Anti-CCR8 antibodies and uses thereof

Abstract

Provided herein are various embodiments relating to anti-CCR8 binding agents, that bind to CCR8, and uses thereof. Some of the embodiments include antibodies, fragments thereof, variants thereof, derivatives thereof, and binding polypeptides targeting the same that bind CCR8. Such ant.i-CCR8 binding agents can be used in methods to treat, for example, cancer.

Description

ANTI-CCR8 ANTIBODIES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 755,466, filed on February 72025, which is incorporated herein by reference in its entirety for all purposes.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 6, 2026, is named 1586-WO-PCT_SL.xml and is 294,735 bytes in size.FIELD

[0003] Antibodies that bind to C-C Motif Chemokine Receptor 8 (CCR8) are provided. Methods of detecting the level of CCR8 expression and / or number of CCR8 expressing cells in a sample using such antibodies are provided. Methods of treatment that include detecting CCR8 using such antibodies and / or administering such antibodies are also provided. Related methods for monitoring the level of CCR8 expression and / or number of CCR8 expressing cells that are useful in diagnostic and / or therapeutic settings, such as in the treatment of cancer with an anti-CCR8 antibody, are also provided.BACKGROUND

[0004] CCR8 belongs to the G protein-coupled receptor (GPCR) family. CCR8 is primarily expressed on tumor regulatory T (Treg) cells, a type of immunosuppressive cell found in the tumor microenvironment. Inhibition of CCR8 in the context of cancer treatment is an expanding therapeutic area. However, there remains a need for antibodies that bind CCR8 for treatment of cancer and other diseases and disorders. There also remains a need for antibodies that bind to CCR8 in a sample from a patient treated with a CCR8 antibody. The emergence of therapeutic CCR8 antibodies poses a new problem for diagnostic CCR8 antibodies that remains to be solved, i.e., the need for non-competing antibodies that can reliably and specifically detect CCR8 in the samples of patients that may contain potentially interfering therapeutic CCR8 antibodies. The compositions and methods disclosed herein satisfy this need and provide related advantages.SUMMARY

[0005] In a first aspect, provided herein is an isolated antibody or an antigen-binding fragment thereof that binds to human C-C motif chemokine receptor (CCR8), wherein the antibody or fragment thereof includes a heavy chain variable (VH) region including an HCDR 1 including the amino acid sequence of SEQ ID NO: 214, an HCDR2 including the amino acid sequence of SEQ ID NO: 215, an HCDR3 including the amino acid sequence of SEQ ID NO: 216, and a light chain variable (VL) region including an LCDR1 including the amino acid sequence of SEQ ID NO: 217, an LCDR2 including the amino acid sequence of SEQ ID NO: 218, and an LCDR3 including the amino acid sequence of SEQ ID NO: 219.

[0006] In some embodiments of the first aspect, tlie antibody or fragment thereof includes a VHVH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including tlie amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241, an LCDR2 including the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39.

[0007] In some embodiments of the first aspect, the antibody or fragment thereof includes: a) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 56, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including die amino acid sequence of SEQ ID NO: 82, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; b) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; c) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 83, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; d) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an IICDR2 including tlie amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including die amino acid sequence of SEQ ID NO: 84, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; e) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 58, an HCDR3 including tlie amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including tlie amino acid sequence of SEQ ID NO: 39; f) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 59, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; g) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; h) a VH region including an HCDR1 including theamino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; i) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; j) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR 1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; k) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; l) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; m) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; n) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; o) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 35, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; p) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3including the amino acid sequence of SEQ ID NO: 39; q) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; r) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; s) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; t) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including tire amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; u) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including tire amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; v) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; w) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDRl including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; x) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; y) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRlcomprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; or z) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0008] In some embodiments of die first aspect, a) the VH region further includes: i) a framework 1 (VH FR1), a framework 2 ( VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; or ii) a VH FR1 including the sequence in SEQ ID NO: 222, a VH FR3 including the sequence in SEQ ID NO: 224, and / or a VH FR4 including the sequence in SEQ ID NO: 225; and / or b) the VL region further includes: i) a VI, FR1 including the sequence in SEQ ID NO: 226, a VL FR2 including the sequence in SEQ ID NO: 227, a VL FR3 including the sequence in SEQ ID NO: 228, and / or a VL FR4 including the sequence in SEQ ID NO: 229; or ii) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

[0009] In some embodiments of the first aspect, the antibody or fragment includes: a) a VH region including an amino acid sequence of SEQ ID NO: 220; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 221.

[0010] In some embodiments of tire first aspect, tire antibody or fragment includes: a) a VH region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments of the first aspect, the antibody or fragment includes: a) a VH region including an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

[0011] In some embodiments of the first aspect, the antibody or fragment includes: a) a heavy chain (HC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212; and / or b) a light chain (LC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161,163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213. In some embodiments, the antibody or fragment includes: a) a heavy chain (HC) including an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200. 202, 204, 206, 208, 210 or 212: and / or b) a light chain (LC) including an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

[0012] In some embodiments of the first aspect, the antibody or fragment targets an epitope of SEQ ID NO: 1.

[0013] In some embodiments of the first aspect, a portion of the CCR8 is expressed on a cell, and wherein the antibody of fragment mediates depletion of the CCR8 expressing cell by antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), or complement dependent cytotoxicity, or any combination thereof.

[0014] In some embodiments of the first aspect, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized, human or chimeric antibody. In some embodiments, wherein the antibody or fragment thereof is a Fab, Fab", F(ab')2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, or a multispecific antibody formed from antibody fragments.

[0015] In some embodiments of the first aspect, the antibody or fragment thereof includes one or more post-translational modifications. In some embodiments, the one or more post-translational modifications enhances one or more activity of the isolated antibody or an antigen-binding fragment or imparts one or more activity unto tlie isolated antibody or antigen-binding fragment thereof. In some embodiments, the one or more activity is measured relative to an isolated antibody or antigen-binding fragment thereof without die one or more modification in a suitable in vitro assay. In some embodiments, the one or more post-translational modifications includes one or more amino acid alterations, one or more conjugation or fusion to one or more second agents, one or more chemical alterations, or any combination thereof. In some embodiments, the one or more amino acid alterations is one or more conservative or non-conservative substitutions. In some embodiments, the one or more chemical alterations is afucosylation.

[0016] In some embodiments of the first aspect, die antibody or fragment thereof includes enhanced binding activity, stability, solubility, half-life, or aggregation relative to an isolated antibody or an antigen¬ binding fragment thereof consisting of a non-altered sequence.

[0017] In some embodiments of the first aspect, the antibody or fragment thereof includes enhanced binding activity. In some embodiments of the first aspect, the antibody or fragment thereof includes enhanced binding activity, as measured by flow cytometry. In some embodiments, the antibody or fragment thereof includes enhanced binding activity as compared to an antibody or fragment thereof including a heavy chain including an amino acid of SEQ ID NO: 152, and a light chain including an amino acid sequence of SEQ ID NO: 153, as measured by flow cytometry.

[0018] In some embodiments of die first aspect, the antibody or fragment thereof includes enhanced stability. In some embodiments, the antibody or fragment thereof includes enhanced stability as compared to an antibody or fragment thereof including a heavy chain including an amino acid of SEQ ID NO: 152, and a light chain including an amino acid sequence of SEQ ID NO: 153. In some embodiments, the enhanced stability is enhanced thermal stability.

[0019] In some embodiments of the first aspect, the antibody or fragment thereof includes from 4% to 0% deamidation. In some embodiments, the antibody or fragment thereof includes reduced deamidation as compared to an antibody or fragment thereof including a heavy chain including an amino acid of SEQ ID NO: 152, and a light chain including an amino acid sequence of SEQ ID NO: 153.

[0020] In some embodiments of lite first aspect, the second agent includes a diagnostic agent, a detectable agent, or a therapeutic agent. In some embodiments, the antibody or fragment thereof includes diagnostic activity of a CCR8-related condition or disease, detecting activity of a CCR8-related condition or disease, or therapeutic activity of a therapy aimed at a CCR8-related condition or disease,

[0021] In some embodiments of the first aspect, the antibody or fragment includes enhanced FcyRIIIa receptor binding, enhanced antibody-dependent cellular cytotoxicity (ADCC), enhanced antibodydependent cellular phagocytosis (ADCP) activities, enhanced complement dependent cytotoxicity (CDC) or combinations thereof.

[0022] In a second aspect, provided herein is a binding polypeptide that indicates the presence of CCR8 expressing cells in a sample obtained from a subject, wherein the binding polypeptide selectively binds to CCR8 and is labeled with a detectable label or moiety, wherein tlie binding polypeptide includes a heavy chain variable (VH) region including an HCDR1 including tire amino acid sequence of SEQ ID NO: 214, an HCDR2 including the amino acid sequence of SEQ ID NO: 215, an HCDR3 including the amino acid sequence of SEQ ID NO: 216, and a light chain variable (VL) region including an LCDR1 including the amino acid sequence of SEQ ID NO: 217, an LCDR2 including the amino acid sequence of SEQ ID NO: 218, and an LCDR3 including the amino acid sequence of SEQ ID NO: 219.

[0023] In some embodiments of the second aspect, the binding polypeptide includes a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region including an LCDR1 including die amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240 or 241, an LCDR2 including the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39.

[0024] In some embodiments of the second aspect, the binding polypeptide includes: a) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 56, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 82, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; b) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the aminoacid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39: c) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 83, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; d) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 84, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; e) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 58, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR 1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including die amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; f) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 59, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; g) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; h) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39: i) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; j) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; k) a VH region including an HCDR1 including the amino acid sequence of SEQ IDNO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; l) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; m) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; n) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; o) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 35, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; p) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; q) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR 1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; r) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; s) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequenceof SEQ ID NO: 39; t) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; u) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; v) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; w) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; x) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; y) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; or z) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0025] In some embodiments of the second aspect, a) the VH region further includes: i) a framework 1 (VH FR1), a framework 2 (VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; or ii) a VH FR1 including die sequence in SEQ ID NO: 222, a VH FR3 including the sequence in SEQ ID NO: 224, and / or a VH FR4 including the sequence in SEQ ID NO: 225; and / or b) the VL region further includes: i) a VL FR1 including the sequencein SEQ ID NO: 226, a VL FR2 including the sequence in SEQ ID NO: 227, a VL FR3 including the sequence in SEQ ID NO: 228, and / or a VL FR4 including the sequence in SEQ ID NO: 229; or ii) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151,

[0026] In some embodiments of the second aspect, the binding polypeptide includes: a) a VH region including an amino acid sequence of SEQ ID NO: 220; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 221.

[0027] In some embodiments of the second aspect, the binding polypeptide includes: a) a VH region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments, the binding polypeptide includes: a) a VH region including an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

[0028] In some embodiments of the second aspect, die binding polypeptide includes: a) a heavy chain (HC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212 and / or b) a light chain (LC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213. In some embodiments, the binding polypeptide includes: a) a HC including an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184. 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212; and / or b) a LC including an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

[0029] In some embodiments of the second aspect, (i) the binding polypeptide is labeled with a detectable label or moiety that can be detected directly or (ii) the binding polypeptide is recognized by a secondary reporter t hat is labeled with a detectable label or moiety that can be detected directly; and wherein the detectable label or moiety includes fluorescent, chromophoric, electron -dense, chemiluminescent, and radioactive labels or indirectly. In some embodiments, tire detectable label or moiety can be detected indirectly and wherein the detectable label or moiety includes a reporter, a tag, a purification tag, a polymeric sequence designed to hybridize to a complementary polymeric sequence,enzymes, a heterologous protein, or combinations thereof. In some embodiments, the detectable label or moiety is fused. Jinked, conjugated, or covalently or non -covalently bound to the binding polypeptide and / or the secondary reporter.

[0030] In some embodiments of the second aspect, the CCR8 expressing cells are tumor infiltrating Treg cells. In some embodiments, the CCR8 expressing cells are present in a tumor microenvironment. In some embodiments, the tumor microenvironment includes solid tumor cells. In some embodiments, the solid tumor cells are cancer cells chosen from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer (PAC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer (CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of the endometrium, carcinoma of the fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.

[0031] In some embodiments of the second aspect, the binding polypeptide targets an intracellular epitope of SEQ ID NO: 1.

[0032] In a third aspect, provided herein is a binding polypeptide that mediates activity in a diseased microenvironment associated with CCR8 expression in a subject, wherein the binding polypeptide selectively binds to CCR8 and is conjugated or fused to one or more therapeutic agents, wherein the binding polypeptide includes a heavy chain variable (VH) region including an HCDR1 including the amino acid sequence of SEQ ID NO: 214, an HCDR2 including the amino acid sequence of SEQ ID NO: 215, an HCDR3 including the amino acid sequence of SEQ ID NO: 216, and a light chain variable (VL) region including an LCDR1 including the amino acid sequence of SEQ ID NO: 217, an LCDR2 including the amino acid sequence of SEQ ID NO: 218, and an LCDR3 including the amino acid sequence of SEQ ID NO: 219.

[0033] In some embodiments of the third aspect, the binding polypeptide includes a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region including an LCDR1 including the amino acid sequence ofSEQ ID NO: 37, 82, 83, 84, 85, 240, or 241, an LCDR2 including the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39.

[0034] In some embodiments of the third aspect, the binding polypeptide includes: a) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 56, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 82, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; b) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; c) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 83, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; d) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 84, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; e) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 58, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; f) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 59, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; g) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; h) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; i) a VH region including an HCDR1 including theamino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; j) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; k) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; 1) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an IICDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and tin LCDR3 including the amino acid sequence of SEQ ID NO: 39; m) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; n) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; o) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 35, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; p) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; q) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 89, and an LCDR3including the amino acid sequence of SEQ ID NO: 39; r) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 85, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including tlie amino acid sequence of SEQ ID NO: 39; s) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; t) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 69, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; u) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 57, an HCDR3 including the amino acid sequence of SEQ ID NO: 68, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; v) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 60, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including tlie amino acid sequence of SEQ ID NO: 39; w) a VH region including an HCDR1 including the amino acid sequence of SEQ ID NO: 34, an HCDR2 including the amino acid sequence of SEQ ID NO: 61, an HCDR3 including the amino acid sequence of SEQ ID NO: 36, and a VL region including an LCDR1 including the amino acid sequence of SEQ ID NO: 37, an LCDR2 including the amino acid sequence of SEQ ID NO: 38, and an LCDR3 including the amino acid sequence of SEQ ID NO: 39; x) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising tlie amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; y) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; or z) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising tlie amino acid sequence of SEQ ID NO: 36, and a VL regioncomprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0035] In some embodiments of the third aspect, a) the VH region further includes: i) a framework 1 (VH FR1), a framework 2 (VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 1 12, 1 14, 116, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; or ii) a VH FR1 including the sequence in SEQ ID NO: 222, a VH FR3 including the sequence in SEQ ID NO: 224, and / or a VH FR4 including the sequence in SEQ ID NO: 225; and / or b) the VL region further includes: i) a VL FR1 including the sequence in SEQ ID NO: 226, a VL FR2 including the sequence in SEQ ID NO: 227, a VL FR3 including the sequence in SEQ ID NO: 228, and / or a VL FR4 including the sequence in SEQ ID NO: 229; or ii) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

[0036] In some embodiments of the third aspect, the binding polypeptide includes: a) a VH region including an amino acid sequence of SEQ ID NO: 220; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 221.

[0037] In some embodiments of the third aspect, the binding polypeptide includes: a) a VH region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

[0038] In some embodiments of the third aspect, the binding polypeptide includes: a) a VH region including an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / or b) a VL region including an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments, the binding polypeptide includes: a) a heavy chain (HC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212; and / or b) a light chain (LC) including an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

[0039] In some embodiments of the third aspect, the binding polypeptide includes: a) a HC including an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178,180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212; and / or b) a LC including an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

[0040] In some embodiments of the third aspect, the therapeutic agent includes: a radionuclide, a cytotoxic agent, an organic compound, a protein toxin, an immunomodulator, a cytokine, a fluorescent moiety, a cell, a cell receptor, a second antibody or antigen-binding fragments thereof, or combinations thereof. In some embodiments, the radionuclide includes a beta particle, an alpha particle, or an Auger electron emitter. In some embodiments, the cytotoxic agent includes an auristatin, a maytansinoid, a kinesin-spindle protein (KSP) inhibitor, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor or a pyrrolobenzodiazepine derivative. In some embodiments, the cell is a chimeric antigen receptor T cell. In some embodiments, the cell receptor is a chimeric antigen receptor.

[0041] In some embodiments of the third aspect, die binding polypeptide includes one or more linkers linking the binding polypeptide to the one or more therapeutic agents. In some embodiments, the one or more therapeutic agent is directly conjugated or fused to the binding polypeptide. In some embodiments, CCR8 expression is CCR8 expression on tumor infiltrating Trcg cells. In some embodiments, the diseased microenvironment related to CCR8 expression is a tumor microenvironment. In some embodiments, the tumor microenvironment includes solid tumor cells. In some embodiments, the solid tumor cells are cancer cells chosen from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer (PAC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer (CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of the endometrium, carcinoma of the fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.

[0042] In a fourth aspect, provided herein is a polynucleotide including one or more nucleotide sequences encoding: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; or c) any combination thereof.

[0043] In a fifth aspect, provided herein is a vector including any of the polynucleotides provided herein.

[0044] In a sixth aspect, provided herein is a library of vectors including at least two vectors, each individually encoding: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; or c) any combination thereof.

[0045] In a seventh aspect, provided herein is a cell expressing: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; or c) any combination thereof.

[0046] In an eight aspect, provided herein is a cell including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of tire vectors provided herein; e) any library of vectors provided herein; or f) any combination thereof.

[0047] In a ninth aspect, provided herein is a population of cells including any of the cells provided herein.

[0048] In a tenth aspect, provided herein is a system of specifically binding CCR8 in a sample obtained from a subject, the system including components including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; c) any library of vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; or g) any combination thereof.

[0049] In an eleventh aspect, provided herein is a composition including: a) any one of lire isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the compositions provided herein; h) any of the systems provided herein; or i) any combination thereof.

[0050] In a twelfth aspect, provided herein is a method of producing an anti-CCR8 agent including culturing any of the cells provided herein, or any of the population of cells provided herein, under conditions suitable for expressing the isolated antibody, binding polypeptide, or portion thereof. In some embodiments, the method includes isolating the antibody or binding polypeptide.

[0051] In a thirteenth aspect, provided herein is a method of producing an anti-CCR8 agent that specifically binds to an intracellular epitope of CCR8 and not to an extracellular epitope of CCR8 including immunizing a non -human subject with an immunogen including a cell that expresses the intracellular, extracellular epitope and an antibody or antigen-binding fragment thereof that specifically binds to the extracellular epitope for a sufficient number of time to permit the non-human subject to generate the anti-CCR8 agent that specifically binds to the intracellular epitope.

[0052] In a fourteenth aspect, provided herein is a system of detecting CCR8 expressing cells in a sample obtained from a subject, the system including components including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the systems provided herein; h) any of the compositions provided herein; or i) any combination thereof. In some embodiments, the components further inchide a detection reagent or an amplification reagent.

[0053] In some embodiments of the fourteenth aspect, tlie CCR8 expressing cells are tumor infiltrating lymphocytes (TILs). In some embodiments, the CCR8 expressing ’1'ILs include Tregs or Natural Killer cells. In some embodiments, the sample is a solid tissue biopsy. In some embodiments, the sample includes a formalin -fixed paraffin-embedded (FFPE) tissue. In some embodiments, detection of the CCR8 expressing ceils includes an immunohistochemistry assay. In some embodiments, the subject has cancer.

[0054] In some embodiments of the fourteenth aspect, a) each component is suspended in a solution, or any combination of components is suspended in the same solution; b) each component is housed in a container, or any combination of components is housed in a container; c) each component is provided in a device, or any combination of components is provided in a device; or d) any combination of thereof

[0055] In a fifteenth aspect, provided herein is a device for detecting CCR8 in a sample obtained from a subject, the device including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the compositions provided herein; h) any of the systems provided herein; or i) any combination thereof; wherein any of the components arc included in a reagent that is housed in a container.

[0056] In a sixteenth aspect, provided herein is a kit for detecting CCR8 in a sample obtained from a subject, tire kit including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the compositions provided herein; h) any of tlie systems provided herein; i) any of tire devices provided herein; or j) any combination thereof; and instructions for using the components for detecting CCR8 in the sample obtained from a subject.

[0057] In a seventeenth aspect, provided herein is a method of detecting CCR8 in a sample obtained from a subject, including: a) contacting a sample with: i) any one of tlie isolated antibodies provided herein; ii) any one of the binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of tlie systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof; under conditions sufficient and for a period of lime to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; and b) detecting the level of CCR8 or number of CCR8 expressing cells in said sample.

[0058] In an eighteenth aspect, provided herein is a method of assessing responsiveness of a subject having cancer to an anti-CCR8 agent, including: a) obtaining a sample from the subject; b) performing a method of detecting CCR8 in a sample form a subject provided herein; and c) associating the level of CCR8 or number of CCR8 expressing cells with a diseased microenvironment.

[0059] In a nineteenth aspect, provided herein is a method of selecting a subject suspected of having or having cancer for treatment with an anti-CCR8 agent, the method including: a) obtaining a sample from the subject; b) performing a method of detecting CCR8 in a sample form a subject provided herein; c)comparing the level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or number of CCR8 expressing cells; and d) selecting the subject for treatment with an anti-CCR8 agent if the level of the subject's CCR8 or number of CCR8 expressing cells exceed the threshold level of CCR8 or number of CCR8 expressing cells. In some embodiments, the CCR8 expressing cell is a CCR8+Treg cell.

[0060] In a twentieth aspect, provided herein is a system of mediating depletion of a CCR8 expressing cell population in a subject, the system including components including: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the compositions provided herein; or h) any combination thereof. In some embodiments, the system components further include one or more system components to detect the baseline number of CCR8 expressing cells and / or detect the depletion of the CCR8 expressing cell relative to the baseline number of CCR8 expressing cells. In some embodiments, the one or more detection components include: a) any one of the isolated antibodies provided herein; b) any one of the binding polypeptides provided herein; c) any of the polynucleotides provided herein; d) any of the vectors provided herein; e) any library of vectors provided herein; f) any of the population of cells provided herein; g) any of the compositions provided herein; or h) any combination thereof. In some embodiments, the components further include a detection reagent or an amplification reagent.

[0061] In some embodiments of the twentieth aspect, lire system of any one of claims 94-96, wherein the CCR8 expressing cell is a CCR8+ Treg cell.

[0062] In a twenty-first aspect, provided herein is a pharmaceutical composition any of the compositions described herein and a pharmaceutically acceptable excipient.

[0063] In a twenty-second aspect, provided herein is a method of mediating depletion of a level of CCR8 expression or number of CCR8 expressing cells in a subject, the method including: a) determining a baseline level of CCR8 expression or number of CCR8 expressing cells in a sample obtained from the subject, including obtaining a sample, contacting said sample with: i) any one of the isolated antibodies provided herein; ii) any one of tlie binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of ceils provided herein; vii) any of the compositions provided herein; viii) any of die systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof; under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; and detecting the level of CCR8 expression or number of CCR8 expressing cells in said sample; b) administering to the subject an effective amount of a therapeutic anti-CCR8 agent including an antibody or antigen-binding fragment thereof that can specifically bind to CCR8; and c) determining the level of CCR8 expression or number of CCR8 expressing cells in a second sample, wherein the decrease of the level of CCR8 expression or number of CCR8 expressing cells in the second sample relative to the baseline level indicates that the level of CCR8 expression or number of CCR8 expressing cells has been depleted in the subject.

[0064] In some embodiments of the twenty-second aspect, the therapeutic anti-CCR8 agent does not include: i) any one of the isolated antibodies provided herein; ii) any one of the binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of the systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof.

[0065] In some embodiments of the twenty-second aspect, the sample obtained from the subject is obtained from solid tumor tissue. In some embodiments, the CCR8 expressing cell population are CCR8+ Treg cells.

[0066] In a twenty-third aspect, provided herein is a method of treating cancer in a subject in need thereof, the method including a) detecting the level of CCR8 expression or analyzing the number of CCR8 expressing cells in a sample obtained from tire subject, wherein the detecting includes: i) any one of the isolated antibodies provided herein; ii) any one of the binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of the systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof; under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; and) associating the level of CCR8 expression or number of CCR8 expressing cells with a diseased microenvironment; and b) administering to the subject an effective amount of a therapeutic anti-CCR8 agent including an antibody or antigen-binding fragment thereof that can specifically bind to CCR8.

[0067] In some embodiments of the twenty-third aspect, the therapeutic anti-CCR8 agent does not include: i) any one of the isolated antibodies provided herein; ii) any one of the binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of the systems provided herein; ix) any of the devices provided herein; x) any of tlie kits provided herein; or xi) any combination thereof.

[0068] In a twenty-fourth aspect, provided herein is a method of detecting CCR8 in a solid tumor sample obtained from a subject, including: a) contacting the solid tumor sample with: i) any one of the isolated antibodies provided herein; ii) any one of the binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of the systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof; under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; and b) detecting the level of CCR8 or die number of CCR8 expressing cells in said solid tumor sample.

[0069] In a twenty-fifth aspect, provided herein is a method of selecting a subject having a solid cancer for treatment with a therapeutic anti-CCR8 agent, tlie method including: a) obtaining a solid tumor samplefrom the subject; b) detecting the level of CCR8 or analyzing the number of CCR8 expressing cells in the solid tumor sample by performing a method for detecting CCR8 in a solid tumor sample obtained from a subject provided herein: c) comparing the level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells; and d) selecting the subject for treatment with an anti-CCR8 agent if the level of the subject’s CCR8 or number of CCR8 expressing cells exceed the threshold level of CCR8 or number of CCR expressing cells.

[0070] In a twenty-sixth aspect, provided herein is a method of treating a subject having a solid cancer with a therapeutic anti-CCR8 agent, the method including: a) selecting the subject for treatment by performing a method of selecting a subject having a solid cancer for treatment with a therapeutic anti-CCR8 agent provided herein; and b) administering an effective amount of the therapeutic anti-CCR8 agent.

[0071] In some embodiments of the twenty-sixth aspect, the therapeutic anti-CCR8 agent does not include: i) any one of die isolated antibodies provided herein; ii) any one of die binding polypeptides provided herein; iii) any of the polynucleotides provided herein; iv) any of the vectors provided herein; v) any library of vectors provided herein; vi) any of the population of cells provided herein; vii) any of the compositions provided herein; viii) any of the systems provided herein; ix) any of the devices provided herein; x) any of the kits provided herein; or xi) any combination thereof.

[0072] In a twenty- sevendi aspect, provided herein is a method of monitoring therapeutic efficacy of a treatment with a therapeutic anti-CCR8 agent in a subject having a solid cancer, the method including: a) obtaining a solid tumor sample from the subject; b) detecting the level of CCR8 expression or number of CCR8 expressing cells in die solid tumor sample by performing a method of detecting CCR8 in a solid tumor sample obtained from a subject provided herein; and c) comparing the detected level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells; In some embodiments, the treatment of the therapeutic anti-CCR8 agent has therapeutic efficacy if the detected level CCR8 expression or number of CCR8 expressing cells is depleted relative to die threshold level of CCR8 expression or number of CCR8 expressing cells.

[0073] In a twenty-seventh aspect, provided herein is a method of evaluating the prognosis of a subject having a solid cancer and undergoing treatment with a therapeutic anti-CCR8 agent, the method including: a) obtaining a solid tumor sample from the subject; b) detecting the level of CCR8 expression or number of CCR8 expressing cells in the solid tumor sample by performing a method of detecting CCR8 in a solid tumor sample obtained from a subject provided herein; and c) comparing the detected level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells. In some embodiments, the subject has an improved prognosis if the detected level CCR8 expression or number of CCR8 expressing cells is depleted relative to the threshold level of CCR8 expression or number of CCR8 expressing cells.

[0074] In some embodiments of the twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty¬ seventh aspect, the threshold level of CCR8 expression or number of CCR8 expressing cells is a baseline level of CCR8 expression or number of CCR8 expressing cells of the subject prior to receiving the initialtreatment with the therapeutic anti-CCR8 agent, or any subsequent treatment with the therapeutic anti- CCR8 agent.

[0075] In some embodiments of die twenty-third, twenty-fourth, twenty-fifth, twenty-sixdi or twentyseventh aspect, the CCR8 expressing cells are Treg cells and the detection measures the depletion of CCR8+ Treg cells.

[0076] In some embodiments of the twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twentyseventh aspect, the solid cancer is chosen from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer (PAC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer (CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of the endometrium, carcinoma of the fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0077] FIGS, 1A-1B show a multiple sequence alignment of the heavy chain variable region (VH) of Abs 1-31. As used in the figure: asterisk (*), same residue as AB-1; colon (:), conservative amino acid substitution relative to AB-1; blank space ( ), non-conservative amino acid substitution relative to AB-1; CDR, complementarity determining region based on Kabat numbering; FR, framework region.

[0078] FIGS. 2A-2B show a multiple sequence alignment of the light chain variable region (VI.) of Abs 1-31. As used in the figure: asterisk (*), same residue as AB-1; colon (:), conservative amino acid substitution relative to AB-1; blank space ( ), non-conservative amino acid substitution relative to AB-1; CDR, complementarity determining region based on Kabat numbering; FR, framework region.

[0079] FIG. 3 shows exemplary results from immunohistochemistry (IHC) screening of anti-CCR8 antibodies to full-length human CCR8 on a cell pellet array (CPA) of HEK 293 wildtype and HEK 293 overexpressing human CCR8 cell lines.

[0080] FIG. 4 shows exemplary results from IHC screening of anti-CCR8 antibodies for binding of CCR8 in formalin-fixed paraffin embedded (FFPE) human thymus samples.

[0081] FIG. 5 shows exemplary results from IHC validation of anti-CCR8 antibodies for biding of CCR8 in FFPE human thymus samples.

[0082] FIG. 6 shows exemplary results from IHC validation of anti-CCR8 antibodies for binding of CCR8 in human bead and neck squamous cell carcinoma (HNSCC) and human colorectal carcinoma (CRC) samples.

[0083] FIG.7 shows exemplary results from a competitive binding assay for anti-CCR8 antibodies and a therapeutic anti-human CCR8 antibody on a CPA of CCR8-expressing HEK 293 cells.DET AILED DESCRIPTIONDefinitions

[0084] Unless otherwise defined, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context or expressly indicated, singular terms shall include pluralities and plural terms shall include the singular. For any conflict in definitions between various sources or references, the definition provided herein will control.

[0085] It is understood that embodiments described herein include “consisting” and / or “consisting essentially of' embodiments. As used herein, the singular form “a”, “an”, and “the” includes plural references unless indicated otherwise. Use of the term “or” herein is not meant to imply that alternatives are mutually exclusive.

[0086] In this application, the use of “or” means “and / or” unless expressly stated or understood by one skilled in tire art. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim,

[0087] As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0088] The term “affinity” as used herein in reference to an antibody or binding polypeptide refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (for example, an antibody or binding polypeptide) and its binding partner (for example, an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art (such as, for example, ELISA KD, KinExA, bio¬ layer interferometry (BLI), and / or surface plasmon resonance devices (such as a BIAcore® device), including those described herein).

[0089] The term “antibody” (Ab) refers to an immunoglobulin molecule (e.g. without limitation human IgGl, IgG2, IgG3, IgG4, IgM, IgD, IgE, IgAl, IgA2, mouse IgGl, IgG2a, IgG2b, IgG2c, IgG3, IgA, IgD, IgE or IgM, rat IgGl, IgG2a, IgG2b, IgG2c, IgA, IgD, IgE or IgM, rabbit IgAl, IgA2, IgA3, IgE, IgG, IgM, goat IgA, IgE, IgGl, IgG2, IgE, IgM or chicken IgY) that binds to, or is immunologically reactive with, a particular antigen. The term antibody includes, but is not limited to, fragments that are capable ofbinding to an antigen, such as antigen-binding regions and / or effector regions of the antibody, e.g., Fab, Fab’, F(ab’)i. Fv. scFv, (scFvh, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)i (including a chemically linked F(ab’)?), Fd, Fc, diabody, di-diabody, disulfide-linked Fvs (dsFv), single -domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of die variable regions of the heavy and light chains that are non-covalently coupled). Accordingly, it is understood that the term “antibody” also encompasses any antigen binding fragments thereof, and thus the terms “antibody”, “antibody fragment” and “antigen-binding fragment thereof’ are used interchangeably herein. Depending on the respective context, the term antibody may also refer to any proteinaceous binding molecule with immunoglobulin-like function, such as a “binding polypeptide” as described herein.

[0090] The term antibody also includes, specifically covers, but is not limited to, for example polyclonal antibodies, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human versions of antibodies having full length heavy and / or light chains. As the term antibody includes chimeric antibodies, humanized antibodies, and antibodies of various species such as mouse, human, cynomolgus monkey, etc. are also encompassed by an antibody described herein. Furthermore, for all antibody constructs provided herein, variants having the sequences from other organisms are also contemplated. Thus, if a human version of an antibody is disclosed, one of skill in the art will appreciate how to transform the human sequence based antibody into a mouse, rat, cat, dog, horse, etc. sequence.

[0091] A variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (VH) and / or light (VL) chain variable domains. For example, the present disclosure also includes tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer. Thus, for example, the V region domain may be dimeric and contain VH-VH, VH-VL, or VL-VL dimers that bind CCR8. If desired, the VH and VL chains may be covalently coupled either directly or through a linker to form a single chain Fv (scFv) (e.g., an antibody fragment described herein). Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed “minimal recognition un its” or “bypervariable region”) can be obtained by constructing polynucleotides that encode the CDR of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al.. Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley-Liss, Inc. (1995)). The more highly conserved portions of the variable domains are called the framework (FR). As is known in the art, the amino acid position / boundary delineating a hyper variable region of anantibody can vary, depending on die context and the various definitions known in the art. Antibody fragments, regions and / or domains are further described in detail throughout the present disclosure. Antibody fragments may be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9): 1126- 1136, 2005).

[0092] 'The term “antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (for example NK cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The primary ceils for mediating ADCC, NK cells, express FcyRIlI only, whereas monocytes express FcyRI, FcyRII, and FcyRIlI. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991), To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in US Pat. Nos. 5,500,362 or 5,821,337 or U. S. Pat. No. 6,737,056 (Presta), may be performed. Useful effector cells for such assays include PBMC and NK cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. (USA) 95:652-656 (1998). Additional polypeptide variants with altered Fc region amino acid sequences (polypeptides with a variant Fc region) and increased or decreased ADCC activity are described, for example, in U.S. Pat. No. 7,923,538, and U.S. Pat. No. 7,994,290.

[0093] The term “antibody-dependent cellular phagocytosis” or “ADCP” as used herein refers to the mechanism by which antibody-opsonized target cells activate the FcyRs on the surface of immune cells e.g., macrophages to induce phagocytosis), resulting in internalization and degradation of the target cell. For ADCP, binding to macrophages as effector cells typically occurs via the interaction of the antibodies FC part with FcyRIIa (CD32a) expressed by macrophages.

[0094] The term “complement-dependent cytotoxicity” or “CDC” as used herein refers to an effector function of IgG and IgM antibodies when they are bound to a surface antigen on a target cell (e.g. T regulatory cell), the classical complement pathway is triggered by bonding protein Cl q to these antibodies, resulting in formation of a membrane attack complex (MAC) and target cell lysis. Complement system is efficiently activated by antibodies, such as human IgGl, IgG3 and IgM antibodies.

[0095] The term “CCR8” as used herein refers to C-C chemokine receptor type 8. Synonyms for CCR8 are inter alia CC-CKR-8, CCR-8, CDw198, CKRL1, CMKBR8, CMKBRL2, GPRCY6, CY6, TERI. The CCR8 protein is encoded by the gene CCR8 (NCBI gene ID 1237). The term includes human, murine, rabbit, and Rhesus macaque Ct RS protein and further mammalian and non-mammalian homologues. Different isoforms and variants, including splice variants or allelic variants, may exist for the different species and are all comprised by the term CCR8. Also comprised are CCR8 molecules before and after maturation, e.g., independent of cleavage of one or more pro-domains. In addition, synthetic variants of the CCR8 protein may be generated and are comprised by the term CCR8. The protein CCR8 mayfurthermore be subject to various modifications, e.g., synthetic or naturally occurring modifications, such as post translational modifications. Recombinant human CCR8 is commercially available or can be manufactured by any suitable technique. CCR8 is a receptor for the chemokine CCL1 / SCYA1 / I-309.

[0096] The term “CDR” as used in reference to an antibody provided herein describes a complementarity determining region as defined by at least one manner of identification to one of skill in the art. In some instances, CDRs can be defined in accordance with any one of the well-known schemes in the art, such as the Chothia numbering scheme, the Kabat numbering scheme, the IMGT numbering scheme, the CCG numbering scheme, the North numbering scheme, the Honeggar numbering scheme, or a combination of Kabat, Chothia, IMGT, CCG, North, and / or Honeggar. The varioiis CDRs within an antibody can be designated by their appropriate number and chain type, including, without limitation as: a) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3; b) CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3; c) LCDR-1, LCDR-2, LCDR-3, HCDR-1, HCDR-2, and HCDR-3; d) LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3; e) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, VL CDR3; etc. The term “CDR” is used herein to also encompass HVR or a “hyper variable region”, including hypcrvariablc loops. Exemplary hypervariable loops occur 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).)

[0097] The term “chimeric antibody” as used herein refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while at least a part of the remainder of tire heavy and / or light chain is derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody comprising at least one variable region from a first species (such as mouse, rat, cynomolgus monkey, etc.) and at least one constant region from a second species (such as human, cynomolgus monkey, etc.). In some instances, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some instances, a chimeric antibody comprises at least one cynomolgus vari ble region and at least one human constant region. In some instances, all of the variable regions of a chimeric antibody are from a first species and all of the constant regions of the chimeric antibody are from a second species. The chimeric construct can also be a functional fragment, as noted above.

[0098] The term “conjugate” as used herein, refers to antibody or binding polypeptide that is chemically linked to a second agent, such as a therapeutic or cytotoxic agent. The term “agent” includes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.

[0099] The term “detect” and grammatical equivalents thereof as used herein encompasses quantitative or qualitative indication of the presence, absence or abundance of the item being detected. Relatedly, the term “quantify” and grammatical equivalents thereof as used herein encompasses the quantitative indication of the abundance of the item being detected.

[0100] The term “dissociation constant” (KD) as used herein is measured by molar units (M) and refers to the concentration of the binder / antibody at which half of the target proteins are occupied at equilibrium.The smaller the dissociation constant is, the higher is the affinity between the binder or antibody and its target. In some instances, antibodies and / or binding polypeptides provided herein have a target affinity of at least 10⁻⁷ M (as KD value), more preferably of at least 10⁻⁸ M, even more preferably in the range from 10⁻⁹ M to 10⁻¹¹ M. The KD values can be preferably determined by means of surface plasmon resonance spectroscopy, e.g. as described elsewhere herein. Where assay conditions were found to influence the determined KD, the assay setup with the least standard deviation shall be used.

[0101] The term “effective amount” or “therapeutically effective amount” as used interchangeably herein, refer to an number sufficient to achieve a particular biological result or to modulate or ameliorate a symptom in a subject, or the time of onset of a symptom, typically by at least about 10%; usually by at least about 20%, preferably at least about 30%, or more preferably at least about 50%. Efficacy of the use of an antibody in cancer therapy can be assessed based on the change in tumor burden. Both tumor shrinkage (objective response) and time to the development of disease progression are important endpoints in cancer clinical trials. Standardized response criteria, known as RECIST (Response Evaluation Criteria in Solid Tumors), were published in 2000. An update (RECIST 1.1) was released in 2009. RECIST criteria arc typically used in clinical trials where objective response is the primary study endpoint, as well as in trials where assessment of stable disease, tumor progression or time to progression analyses are undertaken because these outcome measures are based on an assessment of anatomical tumor burden and its change over the course of the trial. An effective amount for a particular subject may vary depending on factors such as die condition being treated, the overall health of die subject, die method, route, and dose of administration and die severity of side effects. When in combination, an effective amount is in ratio to a combination of components and the effect is not limited to individual components alone.[01(12] The term “epitope” as used herein refers to a site on a target molecule (for example, an antigen, such as a protein, nucleic acid, carbohydrate or lipid) to which an antigen-binding molecule (for example, an antibody, antibody fragment, or scaffold protein containing antibody binding regions) binds. Epitopes often include a chemically active surface grouping of molecules such as amino acids, polypeptides or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. Epitopes can be formed both from contiguous and / or juxtaposed noncontiguous residues (for example, amino acids, nucleotides, sugars, lipid moiety) of the target molecule. Epitopes formed from contiguous residues (for example, amino acids, nucleotides, sugars, lipid moiety ) typically are retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding typically are lost on treatment with denaturing solvents.. An epitope may include but is not limited to at least 3, at least 5 or 8-10 residues (for example, amino acids or nucleotides). In some examples an epitope is less than 20 residues (for example, amino acids or nucleotides) in length, less than 15 residues or less than 12 residues. Two antibodies may bind the same epitope within an antigen if they exhibit competitive binding for the antigen. In some embodiments, an epitope can be identified by a certain minimal distance to a CDR residue on the antigen-binding molecule. In some embodiments, an epitope can be identified by the above distance, and further limited to those residues involved in a bond (for example, a hydrogen bond) between an antibody residue and an antigen residue. An epitope can be identified by various scans as well, for example, analanine or arginine scan can indicate one or more residues that the antigen-binding molecule can interact with. Unless explicitly denoted, a set of residues as an epitope does not exclude other residues from being part of the epitope for a particular antibody. Rather, the presence of such a set designates a minimal series (or set of species) of epitopes. Thus, in some embodiments, a set of residues identified as an epitope designates a minimal epitope of relevance for the antigen, rather than an exclusive list of residues for an epitope on an antigen.

[0103] The term “heavy chain” or “HC” as used in reference to an antibody provided herein describes a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” as used herein refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0104] The term “heavy chain variable region” or “VII” as used in reference to an antibody provided herein describes a region comprising at least three heavy chain CDRs. In some embodiments, the heavy chain variable region includes the three CDRs and at least FR2 and FR3. In some embodiments, the heavy chain variable region includes at least heavy chain HCDR1, framework (FR) 2, HCDR2, FR3, and HCDR3. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR 1 and / or at least a portion of an FR4.

[0105] The term “human antibody" as used herein encompasses antibodies produced in humans, antibodies produced in non-human animals that comprise human immunoglobulin genes, such as XenoMouse® mice, and antibodies selected using in vitro methods, such as phage display (Vaughan et al., Nature Biotechnology, 14:309-314 (1996); Sheets at al., 1998, Proc. Natl. Acad. Sci. (USA) 95:6157-6162; Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks el al., J. Mol. Biol., 222:581 (1991)), wherein the antibody repertoire is based on a human immunoglobulin sequence. The term “human antibody” denotes the genus of sequences that are human sequences. Thus, the term is not designating the process by which the antibody was created, but the genus of sequences that are relevant.

[0106] The term “humanized antibody” as used herein refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with die corresponding amino acid from a human variable region. In some instances, a humanized antibody comprises at least one human constant region or fragment thereof. In some instances, a humanized antibody is an antibody fragment, such as Fab, an scFv, a (Fab’)2, etc. The term humanized also denotes forms of non-human (for example, murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab’)2 or other antigen-binding subsequences of antibodies) that contain minimal sequence of non-human immunoglobulin. Humanized antibodies can include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are substituted by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody can comprise residues that are found neither in the recipient antibody nor in theimported CDR or framework sequences, but are included to further refine and optimize antibody performance. In some instances, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. In some instances, die humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Other forms of humanized antibodies have one or more CDRs (CDR LI, CDR L2, CDR L3, CDR Hl, CDR 112, and / or CDR H3) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody. As will be appreciated, a humanized sequence can be identified by its primary sequence and does not necessarily denote the process by which the antibody was created.

[0107] The term “isolated” as used herein refers to a molecule that has been separated from at least some of the components with which it is typically found in nature or produced. For example, a polypeptide is referred to as “isolated” when it is separated from at least some of the components of the cell in which it was produced. Where a polypeptide is secreted by a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produced it is considered to be “isolating” the polypeptide. Similarly, a polynucleotide is referred to as “isolated” when it is not part of (he larger polynucleotide (such as, for example, genomic DNA or mitochondrial DNA, in the case of a DNA polynucleotide) in which it is typically found in nature, or is separated from at least some of lire components of the cell in which it was produced, for example, in die case of an RNA polynucleotide. Thus, a DNA polynucleotide that is contained in a vector inside a host ceil may be referred to as “isolated”. An isolated polypeptide or antibody may however be immobilized, e.g. on beads or particles, e.g. via a suitable linker.

[0108] The terms “label” and “detectable label” as used herein mean a moiety or molecule attached to an antibody, a binding polypeptide or its analyte to render a reaction (for example, binding) between the members of the specific binding pair, detectable. The labeled member of the specific binding pair is referred to as “detectably labeled.” In some embodiments, the label is a detectable marker that can produce a signal that is detectable by visual or instrumental means, for example, incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (for example, streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (for example, 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, or 153Sm); chromogens, fluorescent labels (for example, FITC, rhodamine, lanthanide phosphors), enzymatic labels (for example, horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by a secondary reporter (for example, leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly employed for immunoassays include moieties that produce light, for example, acridinium compounds, and moieties that produce fluorescence, for example, fluorescein. In thisregard, the moiety itself may not be detectably labeled but may become detectable upon reaction with yet another moiety. Detectable labels are further described herein.

[0109] The term “light chain” or “LC” as used in reference to an antibody provided herein describes a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0110] The term “light chain variable region” or “VL” as used in reference to an antibody provided herein describes a region comprising at least three light chain CDRs. In some embodiments, the light chain variable region includes the three CDRs and at least FR2 and FR3. In some embodiments, the light chain variable region includes at least light chain LCDR1, framework (FR) 2, LCDR2, FR3, and LCDR3. For example, a light chain variable region may comprise light chain CDR1, framework (FR) 2, CDR2, FR3, and CDR3. Tn some embodiments, a light chain variable region also comprises at least a portion of an FR1 and / or at least a portion of an FR4.

[0111] The term “linker” as used herein refers to any molecule enabling a direct topological connection between two moieties. A moiety may be inter alia a polypeptide, a protein, an antibody, an antibody fragment, a cytotoxic moiety, a binding moiety, a moiety for detection such as a fluorophore, a moiety for immobilization or retrieval such as beads or magnetic beads, a reactive moiety, or any other molecule. The two moieties may be of the same type or different. Linkers may be part of conjugates and may even contribute to their function. For instance, for a conjugate comprising a polypeptide and a biotin, the presence of a spacer of approximately 4 Å (~5 atoms) between the carboxy group of the biotin and the 1st bulky amino acid of the peptide allows the biotin to reach the (strept)avidin binding pocket. Any suitable can be selected, including linkers selected based on the moieties which shall be connected. The linker length typically ranges between 4 atoms and more than 200 atoms. Linkers exceeding 60 atoms in length generally comprise a population of compounds having an average length.

[0112] The term “mediate” as used herein means to bring about a result. For example, when in reference to an agent (e.g., an anti-CCR8 binding agent) or a cell (e.g., a Treg cell), the term mediate describes the action of the agent or cell to induce an action and / or ability of the agent or cell to affect another agent, cell process, or mechanism to induce an outcome.

[0113] The term “monoclonal antibody” as used herein refers to an antibody of a substantially homogeneous population of antibodies, that is, the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor numbers. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. Thus, a sample of monoclonal antibodies can bind to the same epitope on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particularmethod. For example, the monoclonal antibodies may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be made by recombinant DNA methods such as described in U. S. Pat. No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., Nature 348:552-554 (1990), for example.

[0114] The terms “polypeptide'’ and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (e.g., conservative substitutions), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site- directed mutagenesis, or may be accidental, such as through mutations of hosts, which produce the proteins or errors due to PCR amplification. Where generic reference is to a protein or gene from a certain species such as mouse, the analogue from human shall likewise be meant, if not stated otherwise or obviously incompatible.

[0115] The terms “polynucleotide”, “nucleic acid molecule”, and “nucleic acid” may be used interchangeably, and refer to a polymer of nucleotides. Such polymers of nucleotides may contain natural and / or non-natural nucleotides, and include, but are not limited to, DNA, RNA, and PNA. “Nucleotide sequence” refers to the linear sequence of nucleotides that comprise the polynucleotide.

[0116] The term “Regulatory T cells”, “Tregs”, “Treg cells”, or “suppressor T cells" used interchangeable herein describes a subpopulation of T cells that are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express CD4, FOXP3, and CD25 (IL-2 receptor α-chain). Human Foxp3+CD4+ T cells have been divided into three subfractions based upon the expression level of Foxp3 and the cell surface molecules CD25 and CD45RA. The Foxp3hiCD45RA-CD25hi and Foxp31oCD45RA+CD251o phenotypes correspond to immunosuppressive Treg cells, whereas the Foxp31oCD45RA-CD251o fraction marks activated T effector (Teff) cells without immunosuppressive activity. In addition, Treg cells from cancer patients, as compared to those in healthy subjects, are usually characterized by a distinct expression profile of chemokine receptors, such as CCR4, CXCR4, and CCR5, which facilitates their migration into tumors in response to the corresponding chemokine ligands derived from tumor microenvironment. See, e.g., Liu, et al., FEBS J283(14):2731-48, (2016) and Miyara, et al., Immunity 30, 899–911 (2009).

[0117] Under physiological conditions, Treg cells maintain immunological tolerance. During an immune response, Treg cells stop T cell-mediated immunity and suppress auto-reactive T cells that have escaped negative selection within die thymus. Treg cells can also suppress other types of immune cells such as NK cells and B cells. Adaptive Treg cells (called Th3 or Tri cells) are thought to be generated during an immune response.

[0118] Treg cells furthermore play an important role in immune escape by suppressing antitumor immunity, thereby providing an environment of immune tolerance. T cells that recognize cancer cells are often present in large numbers in tumors, but their cytotoxic function is suppressed by nearby immune-suppressor cells. Tregs are abundant in many different cancers, are highly enriched in the tumor microenvironment, and are well known for their role in tumor progression. Tregs that reside in diseased microenvironments, e.g., tumor microenvironments, are described further herein.

[0119] The term “specifically binds” as used herein in reference to an antigen or epitope describes an antibody or a binding polypeptide that reacts or associates more frequently, more rapidly, with greater selectivity, duration and / or with greater affinity with a particular antigen or epitope than it does with alternative antigens or epitopes. For example, an antibody that specifically binds to a certain CCR8 epitope (e.g., an intracellular C-terminal CCR8 epitope) is an antibody that binds this epitope with greater affinity, avidity, selectivity, more readily, and / or with greater duration than it binds to other CCR8 epitopes or non- CCR8 epitopes. It is also understood by reading this definition that, for example, an antibody (or antigen-binding fragment thereof) that specifically binds to a first target may or may not specifically bind to a second target. As such, “specific binding" docs not necessarily require (although it can include) exclusive binding.

[0120] The term “subject” as used herein to refers to an animal; for example, a mammal. In some embodiments, methods of treating mammals, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided. In some examples, a “subject” refers to an individual or subject in need of treatment for a disease or disorder. In some embodiments, the subject to receive the treatment can be a patient, designating the fact that the subject has been identified as having a disorder of relevance to the treatment, or being at adequate risk of contracting the disorder.

[0121] The term “threshold level” or “threshold number” refers generally to an assay cutoff value that is used to assess diagnostic / prognostic / therapeutic efficacy results by comparing the assay results against the predetermined cutoff value, already has been linked or associated with various clinical parameters (for example, severity of disease, progression / nonprogression / improvement, etc.). While the present disclosure may provide exemplary threshold levels and / or threshold numbers, it is well-known that cutoff values may vary depending on the nature of the immunoassay (for example, antibodies employed, etc.). It further is well within the skill of one of ordinary skill in the art to adapt the disclosure herein for other immunoassays to obtain immunoassay-specific threshold levels for those other immunoassays based on this disclosure. Whereas the precise value of the predetermined cutoff value may vary between assays, correlations as described herein (if any) may be generally applicable.

[0122] The term “treatment” as used herein is an approach for obtaining beneficial or desired clinical results. The term covers any administration or application of a therapeutic for disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (for example, metastasis, for example metastasis to the lung or to the lymphnode) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by “treatment” is a reduction of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of ail aspects of the disorder. Tn the context of cancer, the term “treating” includes any or all of: inhibiting growth of cancer cells, inhibiting replication of cancer cells, lessening of overall tumor burden and ameliorating one or more symptoms associated with the disease.

[0123] The term “tumor infiltrating”, “tumoral”, “intra-tumoral”, or “intratumoral” as used herein in the context of cells, structures, proteins, antibodies, or markers refers to their localization within the tumor tissue. Cells which are “positive” or “+” for a certain marker or protein are cells characterized by substantial expression of that marker or protein. Marker or protein expression can be determined and quantified as known in the art, e.g. to define different cell populations. For the characterization of (immune) cell populations, the marker expression can be determined by FACS or using any other technique described herein.

[0124] The term “tumor infiltrating Treg cells” and equivalents thereof as used herein refers to Tregs that express CCR8. Without being bound by theory, it is postulated that CCR8 is expressed with much higher prevalence and at higher levels on the surface of cancer-resident Tregs compared to circulating or normal tissue Tregs and conventional T effector (Teff) cells. Treg cell infiltration in solid tumors is associated with poor clinical outcome, and Tregs suppress the anti-cancer immune response through inhibition of Teff cell cytotoxicity.

[0125] The term “vector” as used herein describes a polynucleotide that can be engineered to contain a cloned polynucleotide or polynucleotides that can be propagated in a host cell. A vector can include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and / or enhancers) that regulate the expression of the polypeptide of interest, and / or one or more selectable marker genes (such as, for example, antibiotic resistance genes and genes that can be used in colorimetric assays, for example, β-galactosidase). In some instances, a vector provided herein is an expression vector which is used to express a polypeptide of interest in a host cell.Overview

[0126] The present disclosure provides anti-CCR8 binding agents (e.g., antibodies, fragments thereof, binding polypeptides, and any modified derivatives or variants of the same) that bind to CCR8, and in some embodiments, specifically to a CCR8 polypeptide, CCR8 polypeptide fragment, a CCR8 peptide or a CCR8 epitope comprised in CCR8. In some embodiments, a CCR8 binding agent (e.g., an antibody), such as a human CCR8 binding agent, can bind to CCR8 expressed on the surface of a mammalian (e.g., human) cell, including a CCR8 expressing cell. In some embodiments, described herein is a CCR8 binding agent (e.g., an antibody) that binds to CCR8, such as human CCR8 or portions thereof. In some embodiments,CCR8 is a human CCR8. In some embodiments, a CCR8 binding agent is a human CCR8 binding agent (e.g., an antibody that binds to human CCR8).

[0127] In some embodiments, a CCR8 binding agent (e.g., an antibody) binds a CCR8 epitope of a CCR8 expressing cell (e.g., a target CCR8 epitope). In some embodiments, a CCR8 binding agent (e.g., an antibody) selectively binds a CCR8 epitope of a CCR8 expressing cell over an epitope of any one or combinations of CCR1, CCR2, CC. R3, CCR4, CCR5, CCR6, CCR7, and / or CCR9 (e.g., a target CCR8 epitope).

[0128] CCR8 as described herein can be human CCR8 having an amino acid sequence as set forth in SEQ ID NO: 1 (UniProt Identifier P51685). However, CCR8 from any species corresponding to the species of any subject in compositions and methods described herein. For example, CCR8 as described herein can be mouse CCR8 (Mus musculus) having an amino acid sequence as set forth in SEQ ID NO: 2 (UniProt Identifier P56484); monkey CCR8 (Macaca mulatta) having an amino acid sequence as set forth in SEQ ID NO: 3 (UniProt Identifier 097665); or a rabbit CCR8 (Oryctolagus cuniculus) having an amino acid sequence as set forth in SEQ ID NO: 4 (Uniprot Identifier G1T2B2).

[0129] Specifically, CCR8 encompassed by the present disclosure has been shown to be selectively upregulated in tumor-resident regulatory T ceils ( Tregs or Treg cells) in multiple cancers (De Simone el al., Immunity, 45(5): 1135-1147 (2016); Plitas et al. Immunity. 45(5): 1122- 1134 (2016), and selectively expressed in tire majority of tumor-infiltrating Tregs (WO 2021 / 194942) which suppress the anti-cancer immune response through inhibition of immune cell cytotoxicity. It has also been found that CCR8 expression has the highest correlation with FOXP3 (master transcriptional regulator of Tregs) in most cancer types and is expressed on the most activated and suppressive subset of FOXP3hitumor Tregs (e.g., immunosuppressive CD4+FOXP3highTregs), and can be associated with poor clinical outcome (see e.g., Plitas et al. Immunity. 45(5):1122-1134 (2016); Wang et al., Nat Immunol. (9):1220-1230 (2019); WO 2021 / 194942). On the other hand. CCR8 is rarely observed on Tregs and effector T cells (Teffs or Teff cells) in the peripheral blood (WO 2021 / 194942); on FOXP3midand FOXP3negCD8 and CD4 effector T cells in patient tumors, or on tumor-infiltrating CD4+T cells and CD8+T cells (WO 2021 / 194942). Thus, CCR8 can be used as a target to selectively deplete tumor-resident CCR8+ Tregs.

[0130] A CCR8-related disease, disorder, or condition as encompassed by the present disclosure refers to refer to any disease, disorder or condition that is characterized by aberrant, upregulated, or selective expression of CCR8, and / or alternatively any disease, disorder, or condition in which it is desirable to deplete the expression of CCR8 and / or CCR8 expressing cells (e.g., Tregs). A CCR8-related disease includes a disease, disorder or condition that is characterized by or associated with immunosuppressive activity of Treg cells, in a diseased microenvironment, such as a tumor microenvironment. In some embodiments, a CCR8-related disease is one which is characterized by or associated with resistance to cancer treatments and / or decreased anti-tumor immunity. Thus, targeting a CCR8-related disease, disorder, or condition, such as diseased microenvironment characterized by CCR8 expression and / or CCR8 expressing cells (e.g., Tregs), would likely also ameliorate resistance to cancer treatments and / or anti-tumor immunity. In some embodiments the CCR8-related disease, disorder, or condition, is cancer. In someembodiments tlie cancer is a solid cancer. In some embodiments the solid cancer includes a microenvironment including tumor infiltrating lymphocytes (TILs). In some embodiments the TILs include Tregs. In some embodiments the Tregs in the tumor microenvironment are characterized by higher levels of CCR8 expression than peripheral Tregs. In some embodiments CCR8 expressing Tregs can be detected in an immunohistochemistry (IHC) assay format.

[0131] In some embodiments, anti-CCR8 binding agents providing herein bind, or specifically bind to a target CCR8 polypeptide, CCR8 polypeptide fragment, a CCR8 peptide or a CCR8 epitope comprised in CCR8. In some embodiments, anti-CCR8 binding agents providing herein specifically bind to a target CCR8 epitope. The target epitope may be continuous or non-continuous, and may be determined by a method known to a person of ordinary skill, including flow cytometry of bound antibody to peptides, hydrogen-deuterium exchange, alanine scanning, and / or x-ray crystallography. The target epitope can comprise or consist of amino acid residues that are determined by anti-CCR8 binding agent binding to CCR8 as described herein. The target epitope can be an epitope comprising or consisting of amino acid residues that are determined by epitope binning. The target epitope can be an epitope comprising or consisting of amino acid residues that arc determined by anti-CCR8 binding agent binding to CCR8 peptide-nanobody complexes. The target epitope can be an epitope comprising or consisting of amino acid residues that are determined by screening anti-CCR8 binding agent binding to CCR8 by phage display. The target epitope can be an epitope comprising or consisting of amino acid residues that are determined by in silico screening anti-CCR8 binding agent binding to CCR8 by computer learning models. The target epitope can be an epitope comprising or consisting of amino acid residues that are determined by anti-CCR8 binding agent binding to CCR8 in a non-competitive assay. The target epitope can be an epitope comprising or consisting of amino acid residues that are not in the extracellular domain and / or the binding of which by an anti-CCR8 binding agent will not sterically hinder the binding of an epitope in an extracellular domain by an antibody, as determined in an immunohistochemistry assay. The target epitope can be an epitope comprising or consisting of non-conserved amino acid residues as determined by multiple sequence alignment of CCR1-9.

[0132] The compositions and methods disclosed herein are based at least in part on the recognition that, with the emergence of therapeutic anti-CCR8 antibodies for the treatment of cancer, anti-CCR8 antibodies are desired to reliably and specifically detect and monitor CCR8 in a subject, such as in evaluating the safety and efficacy of therapeutic anti-CCR8 antibodies. The epitopes of several of the widely used research tool antibodies are not well defined, while others, such as the mouse monoclonal anti-CCR8 antibody generated by the hybridoma 433H (AB-1, WO200744756A2), appear to target extracellular epitopes of CCR8. Recent crystal structural characterization reveals very limited exposed extra- and intra-cellular regions that are available for antibody, ligand, or cofactor binding (see Sun et al., Nat Commun., 14:7940 (2023)), demonstrating the difficulty of generating antibodies that could reliably target and specifically bind a similarly small intracellular C-terminal epitope of CCR8. In addition, targeting of such a small intracellular C-terminal epitope of CCR8 can present challenges in avoiding cross-reactivities with other members of the chemokine receptor families.

[0133] Diagnostic anti-CCR8 antibodies useful for the monitoring of CCR8 expression and CCR8- targeted therapies (e.g.. therapeutic anti-CCR8 antibodies) preferably are insensitive to interference from tiie presence of such CCR8-targeted therapies in a sample. The identification of anti-CCR8 antibodies that can reliably detect and quantify CCR8 expression and CCR8 expressing cells (e.g, CCR8 expressing Tregs) in a tumor microenvironment using standard diagnostic assay formats (e.g., IHC) has proven difficult. Moreover, anti-CCR8 antibodies that do not suffer from the presence of certain therapeutic anti-CCR8 antibodies, such as denikitug, have proven even more difficult to find.

[0134] AB- 1 was previously identified as a candidate antibody with potential for companion diagnostics development. However, a subsequent molecular assessment of AB-1 disclosed herein revealed that this antibody does not meet the necessary criteria to support development of a commercially viable companion diagnostics assay. This disclosure provides anti-CCRS binding agents that have improved developability characteristics while retaining their ability to selectively detect CCR8 (e.g., in immunohistochemistry assay formats) (See Example 1).

[0135] In some embodiments, the target epitope is not an epitope present in any one of CCR1-7 or 9. In some embodiments, the target epitope is not an epitope present in CCR1. In some embodiments, the target epitope is not an epitope present in CCR2. In some embodiments, the target epitope is not an epitope present in CCR3. In some embodiments, the target epitope is not an epitope present in CCR4. In some embodiments, the target epitope is not an epitope present in CCR5. In some embodiments, the target epitope is not an epitope present in CCR6. In some embodiments, the target epitope is not an epitope present in CCR7. In some embodiments, the target epitope is not an epitope present in CCR9. In some embodiments, the target epitope does not comprise or consist of any one of the amino acid sequences set forth in TABLE 1.1. In some embodiments, the target epitope does not comprise or consist of an epitope of any one of the amino acid sequences set forth in TABLE 1.1.

[0136] In some embodiments, the target epitope comprises an amino acid sequence that is about 60% about 65% about 70% about 75% about 80% about 85% about 90% about 95%, about 97%, about 98%, about 99% identical or is identical to any one of the sequences set forth in TABLE 1. In some embodiments, the target epitope comprises an amino acid sequence that is 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, or 20 amino acids which are contiguous or non -contiguous and selected from any one of tire sequences set forth in TABLE 1.

[0137] Examples of anti-CCR8 binding agents are described in further detail herein.I. Anti-CCR8 binding agents

[0138] Provided herein are anti-CCR8 binding agents or uses thereof. An anti-CCR8 binding agent is a molecule comprising one or more antigen-binding moieties. An anti-CCR8 binding agent comprises an anti-CCR8 antibody, an antigen-binding fragment thereof, a binding polypeptide which targets the same, modified derivatives and / or variants thereof.

[0139] In some embodiments, anti-CCR8 binding agents provided herein can bind CCR8. Binding affinities for an anti-CCR8 binding agent provided herein to a target such as CCR8 can be determined by measuring, for example, the half maximal effective concentration (EC50) for binding to CCR8-expressing cell lines. EC50, expressed as a molar concentration (e.g., nM), is the concentration of the anti-CCR8 binding agent that achieves half of the maximal binding. In some embodiments, anti-CCR8 binding agents provided herein can bind CCR8, or bind cells expressing CCR8 with an EC50of about 1 nM or lower, about 0.9 nM or lower, about 0.8 nM or lower, about 0.7 nM or lower, about 0.6 nM or lower, about 0.5 nM or lower, about 0.4 nM or lower, about 0.3 nM or lower, about 0.2 nM or lower, about 0.1 nM or lower, about 0.09 nM or lower, about 0.08 nM or lower, about 0.07 nM or lower, about 0.06 nM or lower, about 0.05 nM or lower, about 0.04 nM or lower, about 0.03 nM or lower, about 0.02 nM or lower, about 0.01 nM or lower, about 0.009 nM or lower, about 0.008 nM or lower, about 0.007 nM or lower, about 0.006 nM or lower, about 0.005 nM or lower, about 0.004 nM or lower, about 0.003 nM or lower, about 0.002 nM or lower, or about 0.001 nM or lower. In some embodiments, anti-CCR8 binding agents provided herein can bind CCR8, or bind cells expressing CCR8 with an EC50of about 0.80 nM or lower, 0.70 nM or lower, 0.60 nM or lower, 0.50 nM or lower, 0.40 nM or lower, or about 0.30 nM or lower.

[0140] An anti-CCR8 binding agent may preferentially bind to CCR8, such as human CCR8, meaning that the antibody or fragment thereof binds CCR8 with greater affinity than it binds to an unrelated control protein and / or binds human CCR8 with greater affinity than it binds to an unrelated control protein. In some embodiments, the unrelated control protein is CCR1. In some embodiments, the unrelated control protein is CCR2. In some embodiments, the unrelated control protein is CCR3. In some embodiments, die unrelated control protein is CCR4. In some embodiments, the unrelated control protein is CCR5. In some embodiments, the unrelated control protein is CCR6. In some embodiments, the unrelated control protein is CCR7. In some embodiments, the unrelated control protein is CCR9.

[0141] For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof. In another example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over any one or combination of CCR1-7, and 9 or portion(s) thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR 1 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR2 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR3 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR4 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR5 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR6 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR7 or a portion thereof. For example, the antibody or fragment thereof may specifically recognize and bind CCR8 or a portion thereof over CCR9 or a portion thereof.

[0142] In another example, the antibody or fragment thereof may specifically recognize and bind an intracellular epitope of CCR8 over an extracellular epitope of CCR8. In another example, the antibody or fragment thereof may specifically recognize and bind C-terminal epitope of CCR8 over a N-terminal epitope of CCR8.

[0143] Binding affinities for an anti-CCR8 binding agent provided herein to a target such as CCR8 can be determined by measuring, for example, the dissociation constant (KD). KD as used herein has molar units (M) and corresponds to the concentration of the binding agent at which half of the target proteins are occupied at equilibrium. The smaller the dissociation constant is, the higher is the affinity between die binder or antibody and its target. In some embodiments, anti-CCR8 binding agents provided herein can specifically bind CCR8, or can specifically bind ceils expressing CCR8 with a KD of at least about 10-' M, at least about 10"8M, at least about IO"9M, at least about 10"10M, at least about 10’11M, or less. The KD values can be determined by means of surface plasmon resonance spectroscopy. Where assay conditions were found to influence the determined KD, the assay setup with the least standard deviation shall be used. In some embodiments, anti-CCR8 binding agents can specifically bind to CCR8 with an affinity that is at least 5, 10, 15, 20, 25, 50, 100, 250, 500, 1000, or 10,000 times greater than tire affinity for an unrelated control protein (e.g., hen egg white lysozyme). In some embodiments, the anti-CCR8 agent may bind CCR8 substantially exclusively (e.g., is able to distinguish CCR8 from other known polypeptides (e.g., CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, or any combination thereof), for example, by virtue of measurable differences in binding affinity). In some embodiments, a CCR8 binding agent (e.g., an antibody) may react with CCR8 sequences other than human CCR8 sequences (e.g., rabbit CCR8 sequences).

[0144] Binding specificity or selectivity can be determined by measuring, for example, a binding signal in an immunohistochemistry (IHC) assay. In some embodiments, a binding signal will be about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or about 10 times more than a background signal or noise. See. e.g., Fundamental Immunology 332-36 (Paul ed„ 2d ed. 1989) for a discussion regarding binding specificity.

[0145] In some embodiments, anti-CCR8 binding agents provided herein does not bind the same or essentially the same epitope as a reference anti-CCR8 binding agent. In some embodiments, anti-CCR8 binding agents provided herein do not recognize identical, overlapping or adjacent epitopes in a three- dimensional space as a reference anti-CCR8 binding agent. In other words, the anti-CCR8 binding agents provided herein do not compete with reference anti-CCR8 binding agents, such as a therapeutic anti-CCR8 agent described herein.

[0016] The most widely used and rapid methods for determining whether two binding agents bind to identical, overlapping or adjacent epitopes in a three-dimensional space are competition assays, which can be configured in a number of different formats, for example, using either labeled antigen or labeled antibody. In some assays, the antigen is immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent or enzyme labels. In other assays, fresh frozen tissue or formalin-fixed paraffin-embedded(FFPE) tissue known to express CCR8 is incubated with an anti-CCR8 binding agent provided herein and a reference anti-CCR8 binding agent, e.g., an antibody targeting an extracellular domain of CCR8, using staining buffers to determine if dual- binding has occurred where both colorimetric stains can be detected. Thus, another method to determine whether two binding agents bind to non-identical, non-overlapping or non-adjacent epitopes in a three-dimensional space are immunohistochemistry (IHC) assays. In some embodiments, a reference anti-CCR8 binding agent is a second anti-CCR8 binding agent as provided herein, including a therapeutic anti-CCR8 agent described herein.

[0147] Accordingly, in some embodiments, and as described in further detail herein, anti-CCR8 agents are useful in systems for detecting CCR8, related systems of diagnosing, and compositions, methods, kits and devices thereof. In some embodiments, systems, compositions, methods, kits and devices can further comprise a second anti-CCR8 agent. In some embodiments, second anti-CCR8 agents are therapeutic anti- CCR8 agents. Such second anti-CCR8 agents, systems, compositions, methods, kits and devices are further described herein.

[0148] In some embodiments, anti-CCR8 binding agents provided herein can bind immune effector cells or bind effector proteins (e.g., effector receptors on inmiune effector cells). Immune effector cells and / or effector proteins can be inherently existing in the immune system of the subject being administered an anti-CCR8 agent, or can be autologous or allogeneic.

[0149] In some embodiments, anti-CCR8 binding agents provided herein can cross-link immune effector cells or effector proteins and CCR8 expressing cells. In some embodiments, cell killing is induced by binding of an anti-CCR8 agent provided herein to a CCR8 expressing cell and to an immune effector cell and / or to an effector protein (e.g., cross-linking), which will then mediate the killing of the CCR8 expressing cell.

[0150] In some embodiments, anti-CCR8 binding agents provided herein can bind immune effector cells with an ECso of about 1 nM or lower, about 0.9 nM or lower, about 0.8 nM or lower, about 0.7 nM or lower, about 0.6 nM or lower, about 0.5 nM or lower, about 0.4 nM or lower, about 0.3 nM or lower, about 0.2 nM or lower, about 0.1 nM or lower, about 0.09 nM or lower, about 0.08 nM or lower, about 0.07 nM or lower, about 0.06 nM or lower, about 0.05 nM or lower, about 0.04 nM or lower, about 0.03 nM or lower, about 0.02 nM or lower, about 0.01 nM or lower, about 0.009 nM or lower, about 0.008 nM or lower, about 0.007 nM or lower, about 0.006 nM or lower, about 0.005 nM or lower, about 0.004 nM or lower, about 0.003 nM or lower, about 0.002 nM or lower, or about 0.001 nM or lower. In some embodiments, anti-CCR8 binding agents provided herein can bind CCR8, or bind cells expressing CCR8 with an EC50of about 0.80 nM or lower, 0.70 nM or lower, 0.60 nM or lower, 0.50 nM or lower, 0.40 nM or lower, or about 0.30 nM or lower, 0.20 nM or lower, 0.10 nM or lower, 0.09 nM or lower, 0.08 nM or lower, 0.07 nM or lower, 0.06 nM or lower, 0.05 nM or lower, 0.04 nM or lower, or 0.03 nM or lower. In some embodiments, anti-CCR8 binding agents provided herein can bind immune effector cells with an EC50of about 0.1 nM or lower, about 0.09 nM or lower, about 0.08 nM or lower, about 0.07 nM or lower, about 0.06 nM or lower, about 0.05 nM or lower, about 0.04 nM or lower, about 0.03 nM or lower, about 0.02 nM or lower, or about 0.01 nM or lower.

[0151] In some embodiments, the immune effector cell is a natural killer cell, macrophage, monocyte, or eosinophil and the effector receptor is the Fey receptor (FcyR or FCGR). In certain embodiments, upon cross-linking the immune effector cell and the CCR8 expressing ceil, the immune effector cell is induced to secrete substances that mediate cell death, such as lyase, perforin, granzyme, TNF. Therefore, in such embodiments, anti-CCR8 agents provided herein can induce ADCC activity.

[0152] In some embodiments, the immune effector cell is a monocyte, macrophage, neutrophil or a dendritic cell and the effector receptor is FcyRIIa, FcyRI, or FcyRIIla. In certain embodiments, upon crosslinking the immune effector cell and the CCR8 expressing cell, the immune effector cell is induced initiate phagocytosis. Therefore, in such embodiments, anti-CCR8 agents provided herein can induce ADCP activity.

[0153] In some embodiments, the immune effector cell is a monocyte, macrophage, neutrophil or a dendritic cell and the effector receptor is FcyRIIa, FcyRI, or FcyRIIla. In certain embodiments, upon cross¬ linking the immune effector cell and the CCR8 expressing cell, the immune effector cell is induced initiate phagocytosis. Therefore, in such embodiments, anti-CCR8 agents provided herein can induce ADCP activity.

[0154] In some embodiments, the effector protein is Clq. In certain embodiments, upon cross-linking the effector protein and the CCR8 expressing cell, tire immune effector cell is induced initiate the complement cascade, resulting in the formation of a membrane attack complex (MAC) and eliciting cell lysis. Therefore, in such embodiments, anti-CCR8 agents provided herein can induce CDC activity.

[0155] Accordingly, there are multiple mechanisms of action encompassed by the present disclosure to induce killing of cells in a diseased microenvironment, wherein any one or combination of mechanism of actions can be effected by the disclosure provided herein. A first mechanism of action comprises inducing antibody-dependent cellular cytotoxicity (ADCC). A second mechanism of action comprises inducing antibody-dependent cellular phagocytosis (ADCP). A third mechanism of action comprises inducing complement-dependent cytotoxicity (CDC). A fourth mechanism comprises delivering a therapeutic agent to the diseased microenvironment, such as targeting CCR8 with the anti-CCR8 binding agent in the form of an antibody drug conjugate. Further examples of each of the foregoing are further described herein.

[0156] In some embodiments, an anti-CCR8 agent provided herein can induce cell killing and therefore mediate depletion of CCR8 expression and / or depletion of the number of CCR8 expressing cells. In some embodiments, the anti-CCR8 agent can mediate depletion of CCR8 expression and / or CCR8 expressing cells by less than 5%, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or by more than 95% relative to the number of CCR8 expression or the number of CCR8 expressing cells relative to a baseline control.

[0157] In some embodiments, an anti-CCR8 agent provided herein can induce ADCC. In some embodiments, an anti-CCR8 agent provided herein can elicit lysis of CCR8 expressing cells in the presence of immune cells (e.g., NK effector cells) by inducing ADCC. In some embodiments, the ADCC induction results in the lysis of at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95% or 99% of the CCR8 expressing cells. In some embodiments, an anti-CCR8 agent provided herein can induce ADCC. In some embodiments, an anti-CCR8 agent provided herein exhibits enhanced ADCC activity relative to a control. In some embodiments, an anti-CCR8 agent provided herein exhibits a 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% enhanced ADCC activity relative to a control. In some embodiments, a control can be a WT control or a parental control.

[0158] In some embodiments, an anti-CCR8 agent provided herein can induce ADCP. In some embodiments, an anti-CCR8 agent provided herein can elicit phagocytosis of CCR8 expressing cells in die presence of immune cells (e.g., macrophages) by inducing ADCP. in some embodiments, the ADCP induction results in die phagocytosis of at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the CCR8 expressing cells.

[0159] In some embodiments, an anti-CCR8 agent provided herein can induce CDC. In some embodiments, an anti-CCR8 agent provided herein can elicit formation of a membrane attack complex and lysis of CCR8 expressing cells in the presence of effector proteins (e.g., Clq) by inducing CDC. In some embodiments, the CDC induction results in the lysis of at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the CCR8 expressing cells.

[0160] In some embodiments, assays, systems, and devices arc provided herein for identifying anti-CCR8 binding agents having one or more biological activity as described herein. Biological activity may include, e.g., antibody -dependent cellular cytotoxicity (ADCC), ADCC against Tregs, antibody-dependent cellular phagocytosis (ADCP), ADCP depletion of Tregs, complement dependent cytotoxicity (CDC), and / or CDC depletion of Tregs. Anti-CCR8 binding agents having such biological activity in vivo and / or in vitro are also provided.

[0161] In some embodiments, cytotoxicity assays, systems, and devices are provided herein to confirm die reduction / depletion induced by ADCP, CDC and / or ADCC activities. Such cytotoxicity assays, systems, and devices can be in vitro and / or in vivo. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression 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 is 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); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med.166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non -rad ioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, Calif.; and CytoTox 96© non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656(1998). Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See. e.g., Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al.,.1. Immunol. Methods 202:163 (1996); Cragg, M. S. et al., Blood 101: 1045- 1052 (2003); and Cragg, M. S. and M. J. 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, e.g., Petkova, S. B. et al., Int'l. Immunol. 18(12): 1759- 1769 (2006); WO 2013 / 120929 Al).

[0162] In some embodiments, the CCR8 expressing cell is an immunosuppressive Tree cell. In some embodiments, the CCR8 expressing cell is tumor resident Treg cell. In some embodiments, the CCR8 expressing cell is tumor infiltrating Treg cell. In some embodiments, the CCR8 expressing cell is a FOXP3hiTreg cell. In some embodiments, the CCR8 expressing cell is a CD4+FOXP3hlTreg cell. In some embodiments, the CCR8 expressing cell is a tumor infiltrating CD4+FOXP3hlTreg cell. In some embodiments, the CCR8 expressing cell is not a peripheral Treg cell, a peripheral Teff cell, a FOXP3midCD8+Teff cell, a FOXP3midCD4+Teff cell, FOXP3negCD8+Teff cell, a FOXP3negCD4+Teff cell, a tumor-infiltrating CD4+T cell, a tumor-infiltrating CD8+T cell, or any combination diereof.

[0163] In some embodiments, the anti-CCR8 agent can mediate depletion of CCR8 expression and / or depletion of the number of CCR8 expressing cells in a diseased microenvironment. Accordingly, in some embodiments, the anti-CCR8 agents provided herein can mediate activity in a diseased microenvironment. In some embodiments, a diseased microenvironment is a microenvironment associated with CCR8 expression, including aberrant, upregulated, and / or selective CCR8 expression. In certain embodiments, CCR8 expression is upregulated and / or selectively expressed on immunosuppressive Treg cells, tumor resident Treg cells, tumor infiltrating Treg cells, FOXP3hiTreg cells, CD4’FOXP3hiTreg cell, tumor infiltrating CD4+FOXP3fl1Treg cells, or any combination thereof. Accordingly, in some embodiments, a diseased microenvironment provided herein is one that is characterized with CCR8 expression on immunosuppressive Treg cells, tumor resident Treg cells, tumor infiltrating Treg cells, FOXP3hiTreg cells, CD4+FOXP3hiTreg cell, tumor infiltrating CD4+FOXP3hiTreg cells, or any combination thereof.

[0164] In some embodiments, mediating activity in a diseased microenvironment comprises mediating the increase of an immune cell population, and specifically an immune effector cell population. In some embodiments, anti-CCR8 agent provided herein can mediate the increase of immune effector cell population by about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, or more relative to a baseline control. In some embodiments, the immune effector cell population comprise CD45+cells (e.g., intra-tumoral CD45+cells), CD8+T cells (e.g., intra-tumoral CD8+T cells), CD4+T cells (e.g., intra-tumoral CD4+T cells), macrophages, such as Ml macrophages or M2 macrophages, (e.g., intra-tumoral macrophages, intratumoral Ml macrophages, intratumoral M2 macrophages), NK cells (e.g., intra-tumoral NK cells), B cells, (e.g., intra-tumoral B cells), Dendritic cells (e.g., intra-tumoral Dendritic cells), Gamma delta T cells(e.g., intra-tumoral Gamma delta T cells), iNKT cells (e.g., intra-tumoral iNKT cells), or any combination thereof,

[0165] In some embodiments, the CCR8 binding agents (e.g., antibodies) described herein compete for the binding to CCR8, such as human CCR8, with a CCR8 binding agent (e.g., an antibody) that comprises a VH region, VL region, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 of any one of the antibodies described herein, such as an amino acid sequence of a VH region, VL region, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 depicted in TABLES 2-4. Accordingly, in some embodiments, a CCR8 binding agent (e.g., an antibody) described herein competes for the binding to CCR8, such as human CCR8, with a CCR8 binding agent (e.g., an antibody) that comprises one, two, and / or three VH CDRs and / or one, two, and / or three VL CDRs from the antibody designated AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB- 19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31 as shown in TABLE 3. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein competes for the binding to CCR8, such as human CCR8, with a CCR8 binding agent (e.g., an antibody) that comprises one, two, and / or three VH CDRs and one, two, and / or three VL CDRs from the antibody designated AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31 TABLE 3. In some embodiments, a CCR8 binding agent (e.g., an antibody ) described herein competes for tire binding to CCR8, such as human CCR8, with a CCR8 binding agent (e.g., an antibody) that comprises a VH region and VL region from the antibody designated AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31 as shown in TABLE 4. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three VH CDRs and / or one, two, and / or three VL CDRs that are different from the antibody designated AB-1. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises a VH region and / or a VL region that is different from the antibody designated AB-1.

[0166] In some embodiments, the CCR8 binding agents (e.g., antibodies) described herein comprise a VH region, VL region, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 of any one of the antibodies described herein, such as an amino acid sequence of a VH region, VL region, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 depicted in TABLES 2-4. Accordingly, in some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three heavy chain CDRs and / or one, two, and / or three light chain CDRs from the antibody designated AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31, as shown in TABLE 3. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three heavy chain CDRs and one, two, and / or three light chain CDRs from the antibody designated AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13,AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31, as shown in TABLE 3, In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three heavy chain CDRs and / or one, two, and / or three light chain CDRs that are different from the antibody designated AB-1 in TABLE 3. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three heavy chain CDRs and one, two, and / or three light chain CDRs that are different from the antibody designated AB-1 in TABLE 3.

[0167] In some embodiments, an anti-CCR8 binding agent comprises a heavy chain variable region and a light chain variable region. In some embodiments, an anti-CCR8 binding agent comprises at least one heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, an anti-CCR8 binding agent comprises two heavy chains, wherein each heavy chain comprises a heavy chain variable region and at least a portion of a heavy chain constant region, and two light chains, wherein each light chain comprises a light chain variable region and at least a portion of a light chain constant region. As used herein, a single-chain Fv (scFv), or any other binding agent (e.g., antibody) that comprises, for example, a single polypeptide chain comprising all six CDRs (three heavy chain CDRs and three light chain CDRs) is considered to have a heavy chain and a light chain. In some embodiments, the heavy chain is the region of the anti-CCR8 binding agent that comprises the three heavy chain CDRs. In some embodiments, the light chain is the region of the anti-CCR8 binding agent that comprises the three light chain CDRs.

[0168] Accordingly, in some embodiments, a CCR8 binding agent (e.g., an antibody) comprises a VH region, which comprises HCDR1, HCDR2, and / or HCDR3, and a VL region, which comprises LCDR1, LCDR2, and / or LCDR3, of any one of the binding agents described herein (see, e.g., TABLE 2 and TABLE 3). Accordingly, in some embodiments, a CCR8 binding agent (e.g., an antibody) described herein comprises one, two, and / or three heavy chain CDRs (e.g., HCDR1, HCDR2, and HCDR3) and / or one, two, and / or three light chain CDRs (e.g., LCDR 1, LCDR2, and LCDR3) from TABLE 2. In some embodiments, a CCR8 binding agent described herein comprises one, two, and / or three heavy chain CDRs (e.g., HCDR1, HCDR2, and HCDR3) and / or one, two, and / or three light chain CDRs (e.g., LCDR 1, LCDR2, and LCDR3) from TABLE 3. In some embodiments, a CCR8 binding agent (e.g., an antibody) described herein is multispecific (e.g., bispecific) and comprises a first binding domain that comprises one, two, and / or three heavy chain CDRs (e.g., HCDR1, HCDR2, and HCDR3) and / or one, two, and / or three light chain CDRs (e.g., LCDR1, LCDR2, and LCDR3) from TABLE 2 or TABLE 3 and a second binding domain that comprises one, two, and / or three heavy chain CDRs (e.g., HCDR1, HCDR2, and HCDR3) and / or one, two, and / or three light chain CDRs (e.g., LCDR1, LCDR2, and LCDR3) from a binding agent that binds to a second target antigen that is not CCR8.

[0169] In some embodiments, die CDRs disclosed herein include consensus sequences derived from groups of related antibodies (see, TABLE 2). A consensus sequence refers to amino acid sequences having conserved amino acids common among a number of sequences and variable amino acids that vary witliina given amino acid sequences. The CDR consensus sequences provided include CDRs corresponding to CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3. Consensus sequences of CDRs of CCR8 binding agents (e.g., Abs 1-31) are shown in TABLE 2. Unless explicitly indicated otherwise, consensus CDRs in the present disclosure have been identified by the Rabat numbering scheme.

[0170] Accordingly, in some embodiments, an anti-CCR8 binding agent comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 214; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

[0171] In some embodiments, an antibody provided herein comprises or consists of six CDRs, for example, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 identified in TABLE 3. In some embodiments, an antibody provided herein can comprise less than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 identified in TABLE 3. In some embodiments, an antibody described herein comprises or consist of one, two, and / or three heavy chain CDRs and / or one, two, and / or three light chain CDRs from tire antibody designated AB-2, AB-3, AB-4, AB-5. AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, or AB-31, as shown in TABLE 3. Accordingly, in some embodiments, the antibody comprises or consists of one, two, three four or five CDRs of anyone of the HCDR1, HCDR2, HCDR3, LCDR 1, LCDR2, and / or LCDR3 identified in TABLE 3. In some embodiments, an antibody described herein comprises or consists of six CDRs, wherein one, two, three, four, or five CDRs are different from the antibody designated AB-1 identified in TABLE 3.

[0172] In some embodiments, an anti-CCR8 binding agent comprises at least one, two, three, four, five, or six CDRs selected from (a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; (c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, or 69; (d); an LCDR 1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89, and (f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0173] In some embodiments, the anti-CCR8 binding agent does not comprises six CDRs that include (a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 35; (c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36; (d); an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37; (e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and / or (f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the CCR8 binding agent comprises one, two, and / or three heavychain CDRs and one, two, and / or three light chain CDRs that are different from the antibody designated AB-1 in TABLE 3.

[0174] In some embodiments, the anti-CCR8 binding agent comprises six CDRs including (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 214; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

[0175] In some embodiments, the antibodies provided herein comprise one or more (e.g., one, two or three) VH CDRs listed in TABLE 3. In other embodiments, tire antibodies provided herein comprise one or more (e.g., one, two or three) VL CDRs listed in TABLE 3. hi yet other embodiments, die antibodies provided herein comprise one or more (e.g., one, two or three) VH CDRs listed in TABLE 3 and one or more VL CDRs listed in TABLE 3. Accordingly, in certain embodiments, the antibodies comprise a HCDR 1 having the amino acid sequence of any one of SEQ ID NO: 34. In another embodiment, the antibodies comprise a HCDR2 having the amino acid sequence of any one of SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61. In another embodiment, the antibodies comprise a HCDR3 having the amino acid sequence of any one of SEQ ID NOS: 36, 68, or 69. In certain embodiments, the antibodies comprise a HCDR1 and / or a HCDR2 and / or a HCDR3 independently selected from a HCDR1, HCDR2, HCDR3 as depicted in any one of the amino acid sequences depicted in TABLE 3. In certain embodiments, the antibodies comprise a LCDR1 having die amino acid sequence of any one of SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241. In another embodiment, the antibodies comprise a LCDR2 having the amino acid sequence of any one of SEQ ID NOS: 38 or 89. In another embodiment, the antibodies comprise a LCDR3 having the amino acid sequence of any one of SEQ ID NO: 39. In certain embodiments, tire antibodies comprise a LCDR1 and / or a LCDR2 and / or a LCDR3 independently selected from a LCDR1, LCDR2, LCDR3 as depicted in any one of the amino acid sequences depicted in TABLE 3.

[0176] Also provided herein are antibodies comprising one or more (e.g., one, two or three) VH CDRs and one or more (e.g., one, two or three) VL CDRs listed in TABLE 3. In particular, provided herein is an antibody comprising: a HCDR1 (SEQ ID NO: 34) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241); a HCDR1 (SEQ ID NO: 34) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR1 (SEQ ID NO: 34) and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR3 (SEQ ID NO: 39); a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241); a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR3 (SEQ ID NO: 39); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61) and a LCDR3 (SEQ ID NO: 39);a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQID NOS: 36, 68, or 69) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR3 (SEQ ID NO: 39); a HCDRI (SEQ ID NO: 34), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR1 (SEQ ID NO: 34), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDRI (SEQ ID NO: 34), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR1 (SEQ ID NOS: 37, 82. 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69) and a LCDR3 (SEQ ID NO: 39); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR1 (SEQ ID NO: 34), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR 1 (SEQ ID NO: 34), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDRI (SEQ ID NO: 34), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDRI (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR2 (SEQ ID NOS: 38 or 89); a HCDRI (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDRI (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241) and a LCDR3 (SEQ ID NO: 39); aHCDR1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR2 (SEQ ID NOS: 38 or 89) and a LCDR3 (SEQ ID NO: 39); a HCDR 1 (SEQ ID NO: 34), a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a LCDR1 (SEQ ID NOS: 37. 82, 83, 84, 85, 240, or 241), a LCDR2 (SEQ ID NOS: 38 or 89), and a LCDR3 (SEQ ID NO: 39): a HCDR1 (SEQ ID NO: 34), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241), a LCDR2 (SEQ ID NOS: 38 or 89), and a LCDR3 (SEQ ID NO: 39); a HCDR2 (SEQ ID NOS: 35, 56, 57, 58, 59, 60 or 61), a HCDR3 (SEQ ID NOS: 36, 68, or 69), a LCDR1 (SEQ ID NOS: 37, 82, 83, 84, 85, 240, or 241), a LCDR2 (SEQ ID NOS: 38 or 89), and a LCDR3 (SEQ ID NO: 39); or any combination thereof of the VH CDRs (SEQ ID NO: 34-36, 56-61, or 68-69) and VL CDRs (SEQ ID NOS: 37-39, 82- 85, or 89) listed in TABLE 3.

[0177] In some embodiments, the anti-CCR8 binding agent comprises six CDRs including (a) an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) an IICDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; (c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, Or 69; (d); an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (c) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89, and (f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0178] In some embodiments, the anti-CCR8 binding agent comprises an HCDR1 comprising die amino acid sequence of SEQ ID NO; 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising die amino acid sequence of SEQ ID NO: 56, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 82, an LCDR2 comprising tire amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising die amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 83, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR 1 comprising the amino acid sequence of SEQ ID NO: 84, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 58, anIICDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 59, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising die amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising die amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising tire amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR 1 comprising die amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising die amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and anLCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 35, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an IICDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR 1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising tire amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an IICDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an L. CDR2 comprising the amino acid sequence of Si Q ID NO: 38, and an LCDR3 comprising the amino add sequence of SEQ ID NO: 39; an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an IICDR3 comprising die amino add sequence of SEQ ID NO: 68, an LCDR1 comprising tire amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising die amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising die amino acid sequence of SEQ ID NO: 68, an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino add sequence of SEQ ID NO: 391; an HCDR1 comprising die amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 61, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR 1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino add sequence of SEQ ID NO: 57, anHCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising die amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising die amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising die amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an IICDR2 comprising die amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising die amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39,

[0179] In some embodiments, any of die six CDRs provided herein can be combined as subparts with any of the other CDRs provided herein, for a total of six CDRs in a construct. Thus, in some embodiments, two CDRs from a first antibody (for example, HCDR1 and HCDR2) can be combined with four CDRs from a second antibody (IICDR3, LCDR1, LCDR2, and LCDR3). In some embodiments, two or fewer amino acid residues in one or more of the CDRs can be modified to obtain a variant or derivative thereof. In some embodiments, two or fewer amino acid residues can be modified in 1, 2, 3, 4, 5, or 6 of the CDRs.

[0180] In some embodiments, the CDRs of anti-CCR8 binding agents including a human CCR8 binding agent, can be determined according to any suitable numbering system. Examples of numbering systems used herein are Kabat, IMGT, Honegger, and Chothia, however, a person of ordinary skill in tlie art would readily understand that the position of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) region of a CCR8 binding agent (e.g., an antibody), including a human CCR8 binding agent, described herein may vary by one, two, three, four, five, or six amino acid positions so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). For example, in some embodiments, the position defining a CDR as described in TABLE 3 may vary by shifting the N-terminal and / or C-terminal boundary of the CDR by one, two, three, four, five, or six amino acids, relative to the current CDR position, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In other embodiments, the length of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) region of a CCR8 binding agent (e.g., an antibody), including a human CCR8 binding agent, described herein may vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). For example, in some embodiments, a VH and / or VL CDR1, CDR2, and / or C. DR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 95% ). In other embodiments, a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In other embodiments, the amino terminus of a VH and / or VI, CDR1, CDR2, and / or CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In other embodiments, the carboxy terminus of a VII and / or VL CDR1, CDR2, and / or CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of tire CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In other embodi ents, the amino terminus of a VII and / or VL CDR1, CDR2, and / or CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, the carboxy terminus of a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by any one of the sequences set forth in TABLES 2 and 3, so long as binding to CCR8 (e.g., human CCR8) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). Any method known in the art can be used to ascertain whether binding to CCR8 (e.g., human CCR8) is maintained, for example, tire binding assays and conditions described in the “Examples” section described herein.

[0181] In some embodiments, CCR8 binding agents (e.g., antibodies), including human CCR8 binding agents, described herein comprise a VH region or VH domain. In other embodiments, CCR8 binding agents (e.g., antibodies), including human CCR8 binding agents, described herein comprise a VL region or VL domain. In some embodiments, CCR8 binding agents (e.g., antibodies), including human CCR8 binding agents, described herein have a combination of (i) a VH domain or VH region; and / or (ii) a VL domain or VL region.

[0182] In certain embodiments, the anti-CCR8 binding agent comprises a VH region that comprises: (1) a VH FR1 having the sequence in SEQ ID NO:222; (2) a VH FR2 having the sequence in SEQ ID NO:223; (3) a VH FR3 having the sequence in SEQ ID NO:224; and / or (4) a VH FR4 having an amino acid selected from SEQ ID NO: 225. Accordingly, in some aspects, the anti-CCR8 binding agent comprises a VII region that includes a VII FR1 having the sequence in SEQ ID NO:222. In some aspects, the anti-CCR8 binding agent comprises a VH region that includes a VH FR2 having the sequence in SEQ ID NO:223. In some aspects, the anti-CCR8 binding agent comprises a VII region that includes a VII FR3having the sequence in SEQ ID NO:224. In some aspects, the anti-CCR8 binding agent comprises a VII region that includes a VH FR4 having an amino acid selected from SEQ ID NO: 225. In some embodiments, such an anti-CCRS binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 214: (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215: and / or (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216. In some embodiments, the OCRS binding agent comprises one, two, and / or three heavy chain CDRs that are different from the antibody designated AB-1 in TABLE 3. In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; and / or (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, or 69.

[0183] In some embodiments, an anti-CCR8 binding agent comprises a heavy chain variable domain (VII) 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: 220. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains amino acid modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 220. In some embodiments, modifications, e.g., substitutions, insertions, or deletions, occur in regions outside the CDRs (that is, in tlie FRs). In some embodiments, the anti-CCR8 binding agent comprises a heavy chain comprising a framework 1 (VH FR1), a framework 2 (VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VII FR4) sequence of SEQ ID NO: 220, with boundaries depicted by the CDRs as determined by Rabat numbering scheme. Exemplary heavy chain VH FR1, VH FR2, VH FR3 and VH FR4 sequences are depicted in FIGS. 1A-1B, with boundaries depicted by tlie CDRs as determined by Kabat numbering scheme. In some embodiments, the anti-CCR8 binding agent comprises a heavy chain comprising a VH FR1, VH FR2, VH FR3 and / or VH FR4 sequence comprising any one or more of the amino acid substitutions in the corresponding VH FR1, VH FR2, VH FR3 and / or VH FR4 sequence of SEQ ID NO: 220, with boundaries depicted by the CDRs as determined by Kabat numbering scheme. In some embodiments, the anti-CCR8 binding agent comprises a heavy chain comprising a VH FR1 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 226, a VH FR2 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 227, a VH FR3 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 228 and / or VH FR4 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 225. Optionally, the anti-CCR binding agent comprises tlie VII sequence in SEQ ID NO: 220, including post-translational modifications of that sequence. In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising tlie amino acid sequence of SEQ ID NO: 214; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215; and / or (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216.

[0184] In some embodiments, an anti-CCR8 binding agent 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: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains amino acid modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150. In some embodiments, modifications, e.g., substitutions, insertions, or deletions, occur in regions outside the CDRs (drat is, in die FRs). In some embodiments, the anti-CCR8 agent comprises a heavy chain comprising a VH FR1, VH FR2, VH FR3 and / or VH FR4 sequence in SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138. 140, 142, 144, 146, 148 or 150. Optionally, the anti- CCR8 binding agent comprises the VII sequence in SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150, including post-translational modifications of that sequence. In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising die amino acid sequence of SEQ ID NO: 34; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; and / or (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, or 69.

[0185] In certain embodiments, the anti-CCR8 binding agent comprises a VL region that comprises: (1) a VL FR1 having the sequence in SEQ ID NO:226; (2) a VL FR2 having the sequence in SEQ ID NO:227; (3) a VL FR3 having the sequence in SEQ ID NO:228; and / or (4) a VL FR4 having an amino acid selected from SEQ ID NO: 229. Accordingly, in some aspects, the anti-CCR8 binding agent comprises a VL region that includes a VL FR1 having the sequence in SEQ ID NO:226. In some aspects, the anti-CCR8 binding agent comprises a VL region that includes a VL FR2 having die sequence in SEQ ID NO:227. In some aspects, the anti-CCR8 binding agent comprises a VL region that includes a VL FR3 having the sequence in SEQ ID NO:228. In some aspects, the anti-CCR8 binding agent comprises a VL region that includes a VL FR4 having an amino acid selected from SEQ ID NO: 229. In some embodiments, such an anti-CCR8 binding agent comprises (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and / or (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the CCR8 binding agent comprises one, two, and / or three light chain CDRs that are different from the antibody designated AB-1 in TABLE 3. In some embodiments, such an anti-CCR8 binding agent comprises (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89 and / or (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0186] In some embodiments, an anti-CCR8 binding agent is provided, wherein die antibody comprises a light chain variable domain (VL) 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: 221. In some embodiments, a VL sequence having at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains amino acid modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 221. In some embodiments, the modifications, e.g., substitutions, insertions, or deletions, occur in regions outside the CDRs (that is, in die FRs). In some embodiments, die anti-CCR8 binding agent comprises a light chain comprising a framework 1 (VI. FR1), a framework 2 (VL FR2), a framework 3 (VL. FR4) sequence of SEQ ID NO: 221 with boundaries depicted by the CDRs as determined by Kabat numbering scheme. Exemplary light chain VL. FR1, VL FR2, VL. FR3 and VI. FR4 sequences are depicted in FIGS, 2A-2B, with boundaries depicted by the CDRs as determined by Kabat numbering scheme. In some embodiments, die anti-CCR8 binding agent comprises a light chain comprising a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence comprising any one or more of the amino acid substitutions in the corresponding VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence of SEQ ID NO: 221, with boundaries depicted by the CDRs as determined by Kabat numbering scheme. In some embodiments, the anti-CCR8 binding agent comprises a light chain comprising a VL FR1 sequence comprising one or more of die amino acid substitutions in SEQ ID NO: 222, a VL FR2 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 223, a VL FR3 sequence comprising one or more of the amino acid substitutions in SEQ ID NO: 224 and / or VL FR4 sequence comprising one or more of die amino acid substitutions in SEQ ID NO: 225. Optionally, the anti-CCR8 binding agent comprises the VL sequence in SEQ ID NO: 221, including post-translational modifications of that sequence. In some embodiments, such an anti-CCR8 binding agent comprises (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and / or (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

[0187] In some embodiments, an anti-CCRS binding agent is provided, wherein the antibody comprises a light chain variable domain (VL) 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: 93, 5, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments, a VL sequence having at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains amino acid modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. hi some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In someembodiments, the modifications, e.g., substitutions, insertions, or deletions, occur in regions outside the CDRs (that is, in the FRs). In some embodiments, the anti-CCR8 agent comprises a light chain comprising a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. Optionally, the anti-CCR8 binding agent comprises the VL sequence in SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151, including post-translational modifications of that sequence. In some embodiments, such an anti-CCR8 binding agent comprises (d) LCDR1 comprising tire amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89 and / or (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0188] In some embodiments, a VH as provided herein can be combined as a subpart of an anti-CCR8 binding agent with any of one VL provided herein, for a total of one VII and one VL in a subpart of a construct, and 2 VHs and 2 VLs in a construct. Thus, in some embodiments, a VH from a first antibody can be combined v.ilh a VL from a second antibody.

[0189] In certain embodiments, the anti-CCR8 binding agent comprises a VH region and a VL region, wherein the VII region further comprises: (1) a VII FR1 having the sequence in SEQ ID NO:222; (2) a VII FR2 having the sequence in SEQ ID NO:223; (3) a VH FR3 having the sequence in SEQ ID NO:224; and / or (4) a VH FR4 having an amino acid sequence of SEQ ID NO: 225; and wherein the VI. region further comprises: (1) a VL FR1 having die sequence in SEQ ID NO:226; (2) a VL FR2 having the sequence in SEQ ID NO:227; (3) a VL FR3 having the sequence in SEQ ID NO:228; and / or (4) a VL FR4 having an amino acid selected from SEQ ID NO: 229. In some embodiments, the anti-CCR8 binding agent comprises: a VH FR1 (SEQ ID NO:222) and a VL FR1 (SEQ ID NO:226); a VH FR1 (SEQ ID NO:222) and a VL FR2 (SEQ ID NO:227); a VH FR1 (SEQ ID NO:222) and a VL FR3 (SEQ ID NO:228); a VH FR1 (SEQ ID NO:222) and a VL FR4 (SEQ ID NO:229); a VII FR2 (SEQ ID NO:223) and a VL FR1 (SEQ ID NO:226); a VH FR2 (SEQ ID NO:223) and a VL FR2 (SEQ ID NO:227); a VH ER2 (SEQ ID NO:223) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224) and a VL FR1 (SEQ ID NO:226); a VH FR3 (SEQ ID NO:224) and a VL FR2 (SEQ ID NO:227); a VH FR3 (SEQ ID NO:224) and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224) and a VL FR4 (SEQ ID NO:229); a VH FR4 (SEQ ID NO:225) and a VL FR1 (SEQ ID NO:226); a VH FR4 (SEQ ID NO:225) and a VL FR2 (SEQ ID NO:227); a VH FR4 (SEQ ID NO:225) and a VL FR3 (SEQ ID NO:228); a VH FR4 (SEQ ID NO:225) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223) and a VL FR1 (SEQ ID NO:226); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223) and a VL FR2 (SEQ ID NO:227); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223) and a VL FR3 (SEQ ID NO:228); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FR1 (SEQ ID NO:226); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FR2 (SEQ ID NO:227); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VI. FR3 (SEQ ID NO:228); a VII FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FR4 (SEQID NO:229); a VII FR1 (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FR1 (SEQ ID NO:222). a VE FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FR1 (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226) find a VL FR4 (SEQ ID NO:229); a VII FR1 (SEQ ID NO:222), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VII FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO: 227) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VII FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VII FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VII FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VII FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VII FRI (SEQ ID NO:222). a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FRI (SEQ ID NO:226); a VH FRI (SEQ ID NO:222), a VII FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FR2 (SEQ ID NO:227); a VH F I (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225) and a VL FRI (SEQ ID NO:226); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222). a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FRI (SEQ ID NO:226); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR3 (SEQ ID NO:228); a VH FR1 (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223). a VH FR3 (SEQ ID NC):224), a VH FR4 (SEQ ID NO:225) and a VL FRI (SEQ ID NO:226); a VH FR2 (SEQ ID NO:223\ a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR2 (SEQ ID NO:227); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR4 (SEQ ID NO:229); a VII FRI (SEQ ID NO:222), a VII FR2 (SEQ ID NO:223), a VL FRI (SEQ IDNO:226) and a VL FR2 (SEQ ID NO:227); a VII FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR1 (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR1 (SEQ ID NO:226) find a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227): a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VII FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:2.25), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VII FR2 (SEQ ID NO:223), a VII FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VII FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VII FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227.) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VI. FR2 (SEQ ID NC):227) and a VI. FR3 (SEQ ID NO: 228); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VII FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH F 1 (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FRI (SEQ ID NO:222), a VH FR4(SEQ ID NO:225), a VL FR3 (SEQ ID NO:228) arid a VL FR4 (SEQ ID NO:229); a VII FR2 (SI iQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FR1 (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR! (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FR2 (SEQ ID NO:223), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VII FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VII FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VII FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO: 229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223). a VH FR3 (SEQ ID NO:224). a VH FR4 (SEQ ID NO:225) and a VL FRI (SEQ ID NO:226); a VH FR 1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223). a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225 ) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222L a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VI. FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NC):223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VII FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224), a VL FR3 (SEQ IDNO:228) and a VL FR4 (SEQ ID NO:229); a VII FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FR2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH F 2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VII F 2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL F (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO: 226). a VL FR2 (SEQ ID NO:227), and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222}, a VH FR2 (SEQ ID NO:223), a VL F I (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227). and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228). and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FR1 (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FR2(SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR4 (SEQ ID NO: 229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR3 (SEQ ID NO:228); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VL FR1 (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227). a VL FR3 (SEQ ID NO:228), and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FRI (SEQ ID NO:226) and a VL FR2 (SEQ ID NO:227); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FRI (SEQ ID NO:226) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223 ), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FRI (SEQ ID NO:226) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FR3 (SEQ ID NO: 228) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL. FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), VL FR3 (SEQ ID NO:228) and a VL FR4(SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VII FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO: 227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NC ):229); a VH FR1 (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VII FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO: 227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VII FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL. FR3 (SEQ ID NO:228); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO: 224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229): a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VI. FR3 (SEQ ID NC):228) and a VI. FR4 (SEQ ID NO:229); a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), a VL FRI (SEQ ID NO:226), a VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FRI (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR3 (SEQ ID NO:228); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FRI (SEQ ID NO:226), VL FR2 (SEQ ID NO:227) and a VL FR4 (SEQ ID NO:229); a VH FRI (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223),a VH FR3 (SEQ ID NO:224), a VH FR4 (SEQ ID NO:225), VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229): a VH FR 1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO:224), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); a VH FR1 (SEQ ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229); or a VH FR I (SF. Q ID NO:222), a VH FR2 (SEQ ID NO:223), a VH FR3 (SEQ ID NO: 224), a VH FR4 (SEQ ID NO:225), a VL FR1 (SEQ ID NO:226), VL FR2 (SEQ ID NO:227), VL FR3 (SEQ ID NO:228) and a VL FR4 (SEQ ID NO:229). In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 214; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216; (d) LCDR I comprising the amino acid sequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the CCR8 binding agent comprises one, two, and / or three heavy chain CDRs and one, two, and / or three light chain CDRs that are different from the antibody designated AB-1 in TABLE 3. In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, or 69; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89; and (f) LCDR3 comprising die amino acid sequence of SEQ ID NO: 39.

[0190] In some embodiments, an anti-CCR8 binding agent 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: 220 and a light chain variable domain (VL) 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: 221. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 221; and a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 221. In some embodiments, modifications, e.g., substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 214; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 215; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 216; (d) LCDR1 comprising die amino acidsequence of SEQ ID NO: 217; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 218; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

[0191] In some embodiments, an anti-CCR8 binding agent 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: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130. 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150 and a light chain variable domain (VL) 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: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains modifications, such as substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CCR8 binding agent comprising that sequence retains the ability to bind to CCR8. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124. 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been modified, e.g., substituted, inserted and / or deleted in SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151. In some embodiments, modifications, e.g., substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). In some embodiments, such an anti-CCR8 binding agent comprises (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68, or 69; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240, or 241; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

[0192] In some embodiments, an anti-CCR8 binding agent is provided, wherein the antibody comprises a heavy chain (HC) 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: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212. Optionally, the anti-CCR8 binding agent comprises the HC sequence in SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212, including post- translation al modifications.

[0193] In some embodiments, an anti-CCR8 binding agent is provided, wherein the antibody comprises a light chain (LC) 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: 155, 157, 159, 161, 163, 165, 167, 169, 171,173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213. Optionally, the anti-CCR8 binding agent comprises the LC sequence in SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213, including post-translational modifications.

[0194] In some embodiments, an anti-CCR8 binding agent comprises a HC as in any of the embodiments provided herein, and a LC as in any of the embodiments provided herein.

[0195] In some embodiments, an anti-CCR8 binding agent is provided, wherein the antibody comprises a heavy chain (HC) 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: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212 and a LC 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: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213, including post-translational modifications of those sequences.

[0196] Anti-CCR8 agents provided herein can be antibodies, fragments thereof or binding polypeptides targeting the same. It is understood that referring to an antibody anti-CCR8 agent, reference is also made to fragments thereof, and binding polypeptides comprising the same, and vice versa. Accordingly, provided herein are anti-CCR8 antibodies and fragments thereof.A. Antibodies

[0197] In some embodiments, an anti-CCR8 agent provided herein is an anti-CCR8 antibody or a functional fragment thereof. Accordingly, provided herein are anti-CCR8 antibodies, fragments thereof, or uses thereof. In some embodiments, provided herein is an isolated anti-CCR8 antibody. In some embodiments, provided herein is an isolated anti-CCR8 antibody fragment. In some embodiments, an anti-CCR8 antibody provided herein can be used in therapeutic and / or diagnostic methods, such as methods of detection of CCR8 in a sample, methods of treatment, methods of diagnosis, methods of assessing responsiveness to an anti-CCR8 agent, and / or methods of prognosis. Diagnostic and therapeutic methods are further described herein. It is understood that when referencing an antibody herein, reference is also being made to a functional fragment thereof (e.g., a single-chain antibody, an isolated antibody hypervariable domain, a binding fragment thereof) and modified variants thereof, including a derivative thereof (e.g., an antibody con jugated with a substrate or with the protein or ligand of a protein-ligand pair).

[0198] In some embodiments, antibodies described herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, including molecules that contain one or more antigen binding sites that bind to a CCR8 antigen.

[0199] Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class, (e.g., IgGl, IgG2, IgG3, IgG4, IgAl or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In some embodiments, antibodies described herein are IgG antibodies (e.g., human IgG), or a class (e.g., human IgGl, IgG2, IgG3 or IgG4) or subclass thereof.

[0200] In some embodiments, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs, wherein the amino acid sequences of the H chains are identical and the amino acid sequences of the L chains are identical. In some embodiments, the H and L chains comprise constant regions, for example, human constant regions. In some embodiments, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In some embodiments, the H chain constant region of such antibodies comprise a gamma heavy chain constant region, for example, a human gamma heavy chain constant region. In some embodiments, such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g., IgGl, IgG2, IgG3, and / or IgG4 constant regions).

[0201] Antibodies and fragments thereof described herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, Fab fragments, F(ab’) fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies, Fabs-in-tandem-lg (FIT-lg); DVD-lg; hybrid hybridoma (quadroma or tetradoma); anticalin platform (Pieris); diabodies; single chain diabodies; tandem single chain Fv fragments; TandAbs, Trispecific Abs (Affimed); Darts dual affinity retargeting (Macrogenics); Bispecific Xinabs (Xencor); Bispecific T cell engagers (BiTE; Amgen; 55kDa); Triplebodies; Tribody = Fab-scFv Fusion Protein multifunctional recombinant antibody derivates (CreativeBiolabs); Duobody platform (Genmab); dock and lock platform; knobs-into-holes (KIH) platform; humanized bispecific IgG antibody (REGN1979) (Regeneron); Mab2 bispecific antibodies (F-Star); DVD-lg = dual variable domain immunoglobulin (AbbVie); kappa-lambda bodies; TBTI = tetravalent bispecific tandem Ig; and CrossMab (Roche), and epitope-binding fragments of any of the above.Antibody Fragments

[0202] In some embodiments, an antibody provided herein is an antibody fragment. In some embodiments, the antibody fragment is a Fab, Fab’, Fab'-SH, or F(ab’)2 fragment, and in particular a Fab fragment. Papain digestion of intact antibodies produces two identical antigen-binding fragments, called Fab fragments containing each the heavy- and light-chain variable domains (VH and VL, respectively) and also the constant domain of the light chain (CL) and the first constant domain of the heavy chain (CH1). A Fab fragment thus refers to an antibody fragment comprising a light chain comprising a VL domain and a CL domain, and a heavy chain fragment comprising a VH domain and a CHI domain. Fab’ fragments differ from Fab fragments by the addition of residues at the carboxy terminus of the CH 1 domain including one or more cysteines from the antibody hinge region. Fab’-SH are Fab’ fragments in which the cysteine residue(s) of the constant domains bear a free diiol group. Pepsin treatment yields an F(ab’)2fragment that has two antigen-binding sites (two Fab fragments) and a part of the Fc region. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo halflife, see U. S. Pat. No. 5,869,046.

[0203] In some embodiments, die antibody fragment is a diabody, a triabody or a tetrabody. Diabodies are antibody fragments with two antigen-binding sites that 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).

[0204] In some embodiments, 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 (CHI), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL.) and a linker, wherein said antibody domains and said linker have one of die following orders in N-terminal to C -terminal direction: 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 some embodiments, said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids. Said single chain Fab fragments are stabilized via tire natural disulfide bond between the CL domain and the CHI domain. In addition, these single chain Fab fragments might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues.

[0205] In some embodiments, the antibody fragment is single-chain variable fragment (scFv). A singlechain variable fragment (or scFv) is a fusion protein of tire variable domains of tlie heavy (VH) and light chains (VL) of an antibody, connected by a linker. In some embodiments, the linker is a short polypeptide of 10 to 25 amino acids and is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of tlie VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original antibody, despite removal of the constant regions and the introduction of the linker. For a review of scFv fragments, see, e.g., Plückthun, 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. Pat. Nos. 5,571,894 and 5,587,458.

[0206] In some embodiments, the antibody fragment is a single-domain antibody. Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In some embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U. S. Pat. No.6,248,516 Bl).

[0207] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as recombinant production by recombinant host cells (e.g., E. coli), as described herein.Chimeric antibodies

[0208] In some embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U. S. Pat. 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 in whichthe class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0209] Nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising the heavy and / or light chain variable regions of an antibody selected from, e.g., AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, and AB- 1 as disclosed herein. Additional nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising heavy chain CDR1, CDR2, and CDR3, and / or light chain CDR1, CDR2, and CDR3 of an antibody selected from AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB- 15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, and AB-31, as disclosed herein. In some embodiments, the chimeric anti-C. CR8 antibody comprises the variable regions described above and binds to CCR8. In some embodiments, the anti-C. CR8 antibody comprises the variable regions described above, binds to CCR8 and mediates an immune response in a subject, mediates activity in a diseased microenvironment and / or depletes CCR8 expression and / or CCR8 expressing cells in a subject following administration of the antibody to the subject. Other effector function includes inducing ADCC activity, ADCP activity, and / or CDC activity.

[0210] In some embodiments, a chimeric antibody described herein comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, IgD, and IgE. In some embodiments, the human light chain constant region is of an isotype selected from κ and λ. In some embodiments, a chimeric antibody described herein comprises a human IgG constant region. In some embodiments, a chimeric antibody described herein comprises a human IgG4 heavy chain constant region. In some embodiments, a chimeric antibody described herein comprises a human IgG4 constant region and a human K light chain.

[0211] Whether or not effector function is desirable may depend on the particular method of treatment intended for an antibody. Thus, in some embodiments, when effector function is desirable, a chimeric anti- CCR8 antibody comprising a human IgGl heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, when effector function is not desirable, a chimeric anti-CCR8 antibody comprising a human IgG4 or IgG2 heavy chain constant region is selected. In some embodiments, enhanced effector function is desirable.Humanized antibodies

[0212] In some embodiments, an antibody provided herein is a humanized antibody. In some 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 parental 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 FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody aresubstituted with corresponding residues from a non-human antibody (e.g., the antibody from which die CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0213] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann etal., Nature 332:323-329 (1988); Queen et al.. Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U. S. Pat. Nos.5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Moi. 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 etal., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

[0214] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence 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 Prcsta 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 FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok el al., J. Biol. Chem. 271:22611-22618 (1996)). Human antibodies

[0215] In some embodiments, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol.20:450-459 (2008).

[0216] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, e.g., U. S. Pat. Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U. S. Pat. No. 5,770,429 describing HUMAB® technology; U. S. Pat. No. 7,041,870 describing K-M MOUSE® technology, and U. S. Patent Application Publication No. US 2007 / 0061900, describing VELOCTMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region,

[0217] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mousehuman heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor, T. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody ProductionTechniques and Applications, pp. 51-63 (1987); and Boenier et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al.. Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U. S. Pat. No.7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing 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).

[0218] Human antibodies may also be generated by isolating variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

[0219] Antibodies may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, for example, in the McCafferty el al, Nature 348:552-554 (1990); Clackson et al, Nature 352: 624-628 (1991); Marks el al, J. Mol. Biol 222: 581-597(1992); Marks and Bradbury, in Methods in Molecular Biology 248: 161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al, J. Mol. Biol.338(2) (2004): 299-310; Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al, (2004) J. Immunol. Methods 284(1-2): 119-132. and PCT publication WO 99 / 10494.

[0220] In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to tlie immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (for example, from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al., EMBO J 12:725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter,.1. Mol. Biol, 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent No.5,750,373, and US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0221] In some embodiments, a chimeric human anti-CCR8 antibody is provided, where the antibody comprises tlie variable region from a human antibody that binds CCR8 and the constant region from adifferent human antibody. In some embodiments, a chimeric human anti-CCR8 antibody, where die antibody comprises the CDRs from a human antibody that binds CCR8 and a framework from a different human antibody is provided. In some embodiments, the antibody is not a naturally occurring human antibody.

[0222] In some embodiments, a human anti-CCR8 antibody comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, IgD, and IgE. In some embodiments, the human light chain constant region is of an isotype selected from K and X. In some embodiments, a human antibody described herein comprises a human IgG constant region. In some embodiments, a human antibody described herein comprises a human IgG4 heavy chain constant region. In some embodiments, a human antibody described herein comprises a human IgG4 constant region and a human K light chain.

[0223] In some embodiments, when effector function is desirable, a human anti-CCR8 antibody comprising a human IgGl heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, when effector function is not desirable, a human anti-CCR8 antibody comprising a human IgG4 or IgG2 heavy chain constant region is selected.

[0224] As noted herein, the term “human antibody” denotes the genus of possible sequences for the antibody construct, rather than a source of tire antibody.Multispecific antibodies

[0225] In some embodiments, an antibody provided herein is a multispecific antibody, e.g., a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites, e.g., different epitopes on different antigens or different epitopes on the same antigen. In certain embodiments, the multispecific antibody has three or more binding specificities. In certain embodiments, one of the binding specificities is for CCR8 and the other specificity is for any other antigen. In certain embodiments, bispecific antibodies may bind to two (or more) different epitopes of CCR8. Multispecific (e.g., bispecific) antibodies may also be used to localize cytotoxic agents or cells to cells which express CCR8. Multispecific antibodies may be prepared as full-length antibodies or antibody fragments.

[0226] Techniques for making multispecific antibodies include, but are not limited to, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having 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)). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making 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)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol,, 148(5): 1547- 1553 (1992) and WO 2011 / 034605); using the common light chain technology for circumventing the light chain mis-pairing problem (see, e.g., WO 98 / 50431); using “diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J.Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991).

[0227] Anti-CCR8 antibodies provided herein can be fused or conjugated to a second molecule. Fusion proteins and antibody conjugates are further described herein.

[0228] In some embodiments, antibodies that compete with the anti-CCR8 antibodies provided herein for binding to CCR8 are provided. In some embodiments, antibodies compete with the anti-CCR8 antibodies provided herein for binding to an epitope on CCR8.

[0229] In some embodiments, competition assays may be used to identify a monoclonal antibody that competes with an anti-CCR8 antibody described herein (such as AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, and AB-31) for binding to CCR8. Competition assays can be used to determine whether two antibodies bind the same epitope by recognizing identical or sterically overlapping epitopes or one antibody competitively inhibits binding of another antibody to the antigen. In some embodiments, such a competing antibody binds to the same epitope that is bound by an antibody described herein. Exemplary competition assays include, but are not limited to, routine assays such as those provided in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y.). Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) “Epitope Mapping Protocols,” in Methods in Molecular Biology vol.66 (Humana Press, Totowa, N. J.). In some embodiments, two antibodies are said to bind to the same epitope if each blocks binding of tire other by 50% or more. In some embodiments, the antibody that competes with an anti-CCR8 antibody described herein is a chimeric, humanized or human antibody. In some embodiments, an antibody that competes with a chimeric, humanized, or human anti-CCR8 antibody as described herein is provided.

[0230] In some embodiments, non-competition assays may be used to identify a monoclonal antibody that competes with an anti-CCR8 antibody described herein (such as AB-2, AB-3, AB -4, AB-5, AB -6, AB- 7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, and AB-31) for binding to CCR8. Non-competition assays can be used to determine whether two antibodies bind the different epitopes. In some embodiments, such a non-competing antibody binds to a different epitope that is bound by an antibody described herein. Exemplary non-competition assays include, but are not limited to, routine assays such as those provided in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y.). Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, N. J.). In some embodiments, two antibodies are said to bind to different epitope if each blocks binding of the other by less than 50%. Other assays include IHC assays as described herein, for example in EXAMPLE 2. In some embodiments, the antibody that does not competes with an anti-CCR8 antibody described herein is a chimeric, humanized orhuman antibody. In some embodiments, provided herein a chimeric, humanized, or human anti-CCR8 antibody that does not competes with an anti-CCR8 antibody.B. Modification

[0231] In some embodiments, anti-CCR8 agents provided herein are engineered with one or more post-translational modifications.

[0232] In some embodiments, one or more post-translational modifications comprises one or more amino acid alterations, one or more chemical alterations, one or more conjugation or fusion to one or more second agents, one or more linkers or any combinations thereof.Amino acid alterations

[0233] In some embodiments, one or more modifications comprise one or more amino acid alterations. In some embodiments, anti-CCR8 agents provided herein are engineered with one, 2, 3, 4, 5 or more amino acid alterations. Amino acid alterations comprise one or more amino acid substitutions, deletions, and / or insertions. In some embodiments, the one or more amino acid substitution comprises conservative substitutions or non-conservative substitutions. With respect to polypeptides that are CCR8 binding agents (e.g., antibodies, fragments, and / or binding polypeptides), such as human CCR8 binding agents, conservative amino acid substitutions that include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, in some embodiments, a predicted nonessential amino acid residue in a CCR8 binding agent is replaced with another amino acid residue from the same side chain family. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate antigen binding are well-known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al. Protein Eng.12(10): 879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). In some embodiments, the conservative amino acid alterations described herein modify the amino acid sequences of the CCR8 binding agents (e.g., antibodies), including human CCR8 binding agents, by 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 98%, or 99%. In some embodiments, the nucleotide and amino acid substitutions refer to at most 1, 2, 3, 4, 5, or 6 amino acid substitutions to the CDRs described in TABLE 2 or TABLE 3. Thus, for example, each such CDR may contain up to 5 conservative amino acid substitutions, for example up to (not more than) 4 conservative amino acid substitutions, for example up to (not more than) 3 conservative amino acid substitutions, for example up to (not more than) 2 conservative amino acid substitutions, or no more than 1 conservative amino acid substitution.

[0234] In some embodiments, antibodies provided here are affinity matured wherein such an antibody comprises one or more amino acid alterations in one or more CDRs compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen. Anti-CCR8 antibodies provided herein can be affinity matured using suitable selection and / or mutagenesis methods. In some embodiments, affinity matured antibodies have an affinity which is 1.5 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 10 times or more, 20 times or more, or 30 times or more than that of the starting antibody (e.g., a murine or rabbit humanized or human antibody) from which the matured antibody is prepared from.

[0235] In some embodiments, anti-CCR8 agents provided herein comprise one or more modifications which modulate the half-life of antibodies in vivo. For example, addressing the interaction of Fc with FcRn allows to modulate the half-life of antibodies in vivo. In some embodiments, abrogating the interaction by e.g. introduction of mutation H435A leads to an extremely short half-life, since die antibody is no longer protected from lysosomal degradation by FcRn recycling. In some embodiments, anti-CCR8 agents provided herein (e.g., an antibody) comprise a modification comprising a H435A substitution or has otherwise been engineered for a reduced half-life.

[0236] In some embodiments, anti-CCR8 agents described herein comprise one or more modifications which extend the half-life of anti-CCR8 agents provided herein. For example, antibodies comprising “YTE” mutations (M252Y / S254T / T256E) and / or equivalent mutations such as “LS” mutations (M428L / N434S) have been shown to significantly extend the half-life by more efficient recycling from endosomes in both pre-clincal species as well as humans (Dall'Acqua, William F., et al. The Journal of Immunology 169.9: 5171-5180 (2002); Zalevsky, Jonathan, et al “Enhanced antibody half-life improves in vivo activity." Nature biotechnology 28.2 (2010): 157-159.). Accordingly, in some embodiments, the anti-CCR8 agents provided herein comprise YTE mutations (M252Y / S254T / T256E) and / or equivalent mutations such as LS (M428L / N434S) or has otherwise been engineered for an improved half-life. Suitable Fc engineering approaches for extension of half-life can be found in Haraya, Kenta, Tatsuhiko Tachibana, and Tomoyuki Igawa. Drug metabolism and pharmacokinetics 34.1: 25-41 (2019), and / or Lee, Chang-Han, et al. Nature communications 10.1: 1-11 (2019), both incorporated herein by reference.

[0237] In some embodiments, an anti-CCR8 agent provided herein comprise one or more modifications which promote the association of the first and the second subunit of the Fc domain. Such modifications include manipulation of the peptide backbone or the post-translational modifications of an Fc domain subunit that reduces or prevents the association of a polypeptide comprising the Fc domain subunit with an identical polypeptide to form a homodimer. Antibodies comprising an Fc region may or may not comprise a modification promoting the association of the first and the second subunit of the Fc domain. A modification promoting association as used herein includes separate modifications made to each of the two Fc domain subunits desired to associate (e.g. the first and the second subunit of the Fc domain), wherein the modifications are complementary to each other so as to promote association of the two Fc domain subunits. For example, a modification promoting association may alter the structure or charge of one or both of the Fc domain subunits so as to make their association sterically or electrostatically favorable.Thus, (hetero)dimerization occurs between a polypeptide comprising the first Fc domain subunit and a polypeptide comprising the second Fc domain subunit, which might be non-identical, e.g. in the sense that further components fused to each of the subunits (e.g. antigen binding moieties) are not the same. In some embodiments the modification promoting association comprises an amino acid alteration in the Fc domain, specifically an amino acid substitution. In a particular embodiment, the modification promoting association comprises a separate amino acid alteration, specifically an amino acid substitution, in each of the two subunits of the Fc domain.Chemical alterations

[0238] In some embodiments, anti-CCR8 agents provided herein are modified by one or more chemical alterations comprising glycosylation (e.g., afucosylation), acetylation, pegylation, phosphorylation, sulfation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In some embodiments, an antibody modified by one or more chemical alterations are referred to herein as a derivatized antibody, or a derivative. Additionally, the derivative may contain one or more non-natural amino acids, e.g., using ambrx technology, see, e.g., Wolfson, Wendy. “Amber codon flashing ambrx augments proteins with unnatural amino acids.’’ Chemistry & biology 13.10 (2006): 1011-1012.

[0239] In some embodiments, anti-CCR8 agents provided herein comprise one or more modifications which alter at least one constant region-mediated biological effector function. For example, in some embodiments, an anti-CCR8 agent may be modified to reduce or enhance at least one constant region-mediated biological effector function relative to die unmodified anti-CCR8 agent, e.g., reduced or improved binding to the Fc receptor (FcyR). FcyR binding may be reduced, e.g. by mutating tire immunoglobulin constant region segment of the antibody at particular regions necessary for FcyR interactions (see, e.g., Canfield. Stephen M.. and Sherie L. Morrison. The Journal of experimental medicine 173.6: 1483-1491 (1991); and Lund, John, et al. The Journal of Immunology 147.8: 2657-2662 (1991)). FcyR binding may be enhanced, e.g. by afucosylation. Reducing FcyR binding may also reduce oilier effector functions which rely on FcyR interactions, such as opsonization (e.g., CDC), phagocytosis (e.g., ADCP) and antigen-dependent cellular cytotoxicity (e.g., ADCC)

[0240] Accordingly, in some embodiments, antibodies and / or binding polypeptides provided herein are modified such that the oligosaccharides in the Fc region of the antibody do not have any or have reduced fucose sugar units (e.g., afucosylated). Removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc can greatly increase ADCC effector function without altering antigen binding or CDC effector function. Several ways are known for reducing or abolishing fucosylation of Fc-containing molecules, e.g., antibodies. These include recombinant expression in certain mammalian cell lines including a FUT8 knockout cell line, variant CIIO line Lecl3, rat hybridoma cell line YB2 / 0, a cell line comprising a small interfering RNA specifically against the FUT8 gene, and a cell line co-expressing a-l,4-N-acetylglucosaminyltransferase III and Golgi ct-mannosidase II. Alternatively, (lie Fc-containingmolecule may be expressed in a non-mammalian cell such as a plant cell, yeast, or prokaryotic cell, e.g., E. coli. Zinc-finger nucleases are another known method of generating afucosylated antibodies. See e.g., Haryadi et al., Bioengineered 4:2, 90-94 (2013); Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); Yamane-Ohnuki etal. Biotech. Bioeng. 87: 614 (2004); Pereira el al. mAbs 10(5): 693-711 (2018).

[0241] In some embodiments, an anti-CCR8 agent provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the anti-CCR8 agent include but are not limited to water soluble polymers. Nonlimiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide / ethylene oxide co-polymers, poly oxy ethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in 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 if more than one polymer are attached, they can be the same or different molecules. In general, tire number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the anti-CCR8 agent to be improved, whether the antibody derivative will be used in a therapy under defined conditions.

[0242] In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in reduced deamidation. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in about 10% to 0% deamidation. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in about 8% to 0% deamidation. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in about 4% to 0% deamidation. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in about 1% to 0% deamidation. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in reduced deamidation as compared to an antibody having the HC and LC sequences of AB-1. In some embodiments, the one or more modifications are located within a deamidation motif in the heavy chain and / or light chain CDRS. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in reduced deamidation upon thermal stress. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in increased thermal stability. In some embodiments, antibodies and / or binding polypeptides provided herein include one or more modifications that result in increased thermal stability as compared to an antibody having tire HC and LC sequences of AB-1. In some embodiments, the enhanced thermal stability includes anincreased in one or more of T, Tonset, and Tagg, as measured by nano differential scanning fluorimetry (nanoDSF).

[0243] In some embodiments, a heavy chain amino acid sequence described herein (e.g., TABLE 5) that is present in the antibodies and / or binding polypeptides provided herein includes a C-terminal lysine residue. In some embodiments, compositions having a population of antibodies and / or binding polypeptides that have a heavy chain amino acid sequence provided herein (e.g., TABLE 5) include a portion of the population (typically a trace amount) with the heavy chain amino acid sequence having the C-terminal lysine residue. The existence of such a portion of the population can be due to partial cleavage of C-terminal lysine residues during production of tire population of antibodies and / or binding polypeptides. The presence or absence of a C-terminal lysine residue generally has no effect on stability, structure, antigen binding or potency of an antibody (Liu, Hongcbeng, et al. “In vitro and in vivo modifications of recombinant and human IgG antibodies.” MAbs. Vol. 6. No. 5. Taylor & Francis, 2014). Fusion or Conjugation alterations

[0244] In some embodiments, a CCR8 binding agent is linked, fused, or conjugated (directly or indirectly), to one or more moieties. which can provide one or more functions. Such moieties include masking moieties, deavable moieties, second agents (e.g., a diagnostic agent, a detectable agent, a therapeutic agent, such as a cytolytic agent, a second antibody or an antigen-binding fragment thereof, including constructs of multispecific antibodies, a heterologous protein, an effector cell, such as a chimeric antigen receptor T cell (CAR)), and combinations thereof.Masking / Cleavable moieties

[0245] In some embodiments, CCR8 binding agent is linked, fused, or conjugated (directly or indirectly), to a masking moiety and / or cleavable moiety in which one or more of the CCR8 binding domains of the CCR8 binding agent (e.g., antibody) are masked (e.g., via a masking moiety) and / or activatable (e.g., via a cleavable moiety). Technologies for masking of a CCR8 binding agent (e.g., an antibody) are well known in the art, including SAFE body masking technology (see, e.g., US Patent Application Publication No. 2019 / 0241886) and Probody masking technology (see, e.g., US Patent Application Publication No. 2015 / 0079088). Such technologies can be used to generate a CCR8 binding agent (e.g., an antibody) that is masked and / or activatable. Such masked and / or activatable CCR8 binding agents (e.g., antibodies) are useful for the preparation of conjugates, including immunoconjugates, antibody-drug conjugates (ADCs), masked ADCs and activatable antibody-drug conjugates (AADCs), comprising any one of the CCR8 binding agents (e.g., antibodies), such as human CCR8 binding agents, of the present disclosure, including those directly or indirectly linked to a second agent with effector function.

[0246] In some embodiments, CCR8 binding agent is linked, fused, or conjugated (directly or indirectly), to a second agent. In some embodiments, a second agent comprises a diagnostic agent, a detectable agent, or a therapeutic agent, such as a cytolytic agent, an effector cell, or a heterologous protein.Detectable / Dia gnostic agents

[0247] In some embodiments, an anti-CCR8 agent provided herein can be linked, fused or conjugated to a detectable agent or a diagnostic agent. Examples of detectable agents include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals, nonradioactive paramagnetic metal ions and reactive moieties. The detectable agent can be coupled or conjugated either directly to die antibody or fragment thereof or indirectly, e.g. through a linker known in the art or another moiety, using techniques known in the art. Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U. S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, β-galactosidase, acetylcholinesterase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like.

[0248] Examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminc fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include 125I, 131I, 111In or 99mTc.

[0249] Detection of expression of a chemokine receptor or CCR8 generally involves contacting a biological sample (tumor, cells, tissue, or body fluid of an individual) witli one or more anti-CCR8 agent provided herein (optionally conjugated to a detectable moiety), and detecting whether or not the sample is positive for CCR8, or whether the sample has altered (e.g., reduced or increased) expression as compared to a control sample. Further detectable agents and diagnostic agents are described further herein, for example as detectable labels and / or diagnostic labels.Antibodies, fragments, and constructs thereof

[0250] In some embodiments, anti-CCR8 binding agents provided herein are linked, conjugated or fused to a second antibody and / or antigen-binding fragments thereof, or constructs of the same.

[0251] In some embodiments, anti-CCR8 binding agents provided herein are linked, conjugated or fused to a second antibody to form an antibody heteroconjugate. In some embodiments, anti-CCR8 binding agents (e.g., anti-CCR8 antibodies) provided herein are linked, conjugated or fused to a second binding moiety generating multispecific antibodies. Multispecific antibodies, such as bispecific antibodies, are monoclonal antibodies that have binding specificities for at least two different targets (e.g., antigens) or two different epitopes on the same target (e.g., a bispecific antibody directed to CCR8 with a first binding domain for a first epitope of a CCR8, and a second binding domain for a second epitope of CCR8). In some embodiments, the multispecific (e.g., bispecific) antibodies can be constructed based on the sequences of the antibodies described herein, for example, the CDR sequences in TABLE 2 and TABLE 3. In some embodiments, die multispecific antibodies described herein are bispecific antibodies. In some embodiments, bispecific antibodies are mouse, chimeric, human or humanized antibodies. In some embodiments, one of die binding specificities of the multispecific antibody is for CCR8 and the other isfor any other target (e.g., antigen). In some embodiments, a multispecific (e.g., bispecific) antibody can comprise more than one target (e.g.., antigen) binding domain, in which different binding domains are specific for different targets (e.g., a first binding domain that binds to CCR8 and a second binding domain that binds another target (e.g., antigen), such as an immune checkpoint regulator (e.g., a negative checkpoint regulator). In some embodiments, multispecific (e.g., bispecific) antibody molecules can bind than one (e.g., two or more) epitopes on the same target (e.g., antigen). For example, a second binding moiety can be a moiety derived from any one of a therapeutic anti-CCR8 binding agent as further described herein.

[0252] In some embodiments, one of the binding specificities is CCR8 and the other is for one or more of a different chemokine receptor, a cell-surface protein such as cell surface protein expressed on immune cells or a tissue- or cell type-specific antigen, or a cell surface molecule associated with T-cell activation. Exemplary different chemokine receptors include CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CXCR 1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 or CXCR1. For example, the second binding moiety of the bispecific antibody is mogamulizumab or an antigen binding fragment thereof. Exemplary binding moictics which target cell-surface proteins such as cell surface protein expressed on immune cells or a tissue- or cell type-specific antigen include an antibody or antigen binding fragment targeting a checkpoint protein, such as an anti-PDl antibody, an anti-PD-L1 antibody, or a CTLA-4 antibody. Suitable checkpoint protein targeting antibodies include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, emiplimab, Ddoslarlimab, or ipilimumab. In some embodiments, the second binding moiety of the bispecific antibody is a IIER2 targeting antibody, such as trastuzumab, pertuzumab and / or margetuximab. Exemplary cell surface molecules associated with T-cell activation include CD25, CTLA-4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor super family members, 4-1BB, OX-40, and GITR.Effector cells

[0253] In some embodiments, anti-CCR8 binding agents provided herein are linked, conjugated or fused to an effector cell. In some embodiments, an effector cell comprises an immune cell as described herein (e.g., NK cell, dendrite, B cell, macrophage, and the like) or a T cell expressing a chimeric antigen receptor (CAR T cell) engineered for chemokine receptor or CCR8 targeting. Recently, CAR T cells have gained attention from their clinical successes and expedited FDA approvals, cf. W02020102240, incorporated herein in its entirety. In the CAR T cell approach, T cells are collected from patient blood and are then genetically engineered to express CARs that are specific for an antigen present on tumor cells. These engineered T cells are then re-administered to the same patient. Upon injection, CAR T cells recognize the targeted antigen on target cells to induce target cell death. CAR T cells thus constitute a novel modality for medical uses such as tumor treatment. The chimeric antigen receptor (CAR) is a genetically engineered receptor that is designed to target a specific antigen, for example, a tumor antigen. This targeting can result in cytotoxicity against the tumor, for example, such that CAR T cells expressing CARs can target and kill tumors via the specific tumor antigens. According to the present disclosure, the anti-CCR8 binding agent as described herein provided for CCR8 or chemokine receptor recognition can be used to engineer CAR Tcells for specific recognition of CCR8 expressing cells or cells expressing the respective chemokine receptor. CARs encompassed herein can comprise a) a recognition region, e.g., a single chain fragment variable (scFv) region derived from a provided anti-CCR8 or anti-chemokine receptor antibody for recognition and binding to the CCR8 or chemokine receptor expressed by the target cell, and b) an activation signaling domain, e.g., the CD3 chain of T cells, which can serve as a T cell activation signal in CARs.

[0254] In some embodiments, CARs provided herein comprise a co-stimulation domain (e.g., CD 137, CD28 or CD 134) to achieve prolonged activation of T cells in vivo. Addition of a co-stimulation domain enhances the in vivo proliferation and survival of T cells containing CARs, and initial clinical data have shown that such constructs are promising therapeutic agents in the treatment of diseases, such as cancer. IN some embodiments, CAR T cells provided herein are useful in methods as described herein. For example, such CAR T cells can be used to treat any disease with local or systemic aberrant presence of cells expressing the target chemokine receptor, in particular CCR8 expressing cells, such as Treg cells.Heterologous proteins

[0255] In some embodiments, anti-CCR8 binding agents provided herein are linked, conjugated or fused to a heterologous protein or polypeptide (or fragment thereof, for example, to a polypeptide (e.g., of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acids). In some embodiments, the linking, conjugation and / or fusion of heterologous proteins to an anti- CCR8 agent of the present disclosure generates fusion proteins, accordingly, provided herein are fusion proteins as well as uses thereof. In some embodiments, described herein are fusion proteins comprising an antigen-binding fragment of a CCR8 binding agent (e.g., an antibody), including a human CCR8 binding agent, described herein (e.g., comprising CDR1, CDR2, and / or CDR3 of VII and / or VL) and a heterologous protein, polypeptide, or peptide. In some embodiments, the heterologous protein, polypeptide, or peptide that a CCR8 binding agent (e.g., an antibody) is linked to is useful for targeting the CCR8 binding agent to a particular cell (e.g., a CCR8-expressing cell, including a tumor cell), In some embodiments, the heterologous protein is a signal peptide. In some embodiments, the heterologous protein is a cell penetrating peptide. In some embodiments, the heterologous protein is a subcellular localization signal.Cytolytic agents

[0256] In some embodiments, anti-CCR 8 binding agents provided herein are linked, conjugated or fused to one or more cytolytic agents. As used herein, a cytolytic agent is a moiety that reduces the proliferative capacity of one or more cells. A cell has reduced proliferative capacity when the cell becomes less able to proliferate, for example, because the cell undergoes apoptosis or otherwise dies, the cell fails to proceed through the cell cycle and / or fails to divide, the cell differentiates, etc. Nonlimiting exemplary cytolytic agents include, but are not limited to, radioisotopes, photosensitizers (PS), cytotoxins, and chemotherapeutic agents.

[0257] In some embodiments, an anti-CCR8 agent provided herein can be linked, fused or conjugated to one or more radioisotopes, also referred to herein as radionuclides. Exemplary radionuclides include: abeta particle, an alpha particle, or an Auger electron emitter. Suitable beta emitters are for example yttrium-90. iodine-131, strontium-89-chloride, lutetium-177, holmium-166, rhenium-186, rhenium-188, copper- 67, promethium- 149, gold-199, and rhodium-105. Suitable Auger electron emitters are for example bromine-77, indium- 111, iodine- 123, and iodine- 125. Suitable alpha emitters are for example thorium-227, bismuth-213, radium-223, actinium-225 and astatine-211.

[0258] For example, thorium-227 (227Th) can be efficiently complexed with octadentate 3,2-hydroxypyridinone (3,2-HOPO) chelators that are conjugated to anti-CCR8 binding agents according to the current disclosure, resulting in highly stable targeted thorium-227 conjugates (TTCs). Targeted thorium conjugates (TTCs) comprise three main building blocks. Following the P-particle decay of actinium-227, die first building block, a-particle-emitting radionuclide 227Th is purified by ion exchange chromatography. The second building block is a chelator, such as a siderophore-derived chelator containing HOPO groups bearing four 3-hydroxy-N-mediyl-2-pyridinone moieties on a symmetrical polyamine scaffold functionalized with a carboxylic acid linker for bioconjugation. Conjugation to a targeting moiety can be achieved through the amide bond formation with the s-amino groups of lysine residues. These octadentate 3,2-HOPO chelators can be efficiently labeled with 227Th, with high yield, purity, and stability at ambient conditions. Compared with the tetra-azacyclododecane-l,4,7,10-tetraacetic acid (DOTA) chelator, which often requires heating, the HOPO chelators are superior due to efficient radiolabeling at ambient temperatures and high stability of formed complexes. The third building block is the targeting moiety, that is the anti-CCR8 agent provided herein.

[0259] In some embodiments, an anti-CCR8 agent provided herein can be linked, fused or conjugated to one or more photosensitizers (PS). Photodynamic therapy (PDT) is a non-invasive treatment that involves the accumulation of a PS in solid tumors followed by the localized delivery of light of the correct wavelength to cause activation of the PS, which, in the presence of oxygen, leads to the in situ generation of reactive oxygen species (ROS) that cause damage to cellular components and, ultimately, necrosis or apoptosis. PDT is a promising tool in oncology but is frequently limited by side-effects caused by inadequate targeting of the photosensitizer. Accordingly, encompassed by the present disclosure is the conjugation of PS’s to tumor-specific binding agents (e.g., antibodies). Also provided herein is the use of antigen-binding Ab fragments, e.g., Fab or scFv fragments, as, in some embodiments, antigen binding fragments retain the same binding specificity as full-size antibodies, but are more efficient at penetrating tumor masses due to their smaller size and are more effectively cleared from the circulation because of the lack of an Fc domain. In some embodiments, provided are porphyrins for use in the field of photodynamic therapy and photodiagnosis, and are one of the most prominent classes of photosensitizer in these areas of biomedical science (Sandland J, Boyle RW, Bioconjug Chem. 30(4):975-993 (2019)). In some embodiments, the photosensitizer is a tetrapyrrolic macrocycle. In some embodiments, the tetrapyrrolic macrocycle is a porphyrin, a chlorin, a bacteriochlorin, or a phthalocyanine.

[0260] In some embodiments, an anti-CCR8 agent provided herein can be linked, fused or conjugated to one or more cytotoxic agents, which can in some embodiments form antibody drug conjugate (ADC), referred to an anti-CCR8 ADC herein. One skilled in the art can select a suitable cytotoxin according tothe intended application. In some embodiments, the cytolytic agent is at least one of an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti -angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, or an apoptotic agent.

[0261] In some embodiments, the cytotoxic agent is an auristatin, a maytansinoid, a kinesin-spindle protein (KSP) inhibitor, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor or a pyrrolobenzodiazepine derivative. Generation of conjugates comprising maytansinoid may occur as described in Chari, Ravi V J, et al. Cancer research 52.1 (1992): 127-131, or EP2424569 Bl, both incorporated herein in their entirety. Generation of conjugates comprising kinesin-spindle protein (KSP) inhibitors may occur as described in WO2019243159 Al, incorporated herein in its entirety. Generation of conjugates comprising a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor may occur as described in WO2019149637 Al, incorporated herein in its entirety. Generation of conjugates comprising a pyrrolobenzodiazepine may be obtained as described in EP3355935 Al, incorporated herein in its entirety.

[0262] 'The cytotoxic and / or cytostatic agent of the anti-CCR8 ADC may be any agent known to inhibit tire growth and / or replication of, and / or kill cells. Numerous agents having cytotoxic and / or cytostatic properties are known in the literature. Non-limiting examples of classes of cytotoxic and / or cytostatic agents include, by way of example and not limitation, cell cycle modulators, apoptosis regulators, kinase inhibitors, protein synthesis inhibitors, alkylating agents, DNA cross-linking agents, intercalating agents, mitochondria inhibitors, nuclear export inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA antimetabolites and antimitotic agents.

[0263] The linkers linking the cytotoxic and / or cytostatic agent(s) to tire antigen binding moiety of an anti-CCR8 ADC may be long, short, flexible, rigid, hydrophilic or hydrophobic in nature, or may comprise segments that have different characteristics, such as segments of flexibility, segments of rigidity, etc. The linker may be chemically stable to extracellular environments, for example, chemically stable in die blood stream, or may include linkages that are not stable and release the cytotoxic and / or cytostatic agents in the extracellular milieu. In some embodiments, the linkers include linkages that are designed to release the cytotoxic and / or cytostatic agents upon internalization of the anti-CCR8 ADC, within the cell. In some specific embodiments, the linkers include linkages designed to cleave and / or immolate or otherwise breakdown specifically or non-specifically inside cells. A wide variety of linkers useful for linking drugs to antigen binding moieties such as antibodies in the context of ADCs are known in the art. Any of these linkers, as well as other linkers, may be used to link the cytotoxic and / or cytostatic agents to the antigen binding moiety of the anti-CCR8 ADCs, described herein.

[0264] The number of cytotoxic and / or cytostatic agents linked to the antigen binding moiety of an anti-CCR8 ADC (drug-to-antibody ratio: DAR; can vary and will be limited only by the number of available attachments sites on the antigen binding moiety and the number of agents linked to a single linker. Typically, a linker will link a single cytotoxic and / or cytostatic agent to the antigen binding moiety of anti-CCR8 ADC. In embodiments of anti-CCR8 ADC, which include more than a single cytotoxic and / or cytostatic agent, each agent may be the same or different. As long as the anti-chemokine receptor or anti-CCR8 ADC, does not exhibit unacceptable levels of aggregation under the conditions of use and / or storage, anti-CCR8 ADCs, with DARs of twenty, or even higher, are contemplated. In some embodiments, the anti-CCR8 ADC s, described herein may have a DAR in the range of about 1-10, 1-8, 1-6, or 1-4. In certain specific embodiments, the anti-CCR8 ADC may have a DAR of 2, 3 or 4. In some embodiments, the anti- CCR8 ADCs, are compounds according to structural formula (1):[D-L-XY]n-AbFormula 1or salts thereof, where each “D" represents, independently of the others, a cytotoxic and / or cytostatic agent; each “L” represents, independently of the others, a linker; “Ab" represents an anti-CCR8 receptor binding moiety, e.g. an anti-CCR8 antibody provided herein; each “XY" represents a linkage formed between a functional group Rx on the linker and a “complementary" functional group Ry on the anti-chemokine receptor binding moiety; and n represents the DAR of the anti-chemokine receptor ADC.

[0265] In a specific exemplary embodiment, the anti-CCR8 ADCs are compounds according to structural formula (1) in which each “D” is the same and is either a cell-permeating auristatin (for example, dolastatin-10 or MMAE) or a cell-permeating minor groove-binding DNA cross-linking agent; each “L" is tiie same and is a linker cleavable by a lysosomal enzyme; each “XY" is a linkage formed between a maleimide and a sulfhydryl group; “Ab” is an antibody or fragment thereof comprising six CDRs corresponding to the six CDRs of an anti-chemokine receptor or CCR8 antibody according to the current disclosure; and n is 2, 3 or 4. In a specific embodiment “Ab” is a fully human antibody comprising human derived CDRs.

[0266] Cytotoxic and cytostatic agents are agents known to inhibit the growth and / or replication of and / or kill cells and in particular tumor cells or intra-tumoral Treg cells. These compounds may be used in a combination therapy with an anti-chemokine receptor antibody such as a CCR8 antibody, or as part of an anti-chemokine receptor ADC as described herein: In some embodiments, the drug moiety of the anti- chemokine receptor or anti-CCR8 ADC is a cytostatic agent selected from radionuclides, alkylating agents, DNA cross-linking agents, DNA intercalating agents (e.g., groove binding agents such as minor groove binders), cell cycle modulators, apoptosis regulators, kinase inhibitors, protein synthesis inhibitors, mitochondria inhibitors, nuclear export inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA anti metabolites and antimitotic agents. In some embodiments, the drug moiety of the anti- chemokine receptor or anti-CCR8 ADC is an alkylating agent selected from asaley (L-Leucine, N—[N-acetyl-4-[bis-(2-chloroethyl)amino...

Claims

CLAIMSWhat is claimed is:

1. An isolated antibody or an antigen-binding fragment thereof that binds to human C-C motif chemokine receptor (CCR8), wherein the antibody or fragment thereof comprises a heavy chain variable (VII) region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 215, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 2.16, and a light chain variable (VL) region comprising anLCDRl comprising the amino acid sequence of SEQ ID NO: 217, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 218, and an LCDR3 comprising lire amino acid sequence of SEQ ID NO: 219.

2. The isolated antibody or an antigen-binding fragment thereof of claim 1, wherein the antibody or fragment thereof comprises a VII region comprising an IICDR1 comprising tire amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO; 35, 56, 57, 58, 59, 60 or 61, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region comprising an LCDRi comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240 or 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

3. The isolated antibody or an antigen-binding fragment thereof of claim 1 or claim 2, wherein the antibody or fragment thereof comprises:a) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;b) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an IICDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRi comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;c) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 83, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;d) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI. region comprising an LCDRI comprising theamino acid sequence of SEQ ID NO: 84, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39:e) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 58, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising I lie amino acid sequence of SEQ ID NO: 37, an I. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;f) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 59, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCD 2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;g) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and tin LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;h) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;i) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;j) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;k) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;l) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;m) a VII region comprising an TICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;n) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an IICDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;o) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 35, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;p) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;q) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;r) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising tire amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;s) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRl comprising theamino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39:t) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an I. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;u) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCD 2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 391;v) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and tin LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;w) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 61, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;x) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;y) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; z) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:

39.

4. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-3, wherein:a) the VH region further comprises:i) a framework 1 (VH FR 1 ), a framework 2 (VH FR2), a framework 3 ( VH FR3) and / or a framework 4 ( VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106. 108, HO, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132. 134, 136, 138, 140, 142, 144, 146, 148 or 150; orii) a VH FR 1 comprising the sequence in SEQ ID NO: 222, a VH FR3 comprising the sequence in SEQ ID NO: 224, and / or a VH FR4 comprising the sequence in SEQ ID NO: 225; and / or b) tire VL region further comprises:i) a VL FR1 comprising the sequence in SEQ ID NO: 226, a VL FR2 comprising the sequence in SEQ ID NO: 227, a VL FR3 comprising the sequence in SEQ ID NO: 228, and / or a VL FR4 comprising the sequence in SEQ ID NO: 229; orif) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

5. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-4, wherein the antibody or fragment comprises:a) a VH region comprising an amino acid sequence of SEQ ID NO: 220; and / orb; a VI. region comprising an amino acid sequence of SEQ ID NO; 221.

6. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-5, wherein lire antibody or fragment comprises:a) a VH region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%-, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / orb) a VL region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

7. The isolated antibody or an antigen -binding fragment thereof of any one of claims 1-6, wherein the antibody or fragment comprises:a) a VH region comprising an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / orb) a VL region comprising an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

8. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-7, wherein the antibody or fragment comprises:a) a heavy chain (HC) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212; and / orb) a light chain (LC) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

9. The isolated antibody or an anti gen -binding fragment thereof of any one of claims 1-8, wherein the antibody or fragment comprises:a) a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164.

166.

168.

170.

172.

174.

176.

178.

180.

182.

184.

186.

188.

190.

192.

194.

196. 198.200.202, 204, 206, 208, 210 or 212; and / orb) a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165.

167.

169.

171.

173.

175.

177.

179.

181.

183.

185.

187.

189.

191.

193.

195.

197. 199.201.203, 205, 207, 209, 21 l or 213.

10. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-9, wherein the antibody or fragment targets an epitope of SEQ ID NO: 1.

11. The isolated antibody or an antigen- binding fragment thereof of any one of claims 1-10, wherein a portion of die CCR8 is expressed on a cell, and wherein the antibody of fragment mediates depletion of the CCR8 expressing cell by antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), or complement dependent cytotoxicity, or any combination thereof.

12. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-11, wherein die antibody is a monoclonal antibody.

13. The isolated antibody or an antigen-binding fragment, thereof of any one of claims 1-12, wherein the antibody is a humanized, human or chimeric antibody.

14. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-13, wherein the antibody or fragment thereof is a Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, or a multispecific antibody formed from antibody fragments.

15. 'The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-14, wherein the antibody or fragment thereof comprises one or more post-translational modifications.

16. The isolated antibody or an antigen-binding fragment thereof of claim 15, wherein the one or more post-translational modifications enhances one or more activity of the isolated antibody or an antigen¬ binding fragment or imparts one or more activity unto the isolated antibody or antigen-binding fragment, thereof.

17. The isolated antibody or an antigen-binding fragment thereof of claim 16, wherein the one or more activity is measured relative to an isolated antibody or antigen-binding fragment thereof without the one or more modification in a suitable in vitro assay.

18. The isolated antibody or an antigen-binding fragment thereof of any one of claims 15-17, wherein the one or more post-translational modifications comprises one or more amino acid alterations, one or more conjugation or fusion to one or more second agents, one or more chemical alterations, or any combination thereof.

19. The isolated antibody or an antigen-binding fragment thereof of claim 18, wherein the one or more amino acid alterations is one or more conservative or non-conservative substitutions.

20. The isolated antibody or an antigen-binding fragment thereof of claim 19, wherein the antibody or fragment thereof comprises enhanced binding activity, stability, solubility, half-life, or aggregation relative to an isolated antibody or an antigen-binding fragment thereof consisting of a non-altered sequence.

21. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1 -20, wherein the antibody or fragment thereof comprises enhanced binding activity, as measured by flow cytometry.

22. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises enhanced binding activity as compared to an antibody or fragment thereof comprising a heavy chain comprising an amino acid of SEQ ID NO: 152, and a light chain comprising an amino acid sequence of SEQ ID NO: 153, as measured by flow cytometry.

23. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-20, wherein lire antibody or fragment thereof comprises enhanced stability.

24. The isolated antibody or an antigen-binding fragment drereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises enhanced stability as compared to an antibody or fragment thereof comprising a heavy chain comprising an amino acid of SEQ ID NO: 152, and a light chain comprising an amino acid sequence of SEQ ID NO: 153.

25. The isolated antibody or antigen-binding fragment thereof of claim 23 or claim 24, wherein the enhanced stability is enhanced thermal stability.

26. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises from 4% to 0% deamidation.

27. The isolated antibody or an antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or fragment thereof comprises reduced deamidation as compared to an antibody or fragment thereof comprising a heavy chain comprising an amino acid of SEQ ID NO: 152, and a light chain comprising an amino acid sequence of SEQ ID NO: 153.

28. The isolated antibody or an antigen-binding fragment thereof of claim 18, wherein the second agent comprises a diagnostic agent, a detectable agent, or a therapeutic agent.

29. The isolated antibody or an antigen-binding fragment thereof of claim 28, wherein the antibody or fragment, thereof comprises diagnostic activity of a CCR8-related condition or disease, detectingactivity of a CCR8-related condition or disease, or therapeutic activity of a therapy aimed at a CCR8- related condition or disease.

30. Tiie isolated antibody or an antigen-binding fragment thereof of claim 18, wherein the one or more chemical alterations is afucosylation.

31. The isolated antibody or an antigen-binding fragment thereof of claim 30, wherein the antibody or fragment comprises enhanced FcyRIIIa receptor binding, enhanced antibody-dependent cellular cytotoxicity (ADCC), enhanced antibody-dependent cellular phagocytosis (ADCP) activities, enhanced complement dependent cytotoxicity (CDC) or combinations thereof.

32. A binding polypeptide that indicates the presence of CCR8 expressing cells in a sample obtained from a subject, wherein the binding polypeptide selectively binds to CCR8 and is labeled with a detectable label or moiety, wherein the binding polypeptide comprises a heavy chain variable (VH) region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 215, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 216, and a light chain variable (VL) region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 217, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 218, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

33. The binding polypeptide of claim 32, wherein the binding polypeptide comprises a VH region comprising an HCDR1 comprising lire amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61, an HCDR3 comprising tire amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240 or 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

34. Die binding polypeptide of claim 32 or claim 33, wherein the binding polypeptide comprises:a) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;b) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising tire amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;c) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising theamino acid sequence of SEQ ID NO: 83, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39:d) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising I lie amino acid sequence of SEQ ID NO: 84, an I. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;e) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 58, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCD 2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;f) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 59, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and tin LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;g) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;h) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;i) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;j) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;k) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;l) a VII region comprising an TICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;nr) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an IICDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;n) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;o) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 35, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;p) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;q) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, n HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising tire amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;r) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising theamino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39:s) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an I. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;t) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising die amino acid sequence of SEQ ID NO: 37, an LCD 2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;u) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and tin LCDR3 comprising the amino acid sequence of SEQ ID NO: 391;v} a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; or w.) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 61, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;x) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;y) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; orz) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

35. The binding polypeptide of any one of claims 32-34, wherein:a) the VH region further comprises:i) a framework 1 (VII FR1), a framework 2 (VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; orii) a VH FR1 comprising die sequence in SEQ ID NO: 222, a VII FR3 comprising the sequence in SEQ ID NO: 224, and / or a VH FR4 comprising the sequence in SEQ ID NO: 225; and / or b) the VL region further comprises:i) a VL FR1 comprising the sequence in SEQ ID NO: 226, a VL FR2 comprising the sequence in SEQ ID NO: 227, a VL FR3 comprising the sequence in SEQ ID NO: 228, and / or a VL FR4 comprising die sequence in SEQ ID NO: 229; orii) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

36. The binding polypeptide of any one of claims 32-35, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence of SEQ ID NO: 220; and / orb) a VL region comprising an amino acid sequence of SEQ ID NO: 221.

37. The binding polypeptide of any one of claims 32-36, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence that is at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118. 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / orb) a VL region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

38. The binding polypeptide of any one of claims 32-37, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / orb) a VL region comprising an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

39. The binding polypeptide of any one of claims 32-38, wherein the binding polypeptide comprises: a) a heavy chain (HC) comprising an amino acid sequence tliat is at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98 ', or 99 ' identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 390, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 or 212 and / orb) a light chain (EC) comprising an amino acid sequence that is at least 90%’, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

40. The binding polypeptide of any one of claims 32-39, wherein the binding polypeptide comprises: a) a HC comprising an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170. 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200,202, 204, 206, 208, 210 or 212; and / orb) a LC comprising an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211 or 213.

41. The binding polypeptide of any one of claims 32-40, wherein (i) the binding polypeptide is labeled with a detectable label or moiety that can be detected directly or (ii) the binding polypeptide is recognized by a secondary reporter that is labeled with a detectable label or moiety that can be detected directly; and wherein the detectable label or moiety comprises fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels or indirectly.

42. T he binding polypeptide of claim 41, wherein the detectable label or moiety can be detected indirectly and wherein the detectable label or moiety comprises a reporter, a tag, a purification tag, a polymeric sequence designed to hybridize to a complementary polymeric sequence, enzymes, a heterologous protein, or combinations thereof.

43. The binding polypeptide of claim 41, wherein the detectable label or moiety is fused, linked, conjugated, or covalently or non-covalently bound to the binding polypeptide and / or the secondary reporter.

44. The binding polypeptide of any one of claims 32-43, wherein CCR8 expressing cells are tumor infiltrating Treg cells.

45. The binding polypeptide of any one of claims 32-44, wherein the CCR8 expressing cells are present in a tumor microenvironment.

46. The binding polypeptide of claim 45, wherein the tumor microenvironment comprises solid tumor cells.

47. The binding polypeptide of claim 46, wherein die solid tumor cells are cancer cells chosen from squamous cell carcinoma, small cell Jung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (HCC ), pancreatic cancer (PAC ), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer ( CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of the endometrium, carcinoma of the fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.

48. The binding polypeptide of any one of claims 32-47, wherein the binding polypeptide targets an intracellular epitope of SEQ ID NO: 1.

49. A binding polypeptide that mediates activity in a diseased microenvironment associated with CCR8 expression in a subject, wherein the binding polypeptide selectively binds to CCR8 and is conjugated or fused to one or more therapeutic agents, wherein the binding polypeptide comprises a heavy chain variable (VH) region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 215, tin HCDR3 comprising the amino acid sequence of SEQ ID NO: 216, and a light chain variable (VL) region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 217, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 218, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 219.

50. The binding polypeptide of claim 48, wherein the binding polypeptide comprises a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 35, 56, 57, 58, 59, 60 or 61, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, 68 or 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, 82, 83, 84, 85, 240 or 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38 or 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

51. The binding polypeptide of claim 49 or claim 50, wherein lire binding polypeptide comprises:a) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, an HCDR3 comprising theamino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 82, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;b) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRi comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;c) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 83, tin LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;d) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an IICDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 84, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;e) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 58, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino add sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;f) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 59, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;g) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;h) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 85, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;i) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;j) a VII region comprising an TICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;k) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an IICDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;l) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;m) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an IICDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VI, region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;n) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRl comprising the amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;o) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRl comprising tire amino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;p) a VII region comprising an IICDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRl comprising theamino acid sequence of SEQ ID NO: 85, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39:q) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising I lie amino acid sequence of SEQ ID NO: 37, an I. CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;r) a VII region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising die amino acid sequence of SEQ ID NO: 85, an LCD 2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;s) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an L. CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and tin LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;t) a VH region comprising an HCDR I comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;u) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 391;v) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VI, region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;w) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising die amino acid sequence of SEQ ID NO: 61, an HCDR3 comprising die amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDRI comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising die ammo acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39;x) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39: ory) a VH region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 240, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39; orz) a VH region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 241, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 39.

52. The binding polypeptide of any of claims 49-51, wherein:a) the VH region further comprises:i) a framework 1 (VH FR1), a framework 2 (VH FR2), a framework 3 (VH FR3) and / or a framework 4 (VH FR4) sequence in SEQ ID NOS: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; orii) a VH FR1 comprising the sequence in SEQ ID NO: 222, a VH FR3 comprising the sequence in SEQ ID NO: 224, and / or a VH FR4 comprising the sequence in SEQ ID NO: 225; and / or b.) die VL region further comprises:i) a VL FR 1 comprising the sequence in SEQ ID NO: 226, a VL FR2 comprising the sequence in SEQ ID NO: 227, a VL FR3 comprising the sequence in SEQ ID NO: 228, and / or a VL FR4 comprising die sequence in SEQ ID NO: 229; orii) a VL FR1, VL FR2, VL FR3 and / or VL FR4 sequence in SEQ ID NOS: 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117. 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

53. The binding polypeptide of any one of claims 49-52, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence of SEQ ID NO: 220; and / orb) a VL region comprising an amino acid sequence of SEQ ID NO: 221.

54. The binding polypeptide of any one of claims 49-53, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence that is at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150; and / orb) a VL region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103.

105.

107. 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

55. The binding polypeptide of any one of claims 49-47, wherein the binding polypeptide comprises: a) a VH region comprising an amino acid sequence of SEQ ID NO: 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 or 150: and / orb) a VL region comprising an amino acid sequence of SEQ ID NO: 93, 95, 97, 99, 101, 103, 105, 107. 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149 or 151.

56. The binding polypeptide of any one of claims 49-55, wherein tire binding polypeptide comprises: a) a heavy chain (HC) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, 156, 158, 160.

162.

164.

166.

168.

170.

172.

174.

176.

178.

180.

182.

184.

186.

188.

190.

192.

194.

196. 198, 200, 202, 204, 206, 208, 210 or 212; and / orb) a light chain (LC) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, 157, 159, 161.

163.

165.

167.

169.

171.

173.

175.

177.

179.

181.

183.

185.

187.

189.

191.

193.

195.

197. 199, 201, 203, 205, 207, 209, 211 or 213.

57. The binding polypeptide of any one of claims 49-56, wherein the binding polypeptide comprises: a) a HC comprising an amino acid sequence of SEQ ID NO: 154, 156, 158, 160, 162, 164, 166, 168, 170.

172.

174. 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200,202, 204, 206, 208, 210 or 212; and / orb) a LC comprising an amino acid sequence of SEQ ID NO: 155, 157, 159, 161, 163, 165, 167, 169, 171.

173.

175. 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201,203, 205, 207, 209, 211 or 213.

58. The binding polypeptide of any one of claims 49-57, wherein the therapeutic agent comprises: a radionuclide, a cytotoxic agent, an organic compound, a protein toxin, an immunomodulator, a cytokine, a fluorescent moiety, a cell, a cell receptor, a second antibody or antigen-binding fragments thereof, or combinations thereof.

59. The binding polypeptide of claim 58, wherein the radionuclide comprises a beta particle, an alpha particle, or an Auger electron emitter.

60. The binding polypeptide of claim 58, wherein the cytotoxic agent comprises an auristatin, a maytansinoid, a kinesin-spindle protein (KSP) inhibitor, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor or a pyrrolobenzodiazepine derivative.

61. The binding polypeptide of claim 58, wherein the cell is a chimeric antigen receptor T cell.

62. The binding polypeptide of claim 58, wherein the cell receptor is a chimeric antigen receptor.

63. The binding polypeptide of any one of claims 49-62, wherein the binding polypeptide comprises one or more linkers linking the binding polypeptide to the one or more therapeutic agetits.

64. The binding polypeptide of any one of claims 49-62, wherein the one or more therapeutic agent is directly conjugated or fused to the binding polypeptide.

65. The binding polypeptide of any one of claims 49-64, wherein CCR8 expression is CCR8 expression on tumor infiltrating Treg cells.

66. The binding polypeptide of any one of claims 49-65, wherein the diseased microenvironment related to CCR8 expression is a tumor microenvironment.

67. The binding polypeptide of claim 66, wherein the tumor microenvironment comprises solid tumor cells.

68. The binding polypeptide of claim 67, wherein the solid tumor cells are cancer cells chosen from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer (PAC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer (CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of (lie endometrium, carcinoma of the fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi’s sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.

69. A polynucleotide comprising one or more nucleotide sequences encoding:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof; ord) any combination of (a)-(c).

70. A vector comprising:a) the polynucleotide of claim 69(a);b) the polynucleotide of claim 69(b);c) the polynucleotide of claim 69(c); ord) the polynucleotide of claim 69(d).

71. A library of vectors comprising at least two vectors, each individually encoding:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof; ord) any combination of (a)-(c).

72. A cell expressing:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof; ord) any combination of (a)-(c).

73. A cell comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d); org) any combination thereof.

74. A population of cells comprising:a) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g), or any combination thereof; orc) any combination thereof.

75. A system of specifically binding CCR8 in a sample obtained from a subject, the system comprising components comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c); orj) any combination thereof.

76. A composition comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d):f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j); ork) any combination of (a)-(j).

77. A method of producing an anti-CCR8 agent comprising culturing the cell of claim 72 or 73, or the population of cells of claims 74, under conditions suitable for expressing the isolated antibody, binding polypeptide, or portion thereof.

78. The method of claim 77, the method comprising isolating the antibody or binding polypeptide.

79. A method of producing an anti-CCR8 agent that specifically binds to an intracellular epitope of CCR8 and not to an extracellular epitope of CCR8 comprising immunizing a non-human subject with an immunogen comprising a cell that expresses the intracellular, extracellular epitope and an antibody or antigen-binding fragment thereof that specifically binds to the extracellular epitope for a sufficient number of time to permit the non-human subject to generate the anti-CCR8 agent that specifically binds to the intracellular epitope.

80. A system of detecting CCR8 expressing cells in a sample obtained from a subject, the system comprising components comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k); orl) any combination thereof;optionally wherein the components further comprise a detection reagent or an amplification reagent.

81. The system of claim 80, wherein the CCR8 expressing cells are tumor infiltrating lymphocytes (TILs).

82. The system of claim 81, wherein the CCR8 expressing TILs comprise Tregs.

83. The system of any one of claims 80-82, wherein the sample is a solid tissue biopsy.

84. The system of any one of claims 80-83, wherein the sample comprises a formalin-fixed paraffin-embedded (FFPE) tissue.

85. The system of any one of claims 80-84, wherein detection of the CCR8 expressing cells comprises an immunohistochemistry assay.

86. The system of any one of claims 80-85, wherein the subject has cancer.

87. The system of any one of claims 75, 80-86, wherein:a) each component is suspended in a solution, or any combination of components is suspended in the same solution;b) each component is housed in a container, or any combination of components is housed in a container;c) each component is provided in a device, or any combination of components is provided in a device; ord) any combination of (a)-(c).

88. A device for detecting CCR8 in a sample obtained from a subject, the device comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k); orl) any combination of (a)-(k); andwherein any of (a)-(l) are comprised in a reagent that is housed in a container.

89. A kit for detecting CCR8 in a sample obtained from a subject, the kit comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71 (c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);l) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(l); orm) any combination of (a)-(l); andinstructions for using (a)-(m) for detecting CCR8 in the sample obtained from a subject, 90. A method of detecting CCR8 in a sample obtained from a subject, comprising:a) contacting a sample with:i) any one of the isolated antibodies of claims 1-31 or a portion thereof;ii) any one of the binding polypeptides of claims 32-48 or a portion thereof;iii) any one of the binding polypeptides of claims 49-68 or a portion thereof;iv) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);v) the vector of claim 70(a), 70(b), 70(c), or 70(d);vi) the library of vectors of claim 69(b), 71(b), 71(c), or 71 (d);vii) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof; viii) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),ix) the population of cells of claim 74(a), 74(b), or 74(c);x) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);xi) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);xii) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(l); orxiii) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i), 89(j), 89(k), 89(1), or 89(m);under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; andb) detecting the level of CCR8 or number of CCR8 expressing cells in said sample.

91. A method of assessing responsiveness of a subject having cancer to an anti-CCR8 agent, comprising:a) obtaining a sample from the subject;b) performing the method of claim 90; andc) associating the level of CCR8 or number of CCR8 expressing cells with a diseased microenvironment.

92. A method of selecting a subject suspected of having or having cancer for treatment with an anti-CCR8 agent, the method comprising:a) obtaining a sample from the subject:b) performing the method of claim 90:c) comparing the level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or number of CCR8 expressing cells: andd) selecting the subject for treatment with an anti-CCR8 agent if the level of the subject’s CCR8 or number of CCR8 expressing cells exceed tire threshold level of CCR8 or number of CCR8 expressing cells.

93. The method of claim 92, wherein the CCR8 expressing cell is a CCR+Treg cell.

94. A system of mediating depletion of a CCR8 expressing cell population in a subject, the system comprising components comprising:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k); ork) any combination thereof.

95. The system of claim 94, wherein the system components further comprise one or more system components to detect the baseline number of CCR8 expressing cells and / or detect the depletion of the CCR8 expressing cell relative to the baseline number of CCR8 expressing cells.

96. The system of claim 95, wherein the one or more detection components comprise:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69 (b), 71 (b), 71 (c), or 71 (d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) die population of cells of claim 74(a), 74(b), or 74(c);j) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k); ork) any combination thereof; andoptionally wherein the components further comprise a detection reagent or an amplification reagent.

97. The system of any one of claims 94-96, wherein the CCR8 expressing cell is a CCR8+ Treg cell.

98. A pharmaceutical composition comprising the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), 76(k), or any combination thereof and a pharmaceutically acceptable excipient.

99. A method of mediating depletion of a level of CCR8 expression or number of CCR8 expressing cellsin a subject, the method comprising:a) determining a baseline level of CCR8 expression or number of CCR8 expressing cells in a sample obtained from the subject, comprising obtaining a sample, contacting said sample with: i) any one of the isolated antibodies of claims 1-31 or a portion thereof;ii) any one of the binding polypeptides of claims 32-48 or a portion thereof;iii) any one of the binding polypeptides of claims 49-68 or a portion thereof;iv) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);v) the vector of claim 70(a), 70(b), 70(c), or 70(d);vi) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);vii) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof; viii) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),ix) the population of cells of claim 74(a), 74(b), or 74(c);x) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);xi) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);xii) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);xiii) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i), 89(j), 89(k), 89(l), or 89(m); orxiv) any combination thereof;under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; anddetecting the level of CCR8 expression or number of CCR8 expressing cells in said sample; b) administering to the subject an effective amount of a therapeutic anti-CCR8 agent comprising an antibody or antigen-binding fragment thereof that can specifically bind to CCR8; and c) determining the level of CCR8 expression or number of CCR8 expressing cells in a second sample, wherein the decrease of the level of CCR8 expression or number of CCR8 expressingcells in the second sample relative to the baseline level indicates that the level of CCR8 expression or number of CCR8 expressing cells has been depleted in the subject.

100. The method of claim 99, wherein the therapeutic anti-CCR8 agent does not comprise:a) any one of the isolated antibodies of claims 1 -31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);l) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);m) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i), 89(j), 89(k), 89(l), or 89(m); orn) any combination thereof.

101. The method of claims 99 or 100, wherein the sample obtained from the subject is obtained from solid tumor tissue.

102. The method of any one of claims 92-101, wherein the CCR8 expressing cell population are CCR8+ Treg cells.

103. A method of treating cancer in a subject in need thereof, the method comprisinga) detecting the level of CCR8 expression or analyzing the number of CCR8 expressing cells in a sample obtained from the subject, wherein the detecting comprises:i) contacting the sample with:1) any one of the isolated antibodies of claims 1-31 or a portion thereof;2) any one of the binding polypeptides of claims 32-48 or a portion thereof;3) any one of the binding polypeptides of claims 49-68 or a portion thereof;4) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);5) the vector of claim 70(a), 70(b), 70(c), or 70(d);6) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);7) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof; 8) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g), 9) the population of cells of claim 74(a), 74(b), or 74(c); or10) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);11) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);12) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);13) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i ), 89(j), 89(k), 89(1), or 89(m); or14) any combination thereof;under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; andii) associating the level of CCR8 expression or number of CCR8 expressing cells with a diseased microenvironment; andb) administering to the subject an effective amount of a therapeutic anti-CCR8 agent comprising an antibody or antigen-binding fragment thereof that can specifically bind to CCR8.

104. The method of claim 103, wherein the therapeutic anti-CCR8 agent does not comprise:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);l) the device of any one of claims 88(a), 88(b), 88(d), 88(c), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);m) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i ), 89(j), 89(k), 89(1), or 89(m); orn) any combination thereof.

105. A method of detecting CCR8 in a solid tumor sample obtained from a subject, comprising:a) contacting the solid tumor sample witli:i) any one of the isolated antibodies of claims 1-31 or a portion thereof;ii) any one of the binding polypeptides of claims 32-48 or a portion thereof;iii) any one of the binding polypeptides of claims 49-68 or a portion thereof;iv) the polynucleotide of claim 69(a), 69(b), 69(c), or 69(d);v) the vector of claim 70(a), 70(b), 70(c), or 70(d);vi) the library of vectors of claim 69(b), 71 (b), 71(c), or 71(d);vii) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof; viii) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),ix) the population of cells of claim 74(a), 74(b), or 74(c);x) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);xi) die composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);xii) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);xiii) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i), 89(j), 89(k), 89(1), or 89(m); orxiv) any combination of (i)-(xiii);under conditions sufficient and for a period of time to permit binding between the isolated antibody and / or the binding polypeptide and CCR8; andb) detecting the level of CCR8 or the number of CCR8 expressing cells in said solid tumor sample, 106. A method of selecting a subject having a solid cancer for treatment with a therapeutic anti-CCR8 agent, the method comprising:a) obtaining a solid tumor sample from the subject;b) detecting the level of CCR8 or analyzing the number of CCR8 expressing cells in the solid tumor sample by performing the method of claim 105;c) comparing die level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells; andd) selecting die subject for treatment with an anti-CCR8 agent if the level of the subject's CCR8 or number of CCR8 expressing cells exceed the threshold level of CCR8 or number of CCR8 expressing cells.

107. A method of treating a subject having a solid cancer with a therapeutic anti-CCR8 agent, the method comprising:a) selecting the subject for treatment by performing the method of claim 106; andb) administering an effective amount of the therapeutic anti-CCR8 agent.

108. The method of claim 107, wherein the therapeutic anti-CCR8 agent does not comprise:a) any one of the isolated antibodies of claims 1-31 or a portion thereof;b) any one of the binding polypeptides of claims 32-48 or a portion thereof;c) any one of the binding polypeptides of claims 49-68 or a portion thereof;d) the polynucleotide of claim 69(a). 69(b), 69(c), or 69(d);e) the vector of claim 70(a), 70(b), 70(c), or 70(d);f) the library of vectors of claim 69(b), 71(b), 71(c), or 71(d);g) the cell of any one of claims 72(a), 72(b), 72(c), 72(d), or any combination thereof;h) the cell of any one of claims 73(a), 73(b), 73(c), 73(d), 73(e), 73(f), 73(g),i) the population of cells of claim 74(a), 74(b), or 74(c);j) the system of any one of claims 75(a), 75(b), 75(c), 75(d), 75(e), 75(f), 75(g), 75(h), 75(i), or 75(j);k) the composition of any one of claims 76(a), 76(b), 76(c), 76(d), 76(e), 76(f), 76(g), 76(h), 76(i), 76(j), or 76(k);l) the device of any one of claims 88(a), 88(b), 88(d), 88(e), 88(f), 88(g), 88(h), 88(i), 88(j), 88(k), or 88(1);m) the kit of any one of claims 89(a), 89(b), 89(c), 89(d), 89(e), 89(f), 89(g), 89(h), 89(i), 89(j), 89(k), 89(1), or 89 (m); orn) any combination thereof.

109. A method of monitoring therapeutic efficacy of a treatment with a therapeutic anti-CCR8 agent in a subject having a solid cancer, the method comprising:a) obtaining a solid tumor sample from the subject;b) detecting the level of CCR8 expression or number of CCR8 expressing cells in the solid tumor sample by performing the method of claim 105; andc) comparing the detected level of the subject's CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells;wherein the treatment of the therapeutic anti-CCR8 agent has therapeutic efficacy if the detected level CCR8 expression or number of CCR8 expressing cells is depleted relative to the threshold level of CCR8 expression or number of CCR8 expressing cells.

110. A method of evaluating the prognosis of a subject having a solid cancer and undergoing treatment with a therapeutic anti-CCR8 agent, the method comprising:a) obtaining a solid tumor sample from the subject;b) detecting the level of CCR8 expression or number of CCR8 expressing cells in the solid tumor sample by performing the method of claim 105; andc) comparing the detected level of the subject’s CCR8 or number of CCR8 expressing cells with a threshold level of CCR8 or CCR8 expressing cells;wherein the subject has an improved prognosis if the detected level CCR8 expression or number of CCR8 expressing cells is depleted relative to the threshold level of CCR8 expression or number of CCR8 expressing cells.

111. The method of claim 109 or claim 110, wherein the threshold level of CCR8 expression or number of CCR8 expressing cells is a baseline level of CCR8 expression or number of CCR8 expressingcells of the subject prior to receiving the initial treatment with the therapeutic anti-CCR8 agent, or any subsequent treatment with the therapeutic anti-CCR8 agent.

112. The method of any one of claims 109-111, wherein the CCR8 expressing cells are Treg cells and the detection measures the depletion of CCR8+Treg cells.

113. The method of any one claims 101-112, wherein the solid cancer is chosen from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC., non-squamous NSCLC, head and neck cancer, breast cancer, cancer of the esophagus, gastric cancer, gastrointestinal cancer, cancer of the small intestine, liver cancer, hepatocellular carcinoma (I-ICC), pancreatic cancer (PAC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, cancer of the urethra, cancer of the ureter, colorectal cancer (CRC), colon cancer, colon carcinoma, cancer of the anal region, endometrial cancer, prostate cancer, a fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, carcinoma of the endometrium, carcinoma of tire fallopian tubes, ovarian cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, testicular cancer, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the penis, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, solid tumors of childhood, environmentally-induced cancers, virus related cancers, cancers of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof.

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