Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date

Crotti, Chiara; Raimondo, Maria Gabriella; Becciolini, Andrea; Biggioggero, Martina; Favalli, Ennio Giulio

doi:10.2147/dddt.s104233

Cited by 18 publications

(16 citation statements)

References 70 publications

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“…This drug was designed to improve Treg selectivity and half-life compared to recombinant IL-2. Mavrilimumab targeting BAFF is currently in Phase 2 trial [ 101 ]. Another Phase 3 trial evaluating BAFF-targeting drug, Tabalumab/LY2127399 has been terminated due to lack of efficacy but not the safety concerns [ 102 ].…”

Section: Targeting Immunological Components For Rheumatoid Arthritmentioning

confidence: 99%

Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development

Yap

Tee

Wong

et al. 2018

Cells

355

242

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Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disorder that affects synovial joints, both small and large joints, in a symmetric pattern. This disorder usually does not directly cause death but significantly reduces the quality of life and life expectancy of patients if left untreated. There is no cure for RA but, patients are usually on long-term disease modifying anti-rheumatic drugs (DMARDs) to suppress the joint inflammation, to minimize joint damage, to preserve joint function, and to keep the disease in remission. RA is strongly associated with various immune cells and each of the cell type contributes differently to the disease pathogenesis. Several types of immunomodulatory molecules mainly cytokines secreted from immune cells mediate pathogenesis of RA, hence complicating the disease treatment and management. There are various treatments for RA depending on the severity of the disease and more importantly, the patient’s response towards the given drugs. Early diagnosis of RA and treatment with (DMARDs) are known to significantly improve the treatment outcome of patients. Sensitive biomarkers are crucial in early detection of disease as well as to monitor the disease activity and progress. This review aims to discuss the pathogenic role of various immune cells and immunological molecules in RA. This review also highlights the importance of understanding the immune cells in treating RA and in exploring novel biomarkers.

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Section: Targeting Immunological Components For Rheumatoid Arthritmentioning

confidence: 99%

Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development

Yap

Tee

Wong

et al. 2018

Cells

355

242

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show abstract

“…Patients with RA may still have anemia and occasionally neutropenia . In these cases, or in the presence of infection, it is possible that GM‐CSF is necessary for adequate granulocyte production, and GM‐CSF inhibition may induce neutropenia .…”

mentioning

confidence: 99%

Mavrilimumab, a Fully Human Granulocyte–Macrophage Colony‐Stimulating Factor Receptor α Monoclonal Antibody

Burmester

McInnes

Kremer

et al. 2018

Arthritis & Rheumatology

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ObjectiveMavrilimumab, a human monoclonal antibody, targets granulocyte–macrophage colony‐stimulating factor receptor α. We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).MethodsIn study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti–tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long‐term safety and efficacy of mavrilimumab were assessed.ResultsA total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1–3.3 years). The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.ConclusionLong‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.

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“…Not surprisingly, analysis of cell surface markers on these CRS-associated macrophages showed a high level of Ly6C, indicating a more proinflammatory lineage of monocyte-macrophage. Moreover, blocking IL-6 with its receptor antagonist tocilizumab could abate CRS by several mechanisms [10,19,20]. Myeloid-derived macrophages seemed to have more important functions in CRS than we previously expected, based on accumulating evidence [21][22][23].…”

Section: Macrophages Might Be the Major Source Of The Core Cytokine Imentioning

confidence: 76%

Macrophage, the potential key mediator in CAR-T related CRS

Hao

et al. 2020

Exp Hematol Oncol

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Chimeric antigen receptor (CAR) T cell therapy is a new frontier in cancer therapy. The toxicity of cytokine release syndrome (CRS) has become one of the major challenges that limits the wider use of CAR T cells to fight cancer. Exploration of CRS pathogenesis and treatment is becoming the main focus of ongoing studies. Myeloid-derived macrophages were found to play a critical role in CRS pathogenesis, and these cells mediate the major production of core cytokines, including IL-6, IL-1 and interferon (IFN)-γ. Colocalization of macrophages and CAR T cells was also identified as necessary for inducing CRS, and CD40L-CD40 signaling might be the key cell-cell interaction in the tumor microenvironment. Macrophages might also take part in endocrine and self-amplified catecholamine loops that can directly activate cytokine production and release by macrophages during CRS. In addition to tocilizumab and corticosteroids, several novel CRS therapies targeting macrophage-centered pathways have shown much potential, including GM-CSF blockade and administration of atrial natriuretic peptide (ANP) and α-methyltyrosine (metyrosine, MTR). In the present review, we summarized the role of macrophages in CRS and new developments in therapeutic strategies for CRS-associated toxicities.

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Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date

Cited by 18 publications

References 70 publications

Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development

Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development

Mavrilimumab, a Fully Human Granulocyte–Macrophage Colony‐Stimulating Factor Receptor α Monoclonal Antibody

Macrophage, the potential key mediator in CAR-T related CRS

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