Mogamulizumab

Subramaniam, Joshuan; Whiteside, Glenn; McKeage, Kate; Croxtall, Jamie C

doi:10.2165/11631090-000000000-00000

Cited by 86 publications

(27 citation statements)

References 8 publications

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“…We chose to improve the ESK1 construct by altering Fc glycosylation as a means to enhance ADCC, the major mechanism of ESK1 action in vitro and in vivo (12). Several ADCC-enhanced mAbs to highly expressed cell-surface antigens, produced, either by glyco-engineering or point mutations, are in clinical trials in the U.S. with promising results (38–40). The ESKM mAb had a homogeneous glycosylation pattern lacking N-linked fucose and with terminal hexose (mannose and/or glucose) structure.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein

Veomett

Dao

Liu

et al. 2014

Clinical Cancer Research

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Purpose RMFPNAPYL (RMF), a WT1-derived CD8 T cell epitope presented by HLA-A*02:01, is a validated target for T-cell-based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2nM), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines. Experimental Design We engineered a second-generation mAb, ESKM, to have enhanced antibody dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared to native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice. Results ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1µg/ml, but ESKM was about 5–10 fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 vs 6.5 days), but an identical biodistribution pattern in C57BL6/J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared to the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage. Conclusions The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein

Veomett

Dao

Liu

et al. 2014

Clinical Cancer Research

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“…For example, a therapeutic antibody mogamulizumab (KW-0761) recently approved in Japan for treatment of ATLL [28], [29] is a humanized version of a murine MAb KM2160 which was established by immunizing mice with a peptide corresponding to N-terminal amino acid residues 2–29 of human CCR4 [30]. The humanized antibody KW-0761 is produced as a defucosylated human IgG1 and its apparent mode of action is potent ADCC activity against CCR4 + cells; however, no CDC activity or effects on CCR4-mediated signaling or migration has been documented [27], [31], though induction of phagocytosis has been described [32].…”

Section: Introductionmentioning

confidence: 99%

Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis

Hagemann¹,

Gunnarsson²,

Geraudie³

et al. 2014

PLoS ONE

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BackgroundCC 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.MethodologyUsing 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.SignificanceFor 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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“…However, some drugs have been encouraging, and clinical trials are still ongoing. The anti-CCR4 called mogamulizumab, developed by Amgen and Kyowa-Hakko, is currently being tested to treat lymphoma and allergic diseases (89,90). The anti-CCL11 (bertilimumab), developed by Immune Pharmaceuticals, is currently in a phase II clinical trial to treat various diseases, such as asthma, Crohn's disease, and macular degeneration (91).…”

Section: Chemokine Receptor Antagonists In Therapeutic Strategies Agamentioning

confidence: 99%

Chemokine receptors in allergic diseases

Castan

Magnan

Bouchaud

2016

Allergy

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Under homeostatic conditions, as well as in various diseases, leukocyte migration is a crucial issue for the immune system that is mainly organized through the activation of bone marrow-derived cells in various tissues. Immune cell trafficking is orchestrated by a family of small proteins called chemokines. Leukocytes express cell-surface receptors that bind to chemokines and trigger transendothelial migration. Most allergic diseases, such as asthma, rhinitis, food allergies, and atopic dermatitis, are generally classified by the tissue rather than the type of inflammation, making the chemokine/chemokine receptor system a key point of the immune response. Moreover, because small antagonists can easily block such receptors, various molecules have been developed to suppress the recruitment of immune cells during allergic reactions, representing potential new drugs for allergies. We review the chemokines and chemokine receptors that are important in asthma, food allergies, and atopic dermatitis and their respectively developed antagonists.

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Mogamulizumab

Cited by 86 publications

References 8 publications

Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein

Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein

Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis

Chemokine receptors in allergic diseases

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