CCR4 as a novel molecular target for immunotherapy of cancer

Abstract

Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4(+) T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4(+) Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4(+) T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4(+) tumor cells, but also to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

Figure 1

Skin homing capacity of adult T‐cell leukemia/lymphoma (ATLL) cells. CC chemokine receptor 4 (CCR4) and cutaneous lymphocyte antigen (CLA) on ATLL cells recognize TARC/CCL17 and E‐selectin on endothelial cells in the skin, respectively, and ATLL cells subsequently extravasate into the dermis. ATLL cells often display an affinity for epidermal cells and cluster around Langerhans’ cells, forming Pautrier's microabscesses, principally caused by the interaction of CCR4 on ATLL cells with MDC/CCL22 expressed on Langerhans’ cells in the epidermis.

Figure 2

CD4⁺CD25⁺ regulatory T cell (Treg) capacity of adult T‐cell leukemia/lymphoma (ATLL) cells. CD4⁺CD25⁺CCR4⁺ ATLL cells from a subset of patients suppress the proliferation of CD4⁺ autologous non‐ATLL cells in the presence of autologous antigen‐presenting cell in response to T‐cell receptor (TCR) stimulation.

Figure 3

Specific recruitment of CC chemokine receptor 4 (CCR4)‐positive regulatory T (Treg) cells in Hodgkin's lymphoma (HL) fosters immune privilege, making CCR4 on Treg cells a novel target for cancer immunotherapy. HL tumor cells produce TARC/CCL17 andr MDC/CCL22, and migratory CD4⁺CCR4⁺ cells induced by HL cells function as Treg cells, so that these cells create a favorable environment for tumor immune escape (upper panel). The recognition of the importance of Treg cells not only in HL but also in other cancers will allow the rational design of more effective treatments. The depletion of Treg cells using an anti‐CCR4 monoclonal antibody in patients with cancers including HL could become a promising strategy for overcoming the suppressive effect of CCR4⁺ Treg cells on the host's immune response to tumor cells, thereby boosting antitumor immunity (lower panel).

Figure 4

The defucosylated anti‐CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb). (a) Structure of oligosaccharide in the Fc region of human IgG1 is shown. Antibody‐dependent cellular cytotoxicity (ADCC) requires the presence of oligosaccharides in the Fc region and is sensitive to change in the oligosaccharide structure. Of all the sugar components in the oligosaccharide, fucose has the most important influence on ADCC. Defucosylation of human IgG1‐type antibody is one of the most powerful ways to improve antibody effector function. (b) Anti‐CCR4 mAb, whose Fc region is defucosylated to enhance ADCC activity by increasing its binding affinity to Fc receptor on effector cells, was developed. The defucosylated anti‐CCR4 mAb recognizes the N‐terminal portion of the CCR4 molecule. (c) The defucosylated chimeric anti‐CCR4 IgG1 mAb KM2760 mediates much higher ADCC against CCR4/EL4 cells in the presence of human peripheral blood mononuctear cells as effector cells compared with the highly fucosylated, but otherwise identical, Chinese hamster ovary (CHO)‐produced anti‐CCR4 IgG1 KM3060 in standard 4‐h ⁵¹Cr release assays. KM2760 needed far fewer effector cells to achieve the same level of ADCC as KM3060 (left panel). KM2760 needed much lower mAb concentrations to achieve the same ADCC as KM3060 (right panel).