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Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis
Affitech Research AS, Oslo, Norway; Algeta/Bayer AS, Oslo, Norway.
Örebro University, School of Science and Technology, Örebro University, Sweden. Affitech Research AS, Oslo, Norway. (Biokemi)
Affitech Research AS, Oslo, Norway; Radiumhospitalet, Oslo, Norway.
Affitech Research AS, Oslo, Norway; ProBioGen AG, Berlin, Germany.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e103776Article in journal (Refereed) Published
Abstract [en]

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.

Methodology: 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.

Significance: 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.

Place, publisher, year, edition, pages
San Francisco, USA: Public Library Science , 2014. Vol. 9, no 7, e103776
National Category
Medical and Health Sciences Immunology Cell Biology
Research subject
URN: urn:nbn:se:oru:diva-45516DOI: 10.1371/journal.pone.0103776ISI: 000339954800080PubMedID: 25080123ScopusID: 2-s2.0-84905119945OAI: diva2:845231
Available from: 2015-08-11 Created: 2015-08-11 Last updated: 2015-10-14Bibliographically approved

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Gunnarsson, Lavinia
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