Abstract
BackgroundCC 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.MethodologyUsing 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.SignificanceFor 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.
Highlights
The G-protein coupled chemokine receptors and their ligands, the chemo-attractant cytokines or chemokines, play crucial roles in both homeostasis and disease [1]
In order to generate initial antibodies against chemokine receptor 4 (CCR4), phage display selection was performed using a single-chain Fv (scFv) antibody library derived from a naıve human IgM/IgD repertoire [33]
To identify antagonistic antibodies against CCR4, the phages binding to the CCR4+ cells and not to CCR42 cells were competitively eluted in presence of CCR4-specific ligands CCL17 or CCL22
Summary
The G-protein coupled chemokine receptors and their ligands, the chemo-attractant cytokines or chemokines, play crucial roles in both homeostasis and disease [1]. The chemokine receptors are involved in a wide variety of pathological inflammatory and immune responses through chemo-attraction of innate and adaptive immune cells. Their homeostatic roles include the leukocyte maturation and trafficking, organogenesis, angiogenesis, and tissue repair [2]. The aberrant expression of the chemokine receptors on tumor cells can promote tumor metastasis in the secondary organs that release the corresponding chemokine ligands [4]. 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
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