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CC chemokine receptor type 4 (CCR4)-directed blocking antibody
Mycosis fungoides;†,$ Sézary syndrome†,$
Mogamulizumab is a recombinant humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4)-expressing cells.9 Mogamulizumab is approved as a breakthrough therapy for the treatment of relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) in patients who have failed at least one prior systemic therapy.9 It has been in use in Japan since 2012 for adult T cell leukemia/lymphoma.102
Mogamulizumab is an example of a glycoengineered IgG1κ immunoglobulin. It is produced from its murine precursor, KW-2160, isolated from mice immunized with a CCR4 N-terminal peptide fragment.50,103,104 The production platform for mogamulizumab, Potelligent® (Kyowa Hakko Kirin), uses a proprietary line of FUT8 knockout Chinese hamster ovary cells.105 In the absence of the FUT8 gene, N-linked glycopeptide molecules lacking fucose sugar units are appended to the Asn297 residue on the Fc tail of the IgG1 molecule during assembly to yield afucosylated antibodies.50,103 The Fab portion of mogamulizumab selectively binds to and blocks the activity of CCR4 to inhibit its signaling pathways that are known to stimulate tumor angiogenesis and the proliferation and migration of malignant T cells.50 Rather than killing CCR4+ cells directly, mogamulizumab instigates cell lysis by recruiting natural killer (NK) cells through IGg1 Fc binding to the NK cell FcγRIIIa (CD16) receptors.106 By binding both elements, the monoclonal antibody serves to present CCR4+ cells for destruction through the innate antibody-dependent cellular cytotoxicity (ADCC) process.103,104,107
Mogamulizumab is the third afucosylated monoclonal antibody to be marketed in the U.S. It was preceded to market by benralizumab (for depletion of eosinophils and basophils in eosinophilic asthma) and obinutuzumab (a fucose-reduced version of the anti-CD20 antibody rituximab for B-cell depletion in chronic lymphocytic leukemia).103,106 At least 15 other afucosylated antibodies are in clinical development.103,108,109 Afucosylated antibodies have FC regions with improved binding affinity for FcγRIIIa (CD16) receptors on natural killer cells, resulting in more aggressive depletion of targeted cell lines than non-glycoengineered (fucosylated) forms.50,103,107 In the case of mogamulizumab, ADCC drives depletion of malignant and nonmalignant CCR4+ cells, including a subset of helper (Th2) and regulatory (Treg) T cell lines.9,107,110 Treg cells are essential for safeguarding the innate system for immune self-recognition/tolerance, and while loss of this functionality through directed cell depletion is associated with immune-mediated regression of the malignancy,110-112 it also points to the cause behind the collateral immune-mediated consequences of mogamulizumab therapy and limits its rational use only for serious diseaes.103,104 In this regard, as a Treg cell–depleting reagent, there is intense clinical interest in the use of mogamulizumab alone or in combination with other targeted immunomodulatory therapies (e.g., durvalumab#, and nivolumab#) and for other types of malignancies.104,110,111
CCR4 is a G protein–coupled receptor (GPCR) for CC chemokines that is prominently expressed on Th2 and Treg cells, where it facilitates trafficking of normal and malignant lymphocytes to extranodal sites.9,107,113 CCR4 is also implicated in the pathogenesis of asthma and eczema.104,113 While many marketed drugs are GPCR-modulating agents, mogamulizumab is among the first four monoclonal antibodies to target a member of the GPCR family.50,103,104 All four mAbs were approved for marketing in the U.S. in 2018, and the other three (erenumab, fremanezumab, and galcanezumab) all target calcitonin gene-related peptide (CGRP) signaling; all were approved as preventive therapies for migraine in 2018 (see the above monograph on Anti-CGRP mAbs).
Mogamulizumab is administered in 28-day cycles, and the half-life for elimination is 17 days.9 Treatment is continued until unacceptable toxicity or disease progression. Consistent with the pharmacology, drug administration is associated with potentially serious adverse effects that can manifest as dermatologic toxicity, infusion-related reactions, infections, and autoimmune disorders.9 Tumor lysis syndrome, myocardial ischemia and infarction, cardiac failure, stress cardiomyopathy, and hepatitis B virus reactivation have all been reported.9 Importantly, preprocedure exposure to mogamulizumab increases the risk of potentially life-threatening complications associated with subsequent allogeneic hematopoietic stem cell transplantation (HSCT).9 Other labeled unwanted effects of mogamulizumab include abdominal pain, alopecia, anemia, anorexia, arrhythmia, chills, constipation, cough, depression, dizziness, dyspnea, dry skin, edema, headache, hyperglycemia, hypertension, hyperuricemia, hypomagnesemia, insomnia, mucositis, muscle spasms, nausea, neuropathy, pyrexia, thrombocytopenia, and weight increase or decrease.9
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell (non-Hodgkin) lymphoma; they occur most often in patients over age 50 and appear to increase the risk for development of other cancers.107,111 MF causes itchy red rashes and skin lesions and can spread to other parts of the body.114 It may progress slowly through patch, plaque, and tumor stages.114 SS affects the skin, blood, and lymph nodes.115 It is typically aggressive and may progress rapidly.115 Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative.107 A review of the different targeted antibody therapies for MF and SS has been published.107
FDA approval of mogamulizumab was based on the results of one randomized, open-label, multicenter, phase 3 trial (NCT01728805) that compared mogamulizumab to therapy with vorinostat (a histone deacetylase inhibitor) in adults with MF (n = 204) or SS (n = 168) who had failed prior systemic therapy and regardless of tumor CCR4 expression status.43 Subjects with histologic transformation, prior allogeneic HSCT, recent autologous HSCT, active autoimmune disease, or active infection were excluded from study. The median progression-free survival time was longer for patients taking mogamulizumab (7.6 months) compared with patients taking vorinostat (3.1 months).41 A benefit of mogamulizumab over vorinostat was also noted for overall response rate: 28% versus 5%.9 The cost of mogamulizumab is approximately $3965 per 20-mg vial or $15,860/dose for a 70- to 80-kg patient.116
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules > Denileukin Diftitox
Chapter 70. Dermatological Pharmacology > Targeted Therapies for Cutaneous T-Cell Lymphoma
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals