1 to 101, wherein the monoclonal antibody that binds to CCR8 is an antibody fragment that binds to CCR8.

103. The method of any one of claims 1 to 101, wherein the monoclonal antibody that binds to CCR8 is a full-length antibody.

104. 104. The method of claim 103, wherein the monoclonal antibody that binds to CCR8 is a full-length IgG1 antibody.

105. The method of any one of claims 1 to 104, wherein the monoclonal antibody that binds to CCR8 comprises an IgG1 constant domain comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:

59.

106. The method of any one of claims 1 to 105, wherein the monoclonal antibody that binds to CCR8 comprises a kappa constant domain comprising the amino acid sequence of SEQ ID NO:

54.

107. The monoclonal antibody that binds to CCR8 is about 1 x 10 －１２ M ~ approx. 1 x 10 －１１ The binding affinity of M (K ｄ The method of any one of claims 1 to 106, wherein the antibody binds to CCR8 via the agonist.

108. The method of any one of claims 1 to 107, wherein the CCR8 is human CCR8.

109. The method of any one of claims 1 to 108, wherein the monoclonal antibody that binds to CCR8 is defucosylated.

110. 110. The method of claim 109, wherein the defucosylation rate is from about 80% to about 95%.

111. 111. The method of any one of claims 1 to 110, wherein regulatory T cells present in the tumor microenvironment of the locally advanced, recurrent, or metastatic solid tumor malignancy are depleted.

112. 112. The method of any one of claims 1 to 111, wherein regulatory T cells outside the tumor microenvironment of the locally advanced, recurrent, or metastatic solid tumor malignancy are depleted.

113. The method of any one of claims 1 to 112, wherein the subject is a human.

114. A monoclonal antibody that binds to CCR8 for use in the treatment of locally advanced, recurrent, or metastatic solid tumor malignancies in a subject in need thereof.

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