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US-12624113-B2 - Anti-human CCR1 monoclonal antibody

US12624113B2US 12624113 B2US12624113 B2US 12624113B2US-12624113-B2

Abstract

A monoclonal antibody is provided which binds to a human CC chemokine receptor 1 (CCR1) and inhibits activation of the human CCR1, or an antibody fragment thereof. The monoclonal antibody binds to an extracellular region of a human CCR1 and inhibits activation of the human CCR1 by a human CC chemokine ligand 15 (CCL15). An antibody fragment thereof, a hybridoma producing the antibody, a nucleic acid having a nucleotide sequence encoding the antibody or the antibody fragment, a transformant cell containing a vector containing the nucleic acid, a method for producing the antibody or the antibody fragment using the hybridoma or the transformant cell; a therapeutic agent and a diagnostic agent containing the antibody or the antibody fragment, and a method for treating and diagnosing a CCR1-related disease using the antibody or the antibody fragment are also provided.

Inventors

  • Masayuki Kai
  • Shinya Ogawa
  • Makoto Taketo
  • Kenji Kawada
  • Hideyo HIRAI
  • Yoshiharu Sakai
  • Taira Maekawa

Assignees

  • KYOWA KIRIN CO., LTD.
  • KYOTO UNIVERSITY

Dates

Publication Date
20260512
Application Date
20230901
Priority Date
20170718

Claims (16)

  1. 1 . A method for diagnosing a CC chemokine receptor 1 (CCR1)-related cancer in a human subject, comprising: detecting CCR1 in a biological sample of the human subject with a monoclonal antibody or antibody fragment thereof, whereby the subject is diagnosed as having the CCR1-related cancer when CCR1 is detected, wherein the monoclonal antibody or antibody fragment thereof binds to an extracellular region of a human CCR1 and inhibits activation of the human CCR1 by a human CC chemokine ligand 15 (CCL15), and wherein the monoclonal antibody is any one antibody selected from the following (a) to (n); (a) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 76, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 78, 79, and 80, respectively, (b) an antibody in which the CDR1 of VH comprises the amino acid sequence of SEQ ID NO: 75, the CDR2 of VH comprises the amino acid sequence of SEQ ID NO: 76 or the amino acid sequence in which at least one modification selected from modifications of substituting Ile at a position 2 with Thr, Val at a position 9 with Ala, Phe at a position 14 with Ala, and Ile at a position 15 with Ala is introduced in the amino acid sequence of SEQ ID NO: 76, and the CDR3 of VH comprises the amino acid sequence of SEQ ID NO: 77 or the amino acid sequence in which at least one of modifications of substituting Tyr at a position 5 with Ala and Thr at a position 7 with Ala is introduced in the amino acid sequence of SEQ ID NO: 77, and in which the CDR1 of VL comprises the amino acid sequence of SEQ ID NO: 126 or the amino acid sequence in which a modification of substituting Phe at a position 15 with Ala is introduced in the amino acid sequence SEQ ID NO: 126, the CDR2 of VL comprises the amino acid sequence of SEQ ID NO: 127 or the amino acid sequence in which at least one of modifications of substituting Val at a position 2 with Ile, and Arg at a position 5 with Lys is introduced in the amino acid sequence of SEQ ID NO: 127, and the CDR3 of VL comprises the amino acid sequence of SEQ ID NO: 128, (c) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 131, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 126, 134, and 128, respectively, (d) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 53, and in which VL comprises the amino acid sequence of SEQ ID NO: 54, (e) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 130, and in which VL comprises the amino acid sequence of SEQ ID NO: 133, (f) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 136 or the amino acid sequence in which at least one of amino acid modifications of substituting Glu at a position 6 with Gln, Leu at a position 20 with Ile, Gly at a position 27 with Phe, Val at a position 29 with Leu, Ser at a position 30 with Asn, Ile at a position 37 with Val, Ile at a position 48 with Leu, Val at a position 67 with Leu, Val at a position 71 with Lys, Thr at a position 73 with Asp, Asn at a position 76 with Ser, Phe at a position 78 with Val, Leu at a position 80 with Phe, Leu at a position 82 with Met, Val at a position 85 with Leu, Val at a position 92 with Ile, and Arg at a position 97 with Lys is introduced in the amino acid sequence of SEQ ID NO: 136, and in which VL comprises the amino acid sequence of SEQ ID NO: 135 or the amino acid sequence in which at least one of amino acid modifications of substituting Ile at a position 2 with Val, Pro at a position 15 with Leu, Gln at a position 50 with Lys, Tyr at a position 92 with Phe, and Val at a position 109 with Leu is introduced in the amino acid sequence of SEQ ID NO: 135, (g) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 135, (h) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 137, (i) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 138, (j) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 139, (k) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 140, (l) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 141, (m) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 142, and (n) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 143, and in which VL comprises the amino acid sequence of SEQ ID NO: 142.
  2. 2 . A method for treating a CCR1-related cancer in a human subject having CCR1-related cancer, comprising: administering to the human subject a therapeutically-effective amount of a monoclonal antibody or antibody fragment thereof, thereby treating the CCR1-related cancer in the subject, wherein the monoclonal antibody or antibody fragment thereof binds to an extracellular region of a human CCR1 and inhibits activation of the human CCR1 by a human CC chemokine ligand 15 (CCL15), and wherein the monoclonal antibody is any one antibody selected from the following (a) to (n); (a) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 76, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 78, 79, and 80, respectively, (b) an antibody in which the CDR1 of VH comprises the amino acid sequence of SEQ ID NO: 75, the CDR2 of VH comprises the amino acid sequence of SEQ ID NO: 76 or the amino acid sequence in which at least one modification selected from modifications of substituting Ile at a position 2 with Thr, Val at a position 9 with Ala, Phe at a position 14 with Ala, and Ile at a position 15 with Ala is introduced in the amino acid sequence of SEQ ID NO: 76, and the CDR3 of VH comprises the amino acid sequence of SEQ ID NO: 77 or the amino acid sequence in which at least one of modifications of substituting Tyr at a position 5 with Ala and Thr at a position 7 with Ala is introduced in the amino acid sequence of SEQ ID NO: 77, and in which the CDR1 of VL comprises the amino acid sequence of SEQ ID NO: 126 or the amino acid sequence in which a modification of substituting Phe at a position 15 with Ala is introduced in the amino acid sequence SEQ ID NO: 126, the CDR2 of VL comprises the amino acid sequence of SEQ ID NO: 127 or the amino acid sequence in which at least one of modifications of substituting Val at a position 2 with Ile, and Arg at a position 5 with Lys is introduced in the amino acid sequence of SEQ ID NO: 127, and the CDR3 of VL comprises the amino acid sequence of SEQ ID NO: 128, (c) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 131, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 126, 134, and 128, respectively, (d) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 53, and in which VL comprises the amino acid sequence of SEQ ID NO: 54, (e) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 130, and in which VL comprises the amino acid sequence of SEQ ID NO: 133, (f) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 136 or the amino acid sequence in which at least one of amino acid modifications of substituting Glu at a position 6 with Gln, Leu at a position 20 with Ile, Gly at a position 27 with Phe, Val at a position 29 with Leu, Ser at a position 30 with Asn, Ile at a position 37 with Val, Ile at a position 48 with Leu, Val at a position 67 with Leu, Val at a position 71 with Lys, Thr at a position 73 with Asp, Asn at a position 76 with Ser, Phe at a position 78 with Val, Leu at a position 80 with Phe, Leu at a position 82 with Met, Val at a position 85 with Leu, Val at a position 92 with Ile, and Arg at a position 97 with Lys is introduced in the amino acid sequence of SEQ ID NO: 136, and in which VL comprises the amino acid sequence of SEQ ID NO: 135 or the amino acid sequence in which at least one of amino acid modifications of substituting Ile at a position 2 with Val, Pro at a position 15 with Leu, Gln at a position 50 with Lys, Tyr at a position 92 with Phe, and Val at a position 109 with Leu is introduced in the amino acid sequence of SEQ ID NO: 135, (g) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 135, (h) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 137, (i) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 138, (j) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 139, (k) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 140, (l) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 141, (m) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 142, and (n) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 143, and in which VL comprises the amino acid sequence of SEQ ID NO: 142.
  3. 3 . The method of claim 1 , wherein the monoclonal antibody is any one antibody selected from the following (a) to (c): (a) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 76, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 78, 79, and 80, respectively, (b) an antibody in which the CDR1 of VH comprises the amino acid sequence of SEQ ID NO: 75, the CDR2 of VH comprises the amino acid sequence of SEQ ID NO: 76 or the amino acid sequence in which at least one modification selected from modifications of substituting Ile at a position 2 with Thr, Val at a position 9 with Ala, Phe at a position 14 with Ala, and Ile at a position 15 with Ala is introduced in the amino acid sequence of SEQ ID NO: 76, and the CDR3 of VH comprises the amino acid sequence of SEQ ID NO: 77 or the amino acid sequence in which at least one of modifications of substituting Tyr at a position 5 with Ala and Thr at a position 7 with Ala is introduced in the amino acid sequence of SEQ ID NO: 77, and in which the CDR1 of VL comprises the amino acid sequence of SEQ ID NO: 126 or the amino acid sequence in which a modification of substituting Phe at a position 15 with Ala is introduced in the amino acid sequence SEQ ID NO: 126, the CDR2 of VL comprises the amino acid sequence of SEQ ID NO: 127 or the amino acid sequence in which at least one of modifications of substituting Val at a position 2 with Ile, and Arg at a position 5 with Lys is introduced in the amino acid sequence of SEQ ID NO: 127, and the CDR3 of VL comprises the amino acid sequence of SEQ ID NO: 128, and (c) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 131, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 126, 134, and 128, respectively.
  4. 4 . The method of claim 2 , wherein the monoclonal antibody is any one antibody selected from the following (a) to (c): (a) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 76, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 78, 79, and 80, respectively, (b) an antibody in which the CDR1 of VH comprises the amino acid sequence of SEQ ID NO: 75, the CDR2 of VH comprises the amino acid sequence of SEQ ID NO: 76 or the amino acid sequence in which at least one modification selected from modifications of substituting Ile at a position 2 with Thr, Val at a position 9 with Ala, Phe at a position 14 with Ala, and Ile at a position 15 with Ala is introduced in the amino acid sequence of SEQ ID NO: 76, and the CDR3 of VH comprises the amino acid sequence of SEQ ID NO: 77 or the amino acid sequence in which at least one of modifications of substituting Tyr at a position 5 with Ala and Thr at a position 7 with Ala is introduced in the amino acid sequence of SEQ ID NO: 77, and in which the CDR1 of VL comprises the amino acid sequence of SEQ ID NO: 126 or the amino acid sequence in which a modification of substituting Phe at a position 15 with Ala is introduced in the amino acid sequence SEQ ID NO: 126, the CDR2 of VL comprises the amino acid sequence of SEQ ID NO: 127 or the amino acid sequence in which at least one of modifications of substituting Val at a position 2 with Ile, and Arg at a position 5 with Lys is introduced in the amino acid sequence of SEQ ID NO: 127, and the CDR3 of VL comprises the amino acid sequence of SEQ ID NO: 128, and (c) an antibody in which the CDRs 1 to 3 of VH comprise the amino acid sequences of SEQ ID NOs: 75, 131, and 77, respectively, and in which the CDRs 1 to 3 of VL comprise the amino acid sequences of SEQ ID NOs: 126, 134, and 128, respectively.
  5. 5 . The method of claim 1 , wherein the monoclonal antibody is any one antibody selected from the following (d) or (e): (d) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 53, and in which VL comprises the amino acid sequence of SEQ ID NO: 54, and (e) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 130, and in which VL comprises the amino acid sequence of SEQ ID NO: 133.
  6. 6 . The method of claim 2 , wherein the monoclonal antibody is any one antibody selected from the following (d) or (e): (d) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 53, and in which VL comprises the amino acid sequence of SEQ ID NO: 54, and (e) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 130, and in which VL comprises the amino acid sequence of SEQ ID NO: 133.
  7. 7 . The method of claim 1 , wherein the monoclonal antibody is the following (f): (f) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 136 or the amino acid sequence in which at least one of amino acid modifications of substituting Glu at a position 6 with Gln, Leu at a position 20 with Ile, Gly at a position 27 with Phe, Val at a position 29 with Leu, Ser at a position 30 with Asn, Ile at a position 37 with Val, Ile at a position 48 with Leu, Val at a position 67 with Leu, Val at a position 71 with Lys, Thr at a position 73 with Asp, Asn at a position 76 with Ser, Phe at a position 78 with Val, Leu at a position 80 with Phe, Leu at a position 82 with Met, Val at a position 85 with Leu, Val at a position 92 with Ile, and Arg at a position 97 with Lys is introduced in the amino acid sequence of SEQ ID NO: 136, and in which VL comprises the amino acid sequence of SEQ ID NO: 135 or the amino acid sequence in which at least one of amino acid modifications of substituting Ile at a position 2 with Val, Pro at a position 15 with Leu, Gln at a position 50 with Lys, Tyr at a position 92 with Phe, and Val at a position 109 with Leu is introduced in the amino acid sequence of SEQ ID NO: 135.
  8. 8 . The method of claim 2 , wherein the monoclonal antibody is the following (f): (f) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 136 or the amino acid sequence in which at least one of amino acid modifications of substituting Glu at a position 6 with Gln, Leu at a position 20 with Ile, Gly at a position 27 with Phe, Val at a position 29 with Leu, Ser at a position 30 with Asn, Ile at a position 37 with Val, Ile at a position 48 with Leu, Val at a position 67 with Leu, Val at a position 71 with Lys, Thr at a position 73 with Asp, Asn at a position 76 with Ser, Phe at a position 78 with Val, Leu at a position 80 with Phe, Leu at a position 82 with Met, Val at a position 85 with Leu, Val at a position 92 with Ile, and Arg at a position 97 with Lys is introduced in the amino acid sequence of SEQ ID NO: 136, and in which VL comprises the amino acid sequence of SEQ ID NO: 135 or the amino acid sequence in which at least one of amino acid modifications of substituting Ile at a position 2 with Val, Pro at a position 15 with Leu, Gln at a position 50 with Lys, Tyr at a position 92 with Phe, and Val at a position 109 with Leu is introduced in the amino acid sequence of SEQ ID NO: 135.
  9. 9 . The method of claim 1 , wherein the monoclonal antibody is any one antibody selected from the following (g) to (n): (g) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 135, (h) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 137, (i) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 138, (j) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 139, (k) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 140, (l) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 141, (m) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 142, and (n) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 143, and in which VL comprises the amino acid sequence of SEQ ID NO: 142.
  10. 10 . The method of claim 2 , wherein the monoclonal antibody is any one antibody selected from the following (g) to (n): (g) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 135, (h) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 137, (i) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 138, (j) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 139, (k) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 140, (l) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 141, (m) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 144, and in which VL comprises the amino acid sequence of SEQ ID NO: 142, and (n) an antibody in which VH comprises the amino acid sequence of SEQ ID NO: 143, and in which VL comprises the amino acid sequence of SEQ ID NO: 142.
  11. 11 . The method of claim 1 , wherein the monoclonal antibody is a genetically recombinant antibody.
  12. 12 . The method of claim 2 , wherein the monoclonal antibody is a genetically recombinant antibody.
  13. 13 . The method of claim 11 , wherein the genetically recombinant antibody is any one of genetically recombinant antibodies selected from a human chimeric antibody, a humanized antibody, and a human antibody.
  14. 14 . The method of claim 12 , wherein the genetically recombinant antibody is any one of genetically recombinant antibodies selected from a human chimeric antibody, a humanized antibody, and a human antibody.
  15. 15 . The method of claim 1 , wherein the antibody fragment is any one of antibody fragments selected from Fab, Fab′, (Fab′) 2 , a single chain antibody (scFv), a dimerized V region (diabody), a disulfide stabilized V region (dsFv), and a peptide comprising CDR.
  16. 16 . The method of claim 2 , wherein the antibody fragment is any one of antibody fragments selected from Fab, Fab′, (Fab′) 2 , a single chain antibody (scFv), a dimerized V region (diabody), a disulfide stabilized V region (dsFv), and a peptide comprising CDR.

Description

SEQUENCE LISTING A sequence listing in electronic (XML file) format is filed with this application and incorporated herein by reference. The name of the XML file is “Sequence Listing.xml”; the file was created on Aug. 29, 2023; the size of the file is 259,647 bytes. TECHNICAL FIELD The present invention relates to a monoclonal antibody which binds to an extracellular region of a human CC chemokine receptor 1 (CC chemokine receptor 1, hereinafter, referred to as human CCR1) and inhibits activation of the human CCR1 by a human CC chemokine ligand (hereinafter, referred to as human CCL) 15, or an antibody fragment thereof, a hybridoma producing the antibody, a nucleic acid having a nucleotide sequence encoding the antibody or the antibody fragment, a transformant cell containing a vector containing the nucleic acid, a method for producing the antibody or the antibody fragment using the hybridoma or the transformant cell; a therapeutic agent and a diagnostic agent containing the antibody or the antibody fragment, and a method for treating and diagnosing a CCR1-related disease using the antibody or the antibody fragment. BACKGROUND ART CCR1 has other names such as surface antigen classification (cluster of differentiation, CD) 191, CKR-1, HM145, Macrophage inflammatory protein 1α receptor (MIP1α R), CMKBR1, SCYAR1, or the like. A gene encoding human CCR1 is identified in 1993 (NPT 1). The cDNA sequence (SEQ ID NO: 1) and amino acid sequence (SEQ ID NO: 2) of human CCR1 are publicly available. For example, in National Center for Biotechnology Information (NCBI), the cDNA sequence can be referred to as NM_001295, and the protein amino acid sequence can be referred to as NP_001286. The cDNA sequence (SEQ ID NO: 3) and amino acid sequence (SEQ ID NO: 4) of a mouse CCR1 are also disclosed. In NCBI, the cDNA sequence can be referred to as NM_009912, and the protein amino acid sequence can be referred to as NP_034042. CCR1 is a G protein-coupled receptor (hereinafter, referred to as GPCR) having a seven-transmembrane structure, and is a membrane protein consisting of a total length of 355 amino acids. As ligands for the human CCR1, human CCL3, CCL5, CCL8, CCL14, CCL15, CCL16, and CCL23 have been reported (NPL 2). Further, as ligands for mouse CCR1, mouse CCL3, CCL5, CCL7, and CCL9 have been reported (NPL 3). The human CCL15 is a ligand included in the C-C chemokine family and consists of a total of 92 amino acids. CCR1 and CCR3 are known to function as CCL15 receptors. It has been known that CCL15 exhibits stronger activity when an N-terminus thereof is degraded by the action of proteases and becomes an activated form of about 68 amino acids (NPL 4). The activation of the chemokine receptors including CCR1 is considered to occur through the following two steps (NPL 5). As a step 1, the interaction between the chemokine (ligand) and an N-terminus extracellular region of the receptor is generated. As a step 2, the N-terminus region of the chemokine interacts with the extracellular loop region of the receptor, and as a result of the structural change of the receptor, a signal is transmitted into the cell. In the intracellular signal transduction of GPCRs, G proteins α, β, and γ trimers associated with a C-terminus of GPCR are activated in response to structural changes in GPCR generated by ligand binding, and α subunits is dissociated from a βγ complex. The α subunit acts on further downstream factors and activates signal transduction pathways. When phospholipase C (hereinafter, referred to as “PLC”) is activated by the activation of the α subunit, phosphatidylinositol (4,5) diphosphate [phosphatidylinositol (4,5) bisphosphate, PIP2] is decomposed, and inositol triphosphate (IP3) and diacylglycerol (DAG) are produced. IP3 acts on an endoplasmic reticulum, releases calcium ions (Ca2+) into cells, and causes various cellular responses via calmodulin. This increase in an intracellular calcium concentration can be measured using a fluorescent calcium indicator or the like, and can be used as an index of GPCR activation. For CCR1, it is also possible to measure the activation of intracellular signals by this method. Expression of the human CCR1 in various blood cells such as neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells, NK cells, T cells, and B cells has been reported so far (NPLs 6 to 10). In recent years, it has been reported that cell clusters called immature myeloid cells (hereinafter, referred to as iMC) and myeloid derived suppressor cells (hereinafter, referred to as MDSC) that exist in cancer microenvironment and promote progress of cancer express CCR1 (NPLs 11 and 12). CCR1 has been suggested to be involved in various autoimmune diseases and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and chronic obstructive pulmonary disease (NPL 13). In addition, the expression in iMC and MDSC described above suggests that CCR1 contributes to the progress of cancer and exac