Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis
Urs B Hagemann1, Lavinia Gunnarsson1, Solène Géraudie1
1Affitech Research AS, Oslo, Norway.
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.
Insights
Researchers developed novel anti-CC chemokine receptor 4 (CCR4) antibodies. These antibodies target cancer cells and immune cells, showing potential for cancer immunotherapy by inhibiting signaling and mediating tumor cell killing.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CC chemokine receptor 4 (CCR4) is expressed on tumor-infiltrating immune cells, including regulatory T cells (Tregs), and on tumor cells in various cancers.
- CCR4 plays a role in cancer metastasis, making it a potential target for immunotherapy.
Purpose of the Study:
- To generate novel human antibodies targeting CC chemokine receptor 4 (CCR4).
- To evaluate the efficacy of these antibodies in blocking CCR4 signaling and mediating anti-tumor activity.
Main Methods:
- Phage display and human antibody library were used to generate antibody variants against human CCR4.
- Antibody selection involved affinity maturation and cell-based strategies.
- In vivo efficacy was assessed using a mouse model of human T-cell lymphoma.
Main Results:
- Generated antibodies effectively competed with CCR4 ligand binding and blocked ligand-induced signaling and cell migration.
- Antibodies demonstrated efficient killing of CCR4-positive tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.
- Treatment with anti-CCR4 antibodies significantly improved survival in a mouse lymphoma model.
Conclusions:
- Successfully generated anti-GPCR antibodies using a human non-immune library and phage display.
- The novel anti-CCR4 antibodies exhibit a dual mode of action: inhibiting receptor signaling and mediating antibody-directed tumor cell killing.
- In vivo anti-tumor activity is mediated by Fc-receptor dependent effector mechanisms, highlighting their potential as immunomodulatory antibodies for cancer treatment.
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