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JP-7855519-B2 - Anti-CCR8 antibodies for treating cancer

JP7855519B2JP 7855519 B2JP7855519 B2JP 7855519B2JP-7855519-B2

Inventors

  • ラン，ルース イン－ゾン
  • リー，ジョン ケイ
  • リー，ピーター ソンギュン
  • リアン，リンダ
  • ルー，カイ
  • マクドナルド，ブライアン
  • メスコ，ポール ブレイン
  • ラジパル，アルビンド
  • サンバンタムールティ，シャルミラ
  • セルビー，マーク ジェイ
  • シーマーズ，ネイサン オー
  • アデラクン，オルフェミ エイ
  • ストロップ，パベル
  • テッラチーナ，ゲイビー エイ
  • ワン，シー－タオ
  • バルマン，イシタ
  • キャンベル，ジョセフ リチャード
  • ディオン，エスジェイ ジエン ジョー
  • フィンダイゼン，フェリックス
  • グリーナウォルト，ダニエル エム
  • ジャイン，レニュ
  • ジャタキア，エイミー ディ

Assignees

  • ブリストル－マイヤーズ スクイブ カンパニー

Dates

Publication Date
20260508
Application Date
20210322
Priority Date
20200323

Claims (20)

  1. A modified anti-hCCR8 monoclonal antibody or its antigen-binding moiety, which specifically binds to the human C-C motif chemokine receptor 8 (hCCR8) described in SEQ ID NO: 1, expressed on the surface of human activated regulatory T cells (Treg) at an EC 50 of 20 nM ± 25% or less, as measured by the binding assay described in Example 11, and mediates antibody-dependent cell-mediated cell-mediated cytotoxicity (ADCC) killing of activated human Treg, or a modified version of the anti-hCCR8 monoclonal antibody or its antigen-binding moiety, comprising a modified heavy chain constant region that binds to the Fcγ receptor with higher affinity compared to the unmodified anti-hCCR8 antibody and mediates enhanced ADCC , The monoclonal antibody or modified monoclonal antibody or its antigen-binding moiety contains the following CDR domain as defined by the Kabat method: (a) Heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 33, heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 34, heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 35, light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 36, light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 37, and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 38. (b) Heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 39, heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 40, heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 41, light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 42, light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 43, and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 44. (c) Heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 45, heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 46, heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 47, light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 48, light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 49, and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 50. (d) Heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 69, heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 70, heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 71, light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 72, light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 73, and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 74. (e) Heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 75, heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 76, heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 77, light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 78, light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 79, and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 80, or ( f) Heavy chain variable region CDR1 containing continuously linked amino acids having the sequence described in SEQ ID NO: 103, heavy chain variable region CDR2 containing continuously linked amino acids having the sequence described in SEQ ID NO: 104, heavy chain variable region CDR3 containing continuously linked amino acids having the sequence described in SEQ ID NO: 105, light chain variable region CDR1 containing continuously linked amino acids having the sequence described in SEQ ID NO: 106, light chain variable region CDR2 containing continuously linked amino acids having the sequence described in SEQ ID NO: 107, and light chain variable region CDR3 containing continuously linked amino acids having the sequence described in SEQ ID NO: 108 Monoclonal antibodies or modified monoclonal antibodies, or their antigen-binding moieties, including [the specified substance].
  2. (i) When measured by the binding assay described in Example 11, (a) 10 nM ± 25% or less, (b) 5 nM ± 25% or less, (c) 1.7 nM ± 25% or less, (d) 1 nM ± 25% or less, (e) 0.5 nM ± 25% or less, (f) 0.1 nM ± 25% or less, (g) 0.1 nM ± 25%, (h) 1.7nM±25%, (i) Between 0.1 nM ± 25% and 10 nM ± 25%, (j) Between 0.1 nM ± 25% and 2 nM ± 25%, (k) Between 0.5 nM ± 25% and 5 nM ± 25%, (l) Specifically binds to human CCR8-expressing Chinese hamster ovary cells at an EC 50 between 1 nM ± 25% and 2 nM ± 25%, or (m) between 0.5 nM ± 25% and 1 nM ± 25%, and/or (ii) as measured by the binding assay described in Example 11, ( a ) 14 nM ± 25% or less, ( b ) 5 nM ± 25% or less, ( c ) 2nM ± 25% or less, ( d ) 0.5 nM ± 25% or less, ( e ) 0.3 nM ± 25% or less, ( f ) 0.1 nM ± 25% or less, ( g ) 0.03 nM ± 25% or less, ( h ) 1.7 nM ± 25%, ( i ) Between 0.03 nM ± 25% and 10 nM ± 25%, ( j ) Specifically binds to activated regulatory T cells (Treg) at an EC 50 between 0.1 nM ± 25% and 5 nM ± 25%, or ( k ) between 0.2 nM ± 25% and 2 nM ± 25%, and/or (iii) when measured by surface plasmon resonance (SPR) as described in Example 11, (a) 100 nM ± 25% or less, (b) 50 nM ± 25% or less, (c) 10 nM ± 25% or less, (d) 5 nM ± 25% or less, (e) 1.6 nM ± 25%, (f) 1.0 nM ± 25% or less, (g) 0.5 nM ± 25% or less, (h) 0.1 nM ± 25% or less, (i) Between 100 nM ± 25% and 0.1 nM ± 25%, (j) Between 50 nM ± 25% and 0.5 nM ± 25%, (k) bound to the N-terminal peptide of human CCR8 containing sulfated tyrosine-15 and tyrosine-17 residues at a KD between 10 nM ± 25% and 1 nM ± 25%, or (l) between 2 nM ± 25% and 1 nM ± 25%, and/or (iv) measured by the SPR described in Example 11, (a) 100 nM ± 25% or less, (b) 50 nM ± 25% or less, (c) 25 nM ± 25% or less, (d) 10 nM ± 25% or less, (f) 1.0 nM ± 25% or less, (e) 20 nM ± 25%, (i) Between 100 nM ± 25% and 1 nM ± 25%, (j) between 50 nM ± 25% and 10 nM ± 25%, or (k) between 30 nM ± 25% and 20 nM ± 25%, a single sulfated residue, i.e., tyrosine-15, is bound to the N-terminal peptide of human CCR8. The monoclonal antibody or modified monoclonal antibody according to claim 1 , or the antigen-binding portion thereof.
  3. A monoclonal antibody or modified monoclonal antibody or its antigen-binding moiety according to claim 1 or 2, which specifically binds to rare, scattered immune cells in the thymic medulla and dermis of the skin, but does not bind to any of the human cerebrum, cerebellum, heart, liver, lungs, kidneys, tonsils, spleen, thymus, colon, stomach, pancreas, adrenal gland, pituitary gland, skin, peripheral nerves, testes, or uterine tissue, or peripheral blood mononuclear cells (PBMCs).
  4. (i) When measured by inhibition of calcium flow as described in Example 15, the binding of C-C motif chemokine ligand 1 (CCL1) to CCR8 is inhibited , (a) 10 nM ± 25% or less, (b) 5 nM ± 25% or less, (c) 1 nM ± 25% or less, (d) 0.5 nM ± 25% or less, (e) 0.1 nM ± 25% or less, (f) 0.01 nM ± 25% or less, (g) Between 0.01 nM ± 25% and 10 nM ± 25%, (h) Between 0.05 nM ± 25% and 5 nM ± 25%, (i) between 0.1 nM ± 25% and 1 nM ± 25%, or (j) 0.46 nM ± 25% Inhibits CCR8/CCL1 signaling at IC50 and/or (ii) measured by the CD16 crosslinking assay described in Example 17, (a) 100 pM ± 25% or less, (b) 30 pM ± 25% or less, (c) 10 pM ± 25% or less, (d) 3 pM ± 25% or less, (e) 1 pM ± 25% or less, (e) 0.5 pM ± 25% or less, (f) 0.1 pM ± 25% or less, (g) 0.05 pM ± 25% or less, (h) 0.7 pM ± 25%, (i) Between 0.05 pM ± 25% and 50 pM ± 25%, (j) Between 0.1 pM ± 25% and 10 nM ± 25%, (k) mediating the depletion of CCR8-expressing cells at an EC 50 between 0.3 nM ± 25% and 7 nM ± 25%, or (l) between 0.6 nM ± 25% and 3 nM ± 25%, and/or (iii) as measured by the apoptosis assay described in Example 19, (a) 500 pM ± 25% or less, (b) 100 pM ± 25% or less, (c) 30 pM ± 25% or less, (d) 15 pM ± 25% or less, (e) 5 pM ± 25% or less, (f) 1 pM ± 25% or less, (g) 13 pM ± 25%, (h) Between 1 pM ± 25% and 500 pM ± 25%, (i) Mediates the depletion of activated Treg at EC 50 between 5 pM ± 25% and 100 pM ± 25%, or (j) between 10 pM ± 25% and 50 pM ± 25%. A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof, as described in any one of claims 1 to 3 .
  5. When determined by X-ray crystallography, it binds to an epitope located in the N-terminal domain of human CCR8. (a) The epitope comprises at least one amino acid in a peptide having the sequence Y15 Y16 Y17 P18 D19 I20 F21 (SEQ ID NO: 2) , and comprises a sulfated Y15 or a sulfated Y17 residue. (b) The epitope contains two, three, four, five, six, or all of the amino acids in a peptide having the sequence Y15 Y16 Y17 P18 D19 I20 F21 (SEQ ID NO: 2) , and contains a sulfated Y15 or sulfated Y17 residue . (c) The epitope contains all seven amino acids in a peptide having the sequence Y15 Y16 Y17 P18 D19 I20 F21 (SEQ ID NO: 2) , and contains a sulfated Y15 or sulfated Y17 residue. (d) The epitope consists of all seven amino acids in a peptide having the sequence Y15 Y16 Y17 P18 D19 I20 F21 ( SEQ ID NO : 2 ) , and includes a sulfated Y15 or sulfated Y17 residue. (e) The epitope comprises at least one amino acid in a peptide having the sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (Sequence ID 109), and includes sulfated Y 15 and sulfated Y 17 residues. (f) The epitope contains 2 , 3, 4, 5, 6, 7, 8, 9, 10 , or all of the amino acids in a peptide having the sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (SEQ ID NO: 109) , and contains sulfated Y 15 and sulfated Y 17 residues. (g) The epitope contains all 11 amino acids in a peptide having the sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (SEQ ID NO: 109) , and contains sulfated Y 15 and sulfated Y 17 residues, or (h) The epitope consists of all 11 amino acids in a peptide having the sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (Sequence ID 109) , and includes sulfated Y 15 and sulfated Y 17 residues. A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof, as described in any one of claims 1 to 4 .
  6. A modified anti-hCCR8 monoclonal antibody or its antigen-binding moiety capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC), comprising a modified heavy chain constant region that binds to the Fcγ receptor with higher affinity than an unmodified anti-hCCR8 monoclonal antibody or its antigen-binding moiety and mediates enhanced ADCC, wherein the modified anti-hCCR8 monoclonal antibody or its antigen-binding moiety specifically binds to an epitope on the human C-C motif chemokine receptor 8 (hCCR8) located in the N-terminal domain of human CCR8, and the epitope is (a) Containing amino acids Y15, Y16, Y17, P18 , D19 , I20 , F21 (SEQ ID NO: 2), wherein amino acids Y15 or Y17 are sulfated, or (b) Consists of amino acids Y15, Y16, Y17, P18 , D19 , I20 , F21 (SEQ ID NO: 2), wherein amino acid Y15 or Y17 is sulfated, or (c) A peptide having sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (Sequence ID 109) containing all 11 amino acids, wherein amino acids Y 15 and Y 17 are sulfated, or (d) Consists of all 11 amino acids in a peptide having the sequence V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (Sequence ID 109), wherein amino acids Y 15 and Y 17 are sulfated. Monoclonal antibodies or modified monoclonal antibodies or their antigen-binding moieties.
  7. K10 nM ± 25% or less D A monoclonal antibody or its antigen-binding moiety according to claim 5 or 6, which binds to an epitope located in the N-terminal domain of human CCR8, Epitope, (a) Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 (SEQ ID NO: 2) and sulfated Y 15 or Y 17 A peptide having a sequence containing residues, or (b) V 12 T 13 D 14 Y 15 Y 16 Y 17 P 18 D 19 I 20 F 21 S 22 (SEQ ID NO: 109) and sulfated Y 15 and Y 17 peptides having a sequence, including residues. A monoclonal antibody or its antigen-binding moiety, including the above.
  8. A monoclonal antibody or a modified monoclonal antibody or its antigen-binding moiety according to any one of claims 1 to 7, wherein the monoclonal antibody or a modified monoclonal antibody or its antigen-binding moiety mediates ADCC activity that is at least 2-fold, 5-fold, or 10-fold enhanced compared to an unmodified monoclonal antibody or its antigen-binding moiety, as measured by the decrease in EC50 of cell lysis in the NK cell lysis assay described in Example 17 .
  9. ( a ) promotes the depletion of human tumor-associated Tregs in vitro, and/or ( b) specifically induces the depletion of tumor Tregs without depleting CCR8 + T cells in non-tumor tissue, and/or ( c ) inhibits tumor cell growth in the subject when administered to the subject as monotherapy, and/or ( d ) inhibits tumor cell growth in the subject when administered to the subject in combination with additional therapeutic agents to treat cancer. A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to any one of claims 1 to 8 .
  10. The following characteristics: (a) When measured by the antibody binding assay described in Example 11, it specifically binds to CCR8 expressed on the cell surface at an EC 50 of 2 nM ± 25% or less. (b) It specifically binds to rare, scattered immune cells in the thymic medulla and dermis of the skin, but does not bind to any of the human cerebrum, cerebellum, heart, liver, lungs, kidneys, tonsils, spleen, thymus, colon, stomach, pancreas, adrenal glands, pituitary gland, skin, peripheral nerves, testes, or uterine tissue, or peripheral blood mononuclear cells (PBMCs). (c) Inhibiting the binding of CCL1 to CCR8 with an IC50 of 5 nM ± 25% or less, thereby inhibiting CCR8/CCL1 signaling. (d) When bound to CCR8 on the cell surface, it mediates cell depletion at an EC 50 of 10 pM ± 25% or less. (e) When bound to CCR8 on the cell surface, it does not cause internal migration of CCR8, both in the presence and absence of the cross-linking antibody. (f ) To promote the depletion of human tumor-associated Tregs in vitro , (g ) To promote the depletion of human tumor-related Treg in ex vivo human tumor slice samples, (h) To preserve CCR8 + T cells in non-tumor tissue while specifically mediating the depletion of tumor tregs. (i) When administered to a subject as monotherapy, it inhibits the growth of tumor cells in the subject; and (j) When administered to a subject in combination with additional therapeutic agents for treating cancer, it inhibits the growth of tumor cells in the subject, exhibiting at least one, two, three, four, five, or six , or all of these effects. A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to any one of claims 1 to 9 .
  11. A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to any one of claims 1 to 10, wherein the monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof binds to the same hCCR8 epitope as the reference antibody and/or cross-competes with the reference antibody for binding to hCCR8, and the reference antibody comprises VH containing a sequence of linked amino acids having the sequence described in SEQ ID NO: 6, and VL containing a sequence of linked amino acids having the sequence described in SEQ ID NO: 18 .
  12. (a) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 4, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 16. (b) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 5, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 17. (c) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 6, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 18. (d) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 10, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 22. (e) VH containing a sequence of amino acids having the sequence described in SEQ ID NO: 11, and VL containing a sequence of amino acids having the sequence described in SEQ ID NO: 23, or (f) VH containing a sequence of amino acids having the sequence described in SEQ ID NO: 115, and VL containing a sequence of amino acids having the sequence described in SEQ ID NO: 116 A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to any one of claims 1 to 11 , comprising the CDR1, CDR2, and CDR3 domains in each of the above.
  13. A monoclonal antibody or a modified monoclonal antibody or its antigen-binding moiety according to any one of claims 1 to 12, which , when bound to CCR8 on the surface of a cell, does not cause internal migration of CCR8, whether in the presence or absence of a cross-linking antibody .
  14. The following CDR domains are defined by the Kabat method: heavy chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 45; heavy chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 46; heavy chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 47; light chain variable region CDR1 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 48; light chain variable region CDR2 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 49; and light chain variable region CDR3 containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 50 . A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to any one of claims 1 to 13.
  15. The antibody comprises VH containing a sequence of continuously linked amino acids having a sequence that is at least 80% identical to the sequence described in SEQ ID NO: 6, and VL containing a sequence of continuously linked amino acids having a sequence that is at least 80% identical to the sequence described in SEQ ID NO: 18, and retains the functional properties of an antibody comprising VH and VL regions having the sequences described in SEQ ID NO: 6 and SEQ ID NO: 18, respectively. Alternatively, VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 6, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 18, Alternatively, the material may include a heavy chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 102, and a light chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 114. The monoclonal antibody or modified monoclonal antibody according to claim 14 , or the antigen-binding portion thereof.
  16. ( a ) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 4, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 16. ( b ) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 5, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 17. ( c ) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 6, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 18. ( d ) VH containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 10, and VL containing a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 22. ( e ) VH containing a sequence of amino acids having the sequence described in SEQ ID NO: 11, and VL containing a sequence of amino acids having the sequence described in SEQ ID NO: 23, or ( f ) VH containing a sequence of amino acids having the sequence described in SEQ ID NO: 115, and VL containing a sequence of amino acids having the sequence described in SEQ ID NO: 116 Includes or, ( g ) A heavy chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 100, and a light chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 112. ( h ) A heavy chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 101, and a light chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 113. ( i ) a heavy chain comprising a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 102, and a light chain comprising a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 114, or ( j ) a heavy chain comprising a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 117, and a light chain comprising a sequence of continuously linked amino acids having the sequence described in SEQ ID NO: 118, the monoclonal antibody or modified monoclonal antibody or antigen-binding moiety thereof according to any one of claims 1 to 15 .
  17. An anti-hCCR8 monoclonal antibody or modified monoclonal antibody or antigen-binding moiety thereof according to any one of claims 1 to 16, comprising a chimeric antibody, a humanized antibody, a human antibody, a human IgG1 isotype, a human IgG3 isotype, or a modified IgG1 heavy chain constant region that mediates enhanced ADCC, or a fragment that mediates ADCC of any of the antibodies.
  18. (i) Low-fucosylated, or non-fucosylated, and/or (ii) containing enhanced ADCC-mediated mutations or multiple mutations A monoclonal antibody or a modified monoclonal antibody or an antigen-binding moiety thereof according to claim 17, comprising a modified IgG1 heavy chain constant region .
  19. Mutations or multiple mutations of IgG1 are selected from G236A;S239D;F243L;E333A;G236A/I332E;S239D/I332E;S267E/H268F;S267E/S324T;H268F/S324T; and G236A/S239D/I332E. The modified anti-hCCR8 monoclonal antibody or its antigen-binding moiety according to claim 18 .
  20. A modified monoclonal antibody comprising a heavy chain constant region that is low-fucosylated or non-fucosylated, which specifically binds to human C-C motif chemokine receptor 8 (hCCR8) described in SEQ ID NO: 1 , which is expressed on the surface of cells, and mediates the depletion of CCR8-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), comprising a heavy chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 102, and a light chain containing continuously linked amino acids having the sequence described in SEQ ID NO: 114.

Description

Throughout this application, various publications are referenced in parentheses by author name and date, or by patent number or patent publication number. The complete sources of these publications will be found at the end of this specification immediately preceding the claims. Thus, the disclosures of these publications are incorporated into this application by whole reference to more completely describe the latest art known to those skilled in the art as of the date of the invention described herein and claimed. However, these disclosures are incorporated into this application only to the extent that there is no conflict between the information incorporated by reference and the information provided by explicit disclosures in this application. Furthermore, references to references in this specification should not be construed as an admission that such references constitute prior art of the invention. Cross-reference of Related Applications This application claims the benefits of U.S. Provisional Applications No. 63/157,618 filed on 5 March 2021, No. 63/041,992 filed on 21 June 2020, and No. 62/993,570 filed on 23 March 2020, the entire contents of which are incorporated herein by reference. Sequence Listing This application is filed electronically in ASCII format and contains a sequence listing which is incorporated herein by reference in its entirety. An ASCII copy was created on 19 March 2021, named 20210319_SEQL_13358WOPCT.txt, and is 81,920 bytes in size. The disclosed invention relates to an isolated antibody (Ab), such as a monoclonal antibody (mAb), that specifically binds to C-C motif chemokine receptor 8 (CCR8), and a method for treating cancer in a subject, comprising administering the anti-CCR8 Ab to the subject as monotherapy or in combination with an anticancer agent such as an immune checkpoint inhibitor. Human cancers encompass numerous genetic and epigenetic alterations that generate novel antigens potentially recognizable by the immune system (Chakravarthi et al., 2016). Leveraging the cancer-treating properties of the adaptive immune system makes immunotherapy unique among all cancer treatment modalities, due to its applicability to a wide range of cancers and its ability to induce sustained antitumor effects. Considerable success has already been achieved in treating a variety of solid tumors and hematological malignancies by stimulating cytotoxic T cell activity with checkpoint inhibitors such as the anti-PD-1 antibody nivolumab [OPDIVO®] and the anti-CTLA-4 antibody ipilimumab [YERVOY®]. However, typically, less than 15% of patients with cancers for which this treatment is possible benefit from checkpoint inhibitor therapy in the long term (Haslam and Prasad, 2019), and checkpoint inhibitors have proven to be relatively ineffective in certain cancers, including breast and prostate cancer. The persistence of immunosuppressive mechanisms, particularly those mediated by regulatory T cells (Tregs), may contribute to the observed resistance to checkpoint inhibitor therapy in certain cancers or in certain patients (Fares et al., 2019, Han et al., 2019). As one means of overcoming this resistance, this application discloses a method of stimulating the immune system by reducing the immunosuppressive effect of Treg. Tumor-infiltrating CD4 + CD25 + FOXP3 + Tregs, a subset of CD4 + T cells, are mediators of immunological self-tolerance. Deletion of genes involved in Treg development and function results in systemic autoimmunity in both mice (Fontenot et al., 2003, Khattri et al., 2003, Tivol et al., 1995) and humans (Yagi et al., 2004, Kuehn et al., 2014), highlighting the crucial and essential role of Tregs in maintaining immune homeostasis. Tregs suppress the immune system through multiple mechanisms, including downregulation of effector T cell induction and proliferation, secretion of chemokines and inhibitory cytokines, and suppression of dendritic cell maturation and function (Shitara and Nishikawa, 2018, Han et al., 2019). The self-tolerance-promoting mechanisms utilized by Treg can be incorporated into the tumor microenvironment and suppress the anti-tumor immune response. In fact, systemic depletion of Treg in mice is sufficient to enable immune-mediated tumor reduction (Teng et al., 2010). Therefore, Treg is thought to play a role in mediating peripheral immune tolerance to autoantigens, preventing autoimmune diseases, and suppressing the anti-tumor immune response. As a result, reducing the activity or number of tumor-infiltrating Tregs has been identified as an attractive method for reversing immunosuppressive activity in the tumor microenvironment and enhancing anti-tumor immunity (Finotello and Trajanoski, 2017, Han et al., 2019). Various methods targeting Tregs in cancer immunotherapy, such as ADCC-mediated depletion of Tregs using antibodies (Abs) against antigens expressed on Tregs, including CD25 (Arce Vargas et al., 2017), CCR4 (Ishida et al., 2012, Hagemann et al., 2014), and C