JPWO2021194942A5 - - Google Patents

Claims (37)

An anti-hCCR8 monoclonal antibody, or antigen-binding portion thereof, that specifically binds to human C-C motif chemokine receptor 8 ( hCCR8 ) expressed on the surface of a cell and mediates depletion of CCR8-expressing cells by antibody-dependent cellular cytotoxicity (ADCC) ; or a modified version of said anti-hCCR8 monoclonal antibody, or antigen-binding portion thereof, that comprises a modified heavy chain constant region that binds to Fcγ receptors with higher affinity and mediates enhanced ADCC compared to an unmodified anti-hCCR8 monoclonal antibody, or antigen-binding portion thereof, wherein when bound to CCR8 on the surface of a cell, the monoclonal antibody, or modified monoclonal antibody, or antigen-binding portion thereof, does not cause internalization of CCR8 in either the presence or absence of a cross-linking antibody. 2. The monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof of claim 1 , comprising a heavy chain constant region of the human IgG1 or IgG3 isotype. at _least
(a) 2-fold enhanced ADCC activity;
(a) mediates a 5-fold enhanced ADCC activity; or (c) mediates a 10-fold enhanced ADCC activity;
Optionally,
(i) exhibits reduced fucosylation and may comprise a modified IgG1 heavy chain constant region that is hypofucosylated or afucosylated ; and/or
(ii) contains a mutation or multiple mutations that mediate enhanced ADCC , wherein the mutation or multiple mutations may be selected from G236A, S239D, F243L, E333A, G236A/I332E, S239D/I332E, S267E/H268F, S267E/S324T, H268F/S324T, G236A/S239D/I332E, S239D/A330L/I332E, S267E/H268F/S324T, and G236A/S239D/A330L/I332E;
3. A modified monoclonal antibody or an antigen-binding portion thereof according to claim 1 or 2. (i) as measured by the binding assay described in Example 11,
(a) about 10 nM or less;
(b) about 5 nM or less;
(c) about 1.7 nM or less;
(d) about 1 nM or less;
(e) about 0.5 nM or less;
(f) about 0.1 nM or less;
(g) about 0.1 nM,
(h) about 1.7 nM,
(i) between about 0.1 nM and about 10 nM;
(j) between about 0.1 nM and about 2 nM;
(k) between about 0.5 nM and about 5 nM;
(l) specifically binds to human CCR8-expressing Chinese Hamster Ovary cells with an _EC50 of between about 1 nM and about 2 nM, or (m) between about 0.5 nM and about 1 nM, and/or (ii) as measured by the binding assay described in Example 11.
(a) about 50 nM or less;
(b) about 14 nM or less;
(c) about 5 nM or less;
(d) about 2 nM or less;
(e) about 0.5 nM or less;
(f) about 0.3 nM or less;
(g) about 0.1 nM or less;
(h) about 0.03 nM or less;
(i) about 1.7 nM,
(j) between about 0.03 nM and about 10 nM;
(k) specifically binds to activated regulatory T cells (Tregs) with an _EC50 of between about 0.1 nM and about 5 nM, or (l) with an EC50 of between about 0.2 nM and about 2 nM, and/or (iii) as measured by surface plasmon resonance (SPR) as described in Example 11.
(a) about 100 nM or less;
(b) about 50 nM or less;
(c) about 10 nM or less;
(d) about 5 nM or less;
(e) about 1.6 nM,
(f) about 1.0 nM or less;
(g) about 0.5 nM or less;
(h) about 0.1 nM or less;
(i) between about 100 nM and about 0.1 nM;
(j) between about 50 nM and about 0.5 nM;
(k) binds to an N-terminal peptide of human CCR8 comprising sulfated tyrosine-15 and tyrosine-17 residues with a K _D of between about 10 nM and about 1 nM, or (l) binds to an N-terminal peptide of human CCR8 comprising sulfated tyrosine-15 and tyrosine-17 residues with a K D of between about 2 nM and about 1 nM, and/or (iv) binds to an N-terminal peptide of human CCR8 comprising sulfated tyrosine-15 and tyrosine-17 residues with a K D of between about 10 nM and about 1 nM, as measured by SPR as described in Example 11.
(a) about 100 nM or less;
(b) about 50 nM or less;
(c) about 25 nM or less;
(d) about 10 nM or less;
(f) about 1.0 nM or less;
(e) about 20 nM,
(i) between about 100 nM and about 1 nM;
(j) binds to an N-terminal peptide of human CCR8 that contains a single sulfated residue, i.e., tyrosine-15, with a K _D of between about 50 nM and about 10 nM; or (k) binds to an N-terminal peptide of human CCR8 that contains a single sulfated residue, i.e., tyrosine-15, with a K D of between about 30 nM and about 20 nM.
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 3 . The monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof of any one of claims 1-4, which specifically binds to rare and scattered immune cells in the thymic medulla and skin dermis, but does not bind to human cerebrum, cerebellum, heart, liver, lung, kidney, tonsil, spleen, thymus, colon, stomach, pancreas, adrenal gland, pituitary gland, skin , peripheral nerve, testis, or uterine tissue , or peripheral blood mononuclear cells (PBMCs). (i) inhibiting binding of C-C motif chemokine ligand 1 (CCL1) to CCR8 and inhibiting CCR8/CCL1 signaling, as measured by inhibition of calcium flux as described in Example 15 ; optionally
(a) about 10 nM or less;
(b) about 5 nM or less;
(c) about 1 nM or less;
(d) about 0.5 nM or less;
(e) about 0.1 nM or less;
(f) about 0.01 nM or less;
(g) between about 0.01 nM and about 10 nM;
(h) between about 0.05 nM and about 5 nM;
(i) between about 0.1 nM and about 1 nM; or (j) about 0.46 nM.
and/or (ii) inhibit CCR8/CCL1 signaling with an _IC50 of
(a) about 100 pM or less;
(b) about 30 pM or less;
(c) about 10 pM or less;
(d) about 3 pM or less;
(e) about 1 pM or less;
(e) about 0.5 pM or less;
(f) about 0.1 pM or less;
(g) about 0.05 pM or less;
(h) about 0.7 pM,
(i) between about 0.05 pM and about 50 pM;
(j) between about 0.1 pM and about 10 nM;
(k) mediate depletion of CCR8-expressing cells with an _EC50 of between about 0.3 nM and about 7 nM; or (l) mediate depletion of CCR8-expressing cells with an EC50 of between about 0.6 nM and about 3 nM; and/or (iii) as measured by the apoptosis assay described in Example 19.
(a) about 500 pM or less;
(b) about 100 pM or less;
(c) about 30 pM or less;
(d) about 15 pM or less;
(e) about 5 pM or less;
(f) about 1 pM or less;
(g) about 13 pM,
(h) between about 1 pM and about 500 pM;
(i) mediates depletion of activated Tregs with an _EC50 of between about 5 pM and about 100 pM; or (j) mediates depletion of activated Tregs with an EC50 of between about 10 pM and about 50 pM;
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 5 . binds to an epitope located in the N-terminal domain of human CCR8 as determined by X-ray crystallography;
(a) the epitope comprises at least one amino acid in a peptide having the sequence _{Y15Y16Y17P18D19I20F21 ( SEQ} ID _{NO : 2} ) _;
(i) the epitope may comprise 2 _{, 3} , 4, 5, 6 or all of the amino acids in a peptide having the sequence Y15Y16Y17P18D19I20F21 _{( SEQ ID NO} :2 ) _;
(ii) the epitope may comprise all seven amino acids in a peptide having _the sequence Y15Y16Y17P18D19I20F21 _{( SEQ ID} NO _{: 2} ) _;
(iii) amino acids Y15 _and /or Y17 are optionally sulfated; or
(b) _{the epitope} comprises at least one amino acid in _a peptide having _{the sequence V12T13D14Y15Y16Y17P18D19I20F21S22} (SEQ ID _{NO : 109 ) ;}
(i) the epitope may comprise 2, 3 _{, 4 , 5 , 6} , 7 _{, 8} , 9, 10, or all of the amino acids in a peptide having _the sequence _{V12T13D14Y15Y16Y17P18D19I20F21S22} (SEQ ID NO: ₁₀₉ );
(ii) _the epitope _may comprise all eleven _amino acids in _a peptide having _{the sequence V12T13D14Y15Y16Y17P18D19I20F21S22} ( _SEQ ID _{NO : 109} );
( iii ) the _{epitope may} consist of all ₁₁ amino acids in _a peptide having _{the sequence V12T13D14Y15Y16Y17P18D19I20F21S22 (} SEQ ID _{NO : 109} );
(iv) both amino acids _Y15 and _Y17 are optionally sulfated;
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 6 . An anti-hCCR8 monoclonal antibody or antigen-binding portion thereof capable of mediating antibody-dependent cellular cytotoxicity (ADCC), or a modified version of said anti-hCCR8 monoclonal antibody or antigen-binding portion thereof comprising a modified heavy chain constant region that binds to an Fcγ receptor with higher affinity and mediates enhanced ADCC compared to an unmodified anti-hCCR8 monoclonal antibody or antigen-binding portion thereof, which specifically binds to an epitope on human C-C motif chemokine receptor 8 (hCCR8) that is located in the N-terminal domain of human CCR8, and
(a) amino acid Y ₁₅ Y ₁₆ Y ₁₇ P ₁₈ D ₁₉ I ₂₀ F ₂₁ (SEQ ID NO:2), and ₁₅ and/or Y17 is sulfated, or
(b) Array 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), ₁₅ and/or Y17 is sulfated, or
(c) Array 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)
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof. 9. The monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof of claim 8, which, when bound to CCR8 on the surface of a cell, does not cause internalization of CCR8 in the presence or absence of a cross-linking antibody,
Optionally, the modified monoclonal antibody, or antigen-binding portion thereof, comprises a modified heavy chain constant region that mediates enhanced ADCC activity compared to an unmodified monoclonal antibody, or antigen-binding portion thereof;
Optionally, the modified monoclonal antibody or antigen-binding portion thereof exhibits an EC50 value for cytolysis in the NK cytolysis assay described in Example 17. ₅₀ At a minimum,
(a) 2-fold enhanced ADCC activity;
(a) a 5-fold enhanced ADCC activity, or
(c) 10-fold enhanced ADCC activity
Mediating
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof. (i) promote depletion of human tumor-associated Tregs in vitro; and/or
(ii) specifically induces depletion of tumor Tregs without depleting CCR8 ⁺ T cells in non-tumor tissues, which may be the skin, thymus, spleen, or blood; and/or
(iii) when administered to a subject as a monotherapy, inhibits the growth of tumor cells in the subject; and/or
(iv) inhibits the growth of tumor cells in a subject when administered to a subject in combination with an additional therapeutic agent for treating cancer;
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 9 . The following characteristics:
(a) specifically binds to CCR8 expressed on the surface of a cell with an _EC50 of about 2 nM or less, as measured by the binding assay described in Example 11;
(b) specifically binds to rare, scattered immune cells in the thymic medulla and skin dermis, but does not bind to human cerebrum, cerebellum, heart, liver, lung, kidney, tonsil, spleen, thymus, colon, stomach, pancreas, adrenal gland, pituitary gland, skin, peripheral nerve, testis, or uterine tissue, or to peripheral blood mononuclear cells (PBMCs);
(c) inhibiting the binding of CCL1 to CCR8 with an _IC50 of about 5 nM or less to inhibit CCR8/CCL1 signaling;
(d) when bound to CCR8 on the surface of a cell, mediates cell depletion with an _EC50 of about 10 pM or less;
(e) when bound to CCR8 on the surface of a cell, it does not cause internalization of CCR8 in either the presence or absence of a cross-linking antibody;
(f) promoting the depletion of human tumor-associated Tregs in vitro using the assay described in Example 22;
(g) promoting depletion of human tumor-associated Tregs in ex vivo human tumor slice samples using the assay described in Example 20;
(h) specifically mediating depletion of tumor Tregs while sparing CCR8 ⁺ T cells in non-tumor tissues;
(i) inhibiting the growth of tumor cells in a subject when administered to a subject as a monotherapy; and (j) inhibiting the growth of tumor cells in a subject when administered to a subject in combination with an additional therapeutic agent for treating cancer;
A monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof according to any one of claims 1 to 10 , which may exhibit all of these properties. _12. The monoclonal or modified monoclonal antibody or antigen-binding portion thereof according to any one of claims 1 to 11, which binds to the same hCCR8 epitope as a reference antibody and/or cross-competes with the reference antibody for binding to hCCR8, wherein the reference antibody comprises a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO :6 , and a VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:18. (a) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:4, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:16;
(b) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:5, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:17;
(c) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:6, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:18;
(d) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 10, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 22;
(e) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 11, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 23; or
(f) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:115, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:116.
13. A monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof according to any one of claims 1 to 12, comprising CDR1, CDR2 and CDR3 domains in each of said monoclonal antibodies . The CDR domains as defined by the Kabat method include a heavy chain variable region CDR1 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:45, a heavy chain variable region CDR2 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:46, a heavy chain variable region CDR3 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:47, a light chain variable region CDR1 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:48, a light chain variable region CDR2 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:49, and a light chain variable region CDR3 comprising contiguous linked amino acids having the sequence set forth in SEQ ID NO:50.
or a V comprising consecutively linked amino acids having a sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:6. _H and V comprising consecutively linked amino acids having a sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:18. _L and having the sequences set forth in SEQ ID NO:6 and SEQ ID NO:18, respectively. _H and V _L retaining the functional properties of the antibody containing the region,
or V comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:6. _H and V comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:18. _L including,
or a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 102, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 114;
14. A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 13. An anti-hCCR8 monoclonal antibody or antigen-binding portion thereof that specifically binds to human C-C motif chemokine receptor 8 ( hCCR8 ) expressed on the surface of cells with an _EC50 of about 20 nM or less as measured by the binding assay described in Example 11 and mediates antibody-dependent cellular cytotoxicity (ADCC) killing of activated human Tregs, or a modified version of said anti-hCCR8 monoclonal antibody or antigen-binding portion thereof comprising a modified heavy chain constant region that binds to Fcγ receptors with higher affinity compared to an unmodified anti-hCCR8 antibody, wherein said monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof comprises the following CDR domains as defined by the Kabat method:
(a) a heavy chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 33, a heavy chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 34, a heavy chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 35, a light chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 36, a light chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 37, and a light chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 38;
(b) a heavy chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:39, a heavy chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:40, a heavy chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:41, a light chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:42, a light chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:43, and a light chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:44;
(c) a heavy chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 45, a heavy chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 46, a heavy chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 47, a light chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 48, a light chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 49, and a light chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 50;
(d) a heavy chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:69, a heavy chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:70, a heavy chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:71, a light chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:72, a light chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:73, and a light chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO:74;
(e) a heavy chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 75, a heavy chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 76, a heavy chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 77, a light chain variable region CDR1 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 78, a light chain variable region CDR2 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 79, and a light chain variable region CDR3 comprising contiguously linked amino acids having the sequence set forth in SEQ ID NO: 80;
(f) a heavy chain variable region CDR1 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 103, a heavy chain variable region CDR2 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 104, a heavy chain variable region CDR3 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 105, a light chain variable region CDR1 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 106, a light chain variable region CDR2 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 107, and a light chain variable region CDR3 comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 108.
or
(g) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:4, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:16;
(h) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:5, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:17;
(i) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:6, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:18;
(j) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 10, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 22;
(k) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 11, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 23 ; or
(l) a _VH comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:115, and a _VL comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:116;
or
(m) a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 100, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 112;
(n) a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 101, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 113;
(o) a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 102, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 114; or
(p) a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 117, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 118.
A monoclonal antibody or modified monoclonal antibody, or an antigen-binding portion thereof, comprising: 16. The monoclonal or modified monoclonal antibody or antigen-binding portion thereof of any one of claims 1 to 15 , which is a chimeric antibody, a humanized antibody, a human antibody, a human IgG1 isotype, a human IgG3 isotype, a modified IgG1 heavy chain constant region that mediates enhanced ADCC, or a fragment thereof ,
Optionally, the monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof may be hypofucosylated, or non-fucosylated, or contain a mutation or multiple mutations that mediate enhanced ADCC;
Optionally, the mutation or multiple mutations may be selected from G236A; S239D; F243L; E333A; G236A/I332E; S239D/I332E; S267E/H268F; S267E/S324T; H268F/S324T; G236A/S239D/I332E; S239D/A330L/I332E; S267E/H268F/S324T; and G236A/S239D/A330L/I332E,
A monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof. A monoclonal antibody comprising a heavy chain constant region that is hypofucosylated or nonfucosylated, which specifically binds to human C-C motif chemokine receptor 8 (hCCR8) expressed on the surface of a cell and mediates depletion of CCR8-expressing cells by antibody-dependent cellular cytotoxicity (ADCC), the monoclonal antibody comprising a heavy chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 102, and a light chain comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 114. 20. An immunoconjugate comprising the monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof of any one of claims 1 to 17 linked to a cytolytic agent . The immunoconjugate of claim 18 , wherein the cytolytic agent is a cytotoxin or a radioisotope. A bispecific molecule comprising a monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof according to any one of claims 1 to 17, linked to a binding domain having a binding specificity different from that of the monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof . (a) a monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 17 ,
(b) an immunoconjugate according to claim 18 or 19 , or (c) a bispecific molecule according to claim 20 ;
and a pharma- ceutically acceptable carrier. 18. An isolated nucleic acid encoding the monoclonal antibody or modified monoclonal antibody or an antigen-binding portion thereof according to any one of claims 1 to 17 . 23. An expression vector comprising the nucleic acid of claim 22 . A host cell comprising the expression vector of claim 23 . A method for preparing an anti-CCR8 monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof , comprising expressing the antibody or antigen-binding portion thereof in a host cell described in claim 24 and isolating the antibody or antigen-binding portion thereof from the host cell. 22. A pharmaceutical composition for treating cancer in a subject suffering from cancer , comprising a therapeutically effective amount of a monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof described in any one of claims 1 to 17 , an immunoconjugate described in claim 18 or 19 , a bispecific molecule described in claim 20 , or a composition described in claim 21 , wherein treating cancer comprises administering the monoclonal antibody or modified monoclonal antibody to the subject . 22. A pharmaceutical composition for inhibiting the growth of tumor cells in a subject , comprising a therapeutically effective amount of a monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof described in any one of claims 1 to 17 , an immunoconjugate described in claim 18 or 19 , a bispecific molecule described in claim 20 , or a composition described in claim 21 , wherein inhibiting the growth of tumor cells comprises administering the monoclonal antibody or modified monoclonal antibody to the subject. Treating cancer or inhibiting the growth of tumor cells further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating cancer;
The additional therapeutic agent may be a compound that reduces inhibition or increases stimulation of the immune system;
The additional therapeutic agent may be an immune checkpoint inhibitor, a chemotherapeutic agent, radiation therapy, a small molecule compound, a macrocyclic peptide, a fusion protein, and/or an antibody;
28. A pharmaceutical composition according to claim 26 or 27. Additional therapeutic agents include
(a) an antagonist agent, such as an antagonist monoclonal antibody, that specifically binds to programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-3 (TIM-3), killer immunoglobulin-like receptor (KIR), killer cell lectin-like receptor G1 (KLRG-1), adenosine A2a receptor (A2aR), T-cell immunoreceptor having Ig and ITIM domains (TIGIT), V-domain Ig-containing inhibitor of T-cell activation (VISTA), proto-oncogene tyrosine protein kinase MER (MerTK), natural killer cell receptor 2B4 (CD244), or CD160; or
(b) an agonistic agent, such as an agonistic monoclonal antibody that specifically binds to inducible T cell costimulator (ICOS), CD137 (4-1BB), CD134 (OX40), CD27, glucocorticoid-induced TNFR-related protein (GITR), or herpes virus entry mediator (HVEM), and optionally
(i) the antagonist agent is an antagonist antibody or an antigen-binding portion thereof that specifically binds to PD-1; or (ii) the antibody that specifically binds to PD-1 is selected from nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, retifanlimab, and pimivalimab; or (iii) the antagonist agent is an antagonist antibody or an antigen-binding portion thereof that specifically binds to PD-L1. or (iv) the antibody that specifically binds to PD-L1 is selected from atezolizumab, durvalumab, avelumab, emvaforimab, BMS-936559, CK-301, CS-1001, SHR-1316, CBT-502, and BGB-A333, or (v) the antagonist agent is an antagonist antibody or antigen-binding portion thereof that specifically binds to CTLA-4, or (vi) the antibody that specifically binds to CTLA-4 is ipilimumab or tremelimumab.
29. A pharmaceutical composition according to any one of claims 26 to 28 . (a) the cancer is a solid tumor, and the solid tumor is
(i) 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, esophageal cancer, gastric cancer, gastrointestinal cancer, small intestine cancer, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer (PAC), renal cell carcinoma (RCC), bladder cancer, urethral cancer, ureteral cancer, colorectal cancer (CRC), colon cancer, colon cancer, anal cancer, endometrial cancer, prostate cancer, fibrosarcoma, neuroblastoma, glioma, glioblastoma, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, skin cancer, bone cancer, cervical cancer, uterine cancer, endometrial cancer selected from carcinoma of the fallopian tube, 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, neoplasms 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 carcinoma, squamous cell carcinoma, solid tumors of childhood, environmentally induced cancer, virus-associated cancer, cancer of viral origin, advanced cancer, unresectable cancer, metastatic cancer, refractory cancer, recurrent cancer, and any combination thereof; or (ii) a cancer selected from non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), gastric cancer, gastroesophageal (GE) junction cancer, and cervical cancer; or (iii) a cancer selected from head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), gastric adenocarcinoma (STAD), lung squamous cell carcinoma (LUSC), pancreatic adenocarcinoma (PAAD), rectal adenocarcinoma (READ), esophageal cancer (ESCA), invasive breast cancer (BRCA), colon adenocarcinoma (COAD), and cervical squamous cell carcinoma and adenocarcinoma of the cervix (CESC); or (iv) a cancer selected from squamous cell carcinoma of the head and neck (SCCHN), cervical cancer, colorectal cancer (CRC), non-small cell lung cancer - squamous cell carcinoma (NSCLC-SCC), NSCLC adenocarcinoma (NSCLC-ADC), pancreatic cancer, gastric cancer, bladder cancer, and breast cancer, or (v) a cancer selected from colon adenocarcinoma, bladder cancer, breast cancer, and fibrosarcoma; or (b) the cancer is a hematological malignancy or the tumor cells are cells of a hematological malignancy, and the hematological malignancy may be selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), T-cell lymphoma, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), multiple myeloma, smoldering myeloma, monoclonal gammopathy of undetermined significance (MGUS), advanced, metastatic, refractory, and/or recurrent hematological malignancies, and any combination of said hematological malignancies.
30. A pharmaceutical composition according to any one of claims 26 to 29 . 22. A pharmaceutical composition for enhancing an anti-tumor immune response induced by a therapeutic agent in a subject suffering from cancer, comprising a therapeutically effective amount of a monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof described in any one of claims 1 to 17 , an immunoconjugate described in claim 18 or 19 , a bispecific molecule described in claim 20 , or a composition described in claim 21 , wherein enhancing the anti-tumor immune response comprises administering to the subject the monoclonal antibody or modified monoclonal antibody, immunoconjugate, bispecific molecule, or composition such that the subject experiences a stronger immune response against the cancer compared to the immune response induced by the therapeutic agent alone. The pharmaceutical composition of claim 31, wherein the therapeutic agent is an immune checkpoint inhibitor , a chemotherapy agent, or radiation therapy, and the immune checkpoint inhibitor may be an anti-PD-1, anti-PD-L1, or anti-CTLA- 4 antibody . 20. A pharmaceutical composition for treating cancer in a subject comprising the monoclonal antibody of claim 17, wherein treating the cancer comprises administering the monoclonal antibody to the subject. 34. The pharmaceutical composition of claim 33, wherein treating cancer comprises administering to a subject the monoclonal antibody in combination with nivolumab. 35. The pharmaceutical composition of any one of claims 26 to 34 , wherein the subject is a human. 1. A kit for treating cancer in a subject suffering from cancer, comprising:
(a) one or more doses ranging from about 0.01 to about 20 mg/kg body weight of an anti-CCR8 monoclonal antibody or modified monoclonal antibody or antigen-binding portion thereof according to any one of claims 1 to 17 ;
(b) instructions for treating cancer in a subject , wherein treating the cancer comprises administering to the subject the anti-CCR8 monoclonal antibody or modified monoclonal antibody, or an antigen-binding portion thereof; and
Including the kit. a monoclonal antibody or antigen-binding portion thereof that specifically binds to PD-1, PD-L1, or CTLA-4, in one or more doses ranging from about 0.1 to about 20 mg/kg body weight , or a fixed dose of about 200 to about 1600 mg;
and instructions for administering to a subject a monoclonal antibody or portion thereof that specifically binds to PD-1, PD-L1, or CTLA-4 in combination with the anti-CCR8 monoclonal antibody or modified monoclonal antibody, or antigen- binding portion thereof.