Mogamulizumab (KW-0761, AMG 761, POTELIGEO®)

Agent Description

Mogamulizumab is a recombinant, humanized monoclonal antibody (mAb) of the immunoglobulin (Ig) G subclass 1 kappa (IgG1κ) isotype that targets CC chemokine receptor 4 (CCR4)-expressing cells.

Mechanism of Action

Mogamulizumab was produced using technology developed by Kyowa Hakko Kirin Co., Ltd., that eliminates fucose from the carbohydrate structure of the antibody. Due to the absence of fucose from the complex-type oligosaccharide at the constant (fragment crystallizable) region, mogamulizumab has enhanced antibody-dependent cellular cytotoxicity (ADCC) activity, but does not exhibit any complement dependent cytotoxic (CDC) activity or neutralizing activity of the ligand of CCR4.

Mogamulizumab, which eliminates CCR4+ cells, has induced anti-tumor responses in patients with CCR4+ T-cell malignancies, which is thought to be due to ADCC-mediated killing of CCR4+ malignant cells. Mogamulizumab has also been shown to deplete a subset of T regulatory cells (Tregs) which expresses CCR4. Sugiyama D, et al. showed that CCR4 was specifically expressed by a subset of terminally differentiated highly suppressive CD45RA-FOXP3hiCD4+ Tregs but not by CD45RA+FOXP3loCD4+ naive Treg cells in the peripheral blood of healthy individuals and cancer patients. They showed that mogamulizumab produced a substantial reduction in the number of circulating Tregs in a patient with ATL. In addition, peripheral blood mononuclear cells (PBMCs) were collected from patients with melanoma whose tumors expressed the NY-ESO-1 antigen, but in whom there was no evidence of an immune response against this antigen. When these PBMCs were cultured in the presence of the NY-ESO-1 antigen and with an antibody to CCR4 to deplete the CCR4+ cells, the remaining CD4+ cells activated to secrete interferon gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). This indicated that the immunosuppressive influence of Treg cells had been removed by removing cells expressing CCR4. Based on these data, phase 1a/1b clinical trials of mogamulizumab as a Treg depletion reagent are being conducted. The results of Phase 1a showed that mogamulizumab infusion in a dose range between 0.1 mg/kg and 1 mg/kg was safe and well tolerated. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.

Classification

Anti-CCR4 monoclonal antibody

Molecular Targets

CC chemokine receptor 4 (CCR4)-expressing cells

Monograph

In human clinical trials, doses of up to 1 mg/kg have been well tolerated. As of 30 Sep 2016, more than 800 subjects have received at least one dose of mogamulizumab in company-sponsored clinical studies.

POTELIGEO® (mogamulizumab) was approved by the Ministry of Health, Labor and Welfare in Japan for the treatment of primary (14 Dec 2014) and relapsed or refractory CCR4+ ATL (30 Mar 2012), relapsed or refractory CCR4+ PTCL (17 Mar 2014), and relapsed or refractory CCR4+ CTCL (17 Mar 2014).

Mogamulizumab is being clinically developed for the treatment of T-cell malignancies including peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and adult T-cell leukemia-lymphoma (ATL), and solid tumors outside Japan.

In addition to company-sponsored studies in subjects with T-cell malignancies and solid tumors, partner-sponsored, and investigator-initiated trials are ongoing in Japan and the US in subjects with solid tumors and HTLV-1-associated myelopathy/tropical spastic paraparesis.

Studies of Interest

N/A

Information collaborator would like included in investigator proposals

N/A