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Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis.

Hagemann UB, Gunnarsson L, Géraudie S, Scheffler U, Griep RA, Reiersen H, Duncan AR, Kiprijanov SM - PLoS ONE (2014)

Bottom Line: In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies.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 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.

View Article: PubMed Central - PubMed

Affiliation: Affitech Research AS, Oslo, Norway.

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.

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.

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Related in: MedlinePlus

ADCP activity of defucosylated anti-CCR4 IgG1 antibody 503 K in the presence of isolated human monocytes.Dose-dependent phagocytosis of T-cell leukemia CCRF-CEM cells (a) and human renal cell cancer 786-O cells (b) incubated with monocytes at E:T ratio 5∶1 for 1, 2 or 3 hrs is shown. Dotted lines indicate the levels of spontaneous phagocytosis.
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pone-0103776-g011: ADCP activity of defucosylated anti-CCR4 IgG1 antibody 503 K in the presence of isolated human monocytes.Dose-dependent phagocytosis of T-cell leukemia CCRF-CEM cells (a) and human renal cell cancer 786-O cells (b) incubated with monocytes at E:T ratio 5∶1 for 1, 2 or 3 hrs is shown. Dotted lines indicate the levels of spontaneous phagocytosis.

Mentions: In order to investigate whether the candidate 503 can mediate phagocytic activity of macrophages (ADCP), a phagocytosis assay with human monocytes as effector cells was established. The defucosylated candidate 503 K demonstrated significant enhancement of spontaneous phagocytosis of both T-cell leukemia CCRF-CEM cells and of the human renal cell carcinoma 786-O cells (Figure 11a and b, respectively). Taken together, the affinity matured human anti-CCR4 antibodies, in particular the variant 503, showed improved ADCC and ADCP effector functions, and the ADCC activity could be further enhanced through glycooptimization.


Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis.

Hagemann UB, Gunnarsson L, Géraudie S, Scheffler U, Griep RA, Reiersen H, Duncan AR, Kiprijanov SM - PLoS ONE (2014)

ADCP activity of defucosylated anti-CCR4 IgG1 antibody 503 K in the presence of isolated human monocytes.Dose-dependent phagocytosis of T-cell leukemia CCRF-CEM cells (a) and human renal cell cancer 786-O cells (b) incubated with monocytes at E:T ratio 5∶1 for 1, 2 or 3 hrs is shown. Dotted lines indicate the levels of spontaneous phagocytosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117600&req=5

pone-0103776-g011: ADCP activity of defucosylated anti-CCR4 IgG1 antibody 503 K in the presence of isolated human monocytes.Dose-dependent phagocytosis of T-cell leukemia CCRF-CEM cells (a) and human renal cell cancer 786-O cells (b) incubated with monocytes at E:T ratio 5∶1 for 1, 2 or 3 hrs is shown. Dotted lines indicate the levels of spontaneous phagocytosis.
Mentions: In order to investigate whether the candidate 503 can mediate phagocytic activity of macrophages (ADCP), a phagocytosis assay with human monocytes as effector cells was established. The defucosylated candidate 503 K demonstrated significant enhancement of spontaneous phagocytosis of both T-cell leukemia CCRF-CEM cells and of the human renal cell carcinoma 786-O cells (Figure 11a and b, respectively). Taken together, the affinity matured human anti-CCR4 antibodies, in particular the variant 503, showed improved ADCC and ADCP effector functions, and the ADCC activity could be further enhanced through glycooptimization.

Bottom Line: In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies.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 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.

View Article: PubMed Central - PubMed

Affiliation: Affitech Research AS, Oslo, Norway.

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.

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.

Show MeSH
Related in: MedlinePlus