Differential Expression of Thymus and Activation Regulated Chemokine and Its Receptor CCR4 in Nodal and Cutaneous Anaplastic Large-Cell Lymphomas and Hodgkin’s Disease

Human IgG1 antibodies with low fucose contents in their asparaginelinked oligosaccharides have been shown recently to exhibit potent antibody-dependent cellular cytotoxicity (ADCC) in vitro. To additionally investigate the efficacy of the human IgG1 with enhanced ADCC, we generated the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) IgG1 antibody KM2760. KM2760 exhibited much higher ADCC using human peripheral blood mononuclear cells (PBMCs) as effector cells compared with the highly fucosylated, but otherwise identical IgG1, KM3060. In addition, KM2760 also exhibited potent ADCC in the presence of lower concentrations of human PBMCs than KM3060. Because CCR4 is a selective marker of T-cell leukemia/lymphoma, the effectiveness of KM2760 for T-cell malignancy was evaluated in several mouse models. First, to compare the antitumor activity of KM2760 and KM3060, we constructed a human PBMC-engrafted mouse model to determine ADCC efficacy with human effector cells. In this model, KM2760 showed significantly higher antitumor efficacy than KM3060, indicating that KM2760 retains its high potency in vivo. Second, KM2760 suppressed tumor growth in both syngeneic and xenograft mouse models in which human PBMCs were not engrafted. Although murine effector cells exhibited marginal ADCC mediated by KM2760 and KM3060, KM2760 unexpectedly showed higher efficacy than KM3060 in a syngeneic mouse model, suggesting that KM2760 functions in murine effector system in vivo via an unknown mechanism that differs from that in human. These results indicate that defucosylated antibodies with enhanced ADCC as well as potent antitumor activity in vivo are promising candidates for the novel antibody-based therapy.

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“…3, A-E), indicating that T-cell leukemia/lymphoma frequently express CCR4. This finding coincides well with recent reports (23,(25)(26)(27).…”

Section: T-cell Lymphoma and Leukemia Cell Lines Frequently Expressinsupporting

confidence: 83%

“…Inter-estingly, their data demonstrated for the first time that the CCR4 expression correlates with poor prognosis. With respect to other T-cell malignancies, anaplastic large-cell lymphoma (25,26), mycosis fungoides in transformation (25,27), and cutaneous T-cell lymphoma (27) have been observed for the frequent expression of CCR4.…”

Section: Introductionmentioning

confidence: 99%

Defucosylated Chimeric Anti-CC Chemokine Receptor 4 IgG1 with Enhanced Antibody-Dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-Cell Leukemia and Lymphoma

et al. 2004

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“…HRS cells produce high levels of TARC and MDC, which are chemoattractants for CCR4, and could play an active role in the influx of CCR4 þ T lymphocytes. 2 Although some controversy exists about the presence of CCR4-positive cells immediately surrounding HRS cells in cHL, 16,32 our results showed significantly higher mRNA level of CCR4 for CD4 þ CD26À T cells and CCR4-positive cells are indeed located in close vicinity to HRS cells. Since Mariani et al 33 showed rapid and efficient CCR4 internalization by MDC but not by TARC, the controversy is probably due to CCR4 internalization by binding to its ligand MDC, which is also highly expressed by HRS cells.…”

Section: -25supporting

confidence: 52%

The CD4+CD26− T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

Yue

Visser

Blokzijl

et al. 2008

Laboratory Investigation

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Little is known about the gene expression profile and significance of the rosetting CD4 þ CD26À T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4 þ CD26À and CD4 þ CD26 þ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL) and reactive LNs. mRNA profiles of stimulated and resting cell subsets were evaluated with quantitative RT-PCR for 46 genes. We observed a higher percentage of CD4 þ CD26À T cells in NSHL than in reactive LNs. The resting CD4 þ CD26À T cells in NSHL showed higher mRNA levels of CD25, CTLA4, OX40 and CCR4 compared with in LNs, supporting a regulatory T-cell (Treg) type, and this was validated by immunohistochemistry. Moreover, these cells showed low or no expression of the Th1-or Th2-related cytokines IL-2, IFN-g, IL-13, IL-12B, IL-4, and IL-5, and the chemoattractant receptor CRTH2. Besides Tregs, Th17 cells may exist in NSHL based on the significantly higher IL-17 mRNA level for both T-cell populations in NSHL. Upon stimulation in vitro, lack of upregulation of mRNA levels of most cytokine genes indicated an anergic character for the CD4 þ CD26À T-cell subset. Anergy fits with the Treg profile of these cells, probably explaining the immunosuppressive mechanism involved in NSHL.

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“…To our knowledge, no other investigators, including Vermeer et al, 24 have previously reported the expression of CCR4 by HL tumor cells from patients ex vivo. On the other hand, some groups have already reported that certain HL cell lines do express CCR4, 23,25 as confirmed in this study.…”

Section: Discussionmentioning

confidence: 99%

The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma

et al. 2006

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Differential Expression of Thymus and Activation Regulated Chemokine and Its Receptor CCR4 in Nodal and Cutaneous Anaplastic Large-Cell Lymphomas and Hodgkin’s Disease

Abstract: Recent studies demonstrated that

Cited by 38 publications

References 23 publications

Defucosylated Chimeric Anti-CC Chemokine Receptor 4 IgG1 with Enhanced Antibody-Dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-Cell Leukemia and Lymphoma

Defucosylated Chimeric Anti-CC Chemokine Receptor 4 IgG1 with Enhanced Antibody-Dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-Cell Leukemia and Lymphoma

The CD4+CD26− T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma

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