Review on-Mogamulizumab is a Humanized Monoclonal Antibody (mAb) directed against CC chemokine receptor 4 (CCR4) for the treatment of Mycosis Fungoides (MF)

 

Mayur S. Jain*, Dr. Shashikant D. Barhate

Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jammer

*Corresponding Author E-mail: mayurjain176@gmail.com

 

ABSTRACT:

Mogamulizumab is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4) for the treatment of Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas occur when certain white blood cells, called T cells, become cancerous; these cancers typically affect the skin, causing various types of skin lesions. On August 8 2018, the U.S. Food and Drug Administration (FDA) approved mogamulizumab injection (also known as Poteligeo) for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. Mogamulizumab is derived from Kyowa Hakko Kirin's POTELLIGENT (®) technology, which produces antibodies with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Approval in Japan was granted on April 30 2012 by the Japanese Ministry of Health, Labour and Welfare for patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma.

 

KEYWORDS: Mogamulizumab, humanized monoclonal antibody.

 

 


INTRODUCTION:

Mogamulizumab is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4) for the treatment of Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas occur when certain white blood cells, called T cells, become cancerous; these cancers typically affect the skin, causing various types of skin lesions.

 

On August 8 2018, the U.S. Food and Drug Administration (FDA) approved mogamulizumab injection (also known as Poteligeo) for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.

 

Mogamulizumab is derived from Kyowa Hakko Kirin's POTELLIGENT (®) technology, which produces antibodies with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Approval in Japan was granted on April 30 2012 by the Japanese Ministry of Health, Labour and Welfare for patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma.(1,2,3.)

 

 

 

For the intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for Sézary Syndrome.

 

This drug is a CC chemokine receptor 4 (CCR4) antagonist. It is a monoclonal antibody which blocks T cell proliferation, which leads to malignancy  CCR4 is a chemokine receptor that is preferentially expressed by Th2 and regulatory T (Treg) cells. In response to its ligands, CCL17 (TARC) and CCL22 (MDC), CCR4 promotes T-cell migration to extranodal sites, including the skin.

 

Mogamulizumab selectively binds to and inhibits the activity of CCR4, which may block CCR4-mediated signal transduction pathways and, so, chemokine-mediated cellular migration and proliferation of T cells, as well as chemokine-mediated angiogenesis. Additionally, this agent may induce antibody-dependent cell-mediated cytotoxicity (ADCC) against CCR4-positive T cells. CCR4, a G-coupled-protein receptor for C-C chemokines such MIP-1, RANTES, TARC and MCP-1, is expressed on the surfaces of some types of T cells, endothelial cells, and certain types of neurons. CCR4, also known as CD194, may be overexpressed on adult T-cell lymphoma (ATL) and peripheral T-cell lymphoma (PTCL) cells. In addition to directly targeting malignant T cells expressing CCR4, mogamulizumab depletes Treg cells, an important therapeutic target in many human cancers because of their role in suppressing host antitumor immunity((1,2,3.)

 

Pharmacodynamics:

This drug is a CC chemokine receptor 4 (CCR4) antagonist. It is a monoclonal antibody which blocks T cell proliferation, which leads to malignancy  CCR4 is a chemokine receptor that is preferentially expressed by Th2 and regulatory T (Treg) cells. In response to its ligands, CCL17 (TARC) and CCL22 (MDC), CCR4 promotes T-cell migration to extranodal sites, including the skin.(1,2)

 

Mechanism of action:

Mogamulizumab selectively binds to and inhibits the activity of CCR4, which may block CCR4-mediated signal transduction pathways and, so, chemokine-mediated cellular migration and proliferation of T cells, as well as chemokine-mediated angiogenesis. Additionally, this agent may induce antibody-dependent cell-mediated cytotoxicity (ADCC) against CCR4-positive T cells. CCR4, a G-coupled-protein receptor for C-C chemokines such MIP-1, RANTES, TARC and MCP-1, is expressed on the surfaces of some types of T cells, endothelial cells, and certain types of neurons. CCR4, also known as CD194, may be overexpressed on adult T-cell lymphoma (ATL) and peripheral T-cell lymphoma (PTCL) cells. In addition to directly targeting malignant T cells expressing CCR4, mogamulizumab depletes Treg cells, an important therapeutic target in many human cancers because of their role in suppressing host antitumor immunity(1,2,3.)

 

Indication:

For the intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for Sézary Syndrome.

 

Absorption:

Following repeated dosing of the approved recommended dosage, steady-state concentrations were reached after 8 doses (12 weeks), and the systemic accumulation was 1.6-fold. At steady state, the peak concentration (Cmax,ss) is 32 (68%) μg/mL, the trough concentration (Cmin,ss) is 11 (239%) μg/mL, and AUCss is 5577 (125%) μg•hr/mL.(1,2,3)

 

Volume of distribution:

The central volume of distribution is 3.6 L

 

Half life:

The terminal half-life is 17 days.

 

Clearance:

Clearance is 12 mL/h

 

Toxicity:

The most common adverse reactions (reported in ≥20% of patients randomized to mogamulizumab) were rash (including drug eruption), infusion-related reactions, fatigue, diarrhea, upper respiratory tract infection and musculoskeletal pain. Due to various adverse effects related to this drug, the adverse reactions have been categorized by organ system. Because of the risk of serious/fatal ADRs, patients administered mogamulizumab should be carefully monitored.(1,2,3.)

 

Upper respiratory tract infection:

This may occur due to decreased immunity following the administration of this drug. Monitor for signs of respiratory infection including fever, cough and shortness of breath.

 

Dermatological:

Patients must contact their healthcare provider immediately if they experience a new or worsening skin rash. Treatment should be temporarily interrupted for moderate or severe skin rashes and permanently discontinued for a life-threatening rash. Fatal and life-threatening skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in recipients of mogamulizumab. Rash (drug eruption) is one of the most common adverse reactions associated with mogamulizumab.

 

Infusion Reactions:

Patients must contact their healthcare provider immediately for signs or symptoms of infusion reactions. Treatment should be suspended for any infusion reaction and permanently discontinued for any life-threatening infusion reaction.

 

Infections:

Patients must contact their healthcare provider if they experience fever or other signs of infection. Infections should be monitored and treated promptly.(1,2)

 

CONCLUSION:

Mogamulizumab is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4) for the treatment of Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas occur when certain white blood cells, called T cells, become cancerous; these cancers typically affect the skin, causing various types of skin lesions.

 

On August 8 2018, the U.S. Food and Drug Administration (FDA) approved mogamulizumab injection (also known as Poteligeo) for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.(2,3.)

 

REFERENCES:

1.      www.drugbank.ca/drugs/DB01140,

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3.      Beck A, Reichert JM: Marketing approval of mogamulizumab: a triumph for glyco-engineering. MAbs. 2012 Jul-Aug; 4(4): 419-25. doi: 10.4161/mabs.20996. Epub 2012 Jul 1. [PubMed:22699226].

4.      Ishitsuka K, Yurimoto S, Kawamura K, Tsuji Y, Iwabuchi M, Takahashi T, Tobinai K: Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia-lymphoma in Japan: interim results of postmarketing all-case surveillance. Int J Hematol. 2017 Oct; 106(4): 522-532. doi: 10.1007/s12185-017-2270-9. Epub 2017 Jun 9. [PubMed: 28597329]

5.      Sato T, Coler-Reilly ALG, Yagishita N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y, Yamano Y: Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. N Engl J Med. 2018 Feb 8; 378(6): 529-538. doi: 10.1056/NEJMoa1704827. [PubMed: 29414279].

6.      Wilcox RA: Mogamulizumab: 2 birds, 1 stone. Blood. 2015 Mar 19; 125(12):1847-8. doi: 10.1182/blood-2015-02-625251. [PubMed: 25792728].

 

 

 

 

 

 

 

 

 

 

Received on 15.07.2019         Accepted on 10.08.2019

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2019; 9(4):260-262.

DOI: 10.5958/2231-5691.2019.00042.X