title: Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis.
abstract: BACKGROUND
  CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis.
  
  
  METHODS
  Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies.
  
  
  CONCLUSIONS
  For the first time, successful generation of anti- G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.
authors: Affitech Research AS, Oslo, Norway.
authors: Urs B
authors: UB
authors: Hagemann
authors: Affitech Research AS, Oslo, Norway.
authors: Lavinia
authors: L
authors: Gunnarsson
authors: Affitech Research AS, Oslo, Norway.
authors: Solène
authors: S
authors: Géraudie
authors: Affitech Research AS, Oslo, Norway.
authors: Ulrike
authors: U
authors: Scheffler
authors: Affitech Research AS, Oslo, Norway.
authors: Remko A
authors: RA
authors: Griep
authors: Affitech Research AS, Oslo, Norway.
authors: Herald
authors: H
authors: Reiersen
authors: Affitech Research AS, Oslo, Norway.
authors: Alexander R
authors: AR
authors: Duncan
authors: Affitech Research AS, Oslo, Norway.
authors: Sergej M
authors: SM
authors: Kiprijanov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054414:Chemokine CCL17 / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D008297:Male; D008819:Mice, Nude; D019151:Peptide Library; D010974:Platelet Aggregation / Q000187:drug effects; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D057127:Single-Chain Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D019151:Peptide Library; D054398:Receptors, CCR4; D057127:Single-Chain Antibodies