Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Aira, Lazaro E.; Hernández, Patricia; Prada, Dinorah; Chico, Araceli; Gómez, Jesús María Fernández; González, Zuyén; Fuentes, Karla; Viada, Carmen; Mazorra, Zaima

doi:10.1080/19420862.2015.1105416

Cited by 18 publications

(21 citation statements)

References 67 publications

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“…None of the tested doses was considered dose-limiting for this clinical indication (up to 0Á8 mg/kg administered weekly intravenously, 12 doses in total). In line with these results, itolizumab administration did not induce a measurable antiidiotypical antibody response, as also observed in previous studies [32,34,40].…”

Section: Discussionsupporting

confidence: 91%

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

Rodríguez

Prada²,

Moreno

et al. 2017

Clinical and Experimental Immunology

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Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.

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Section: Discussionsupporting

confidence: 91%

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

Rodríguez

Prada²,

Moreno

et al. 2017

Clinical and Experimental Immunology

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“…The present report is the first human study evaluating the effect of cholecalcipherol administration in eRA patients. Also standard treatment with MTX has no effect of Th cells subsets, previous studies showed an effect of MTX on activated T cells in vitro [48, 49], whereas in a recent paper patients treated with MTX administered orally in a dose ranging from 7 to 25 mg has no decrease in peripheral T cells count [50]. Our data confirm no effect of MTX in combination with GCs of different T cells sub-types.…”

Section: Resultssupporting

confidence: 78%

Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study

Buondonno¹,

Rovera

Sassi³

et al. 2017

PLoS ONE

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The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls. The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial. Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline. Eligible patients were female ≥18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study. Patients with auto-immune or inflammatory diseases other than RA were excluded. Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded. In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments. Three patients didn’t come back to the follow up visit for personal reasons. None of the patients experienced adverse events. The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines. Secondary outcome measure were clinical parameters. In eRA, 25OH vitamin D levels were significantly lower. CD4+/IFNγ+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFNγ+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered. TNFα, TGFβ1, RANKL, IL-23 and IL-6 were increased in eRA. Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity. Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors. After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health. In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed. A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health.

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“…Analysis of a similar number of rheumatoid arthritis patients also showed a suppressive effect of itolizumab, enhancing methotrexate treatment . Unlike lymphocyte numbers, which were transiently reduced, the reduction of inflammatory cytokine production was sustained, suggesting a mechanism other than depletion …”

Section: Introductionmentioning

confidence: 91%

“…In a study of 26 psoriasis patients receiving multiple injections of the humanized version of ior t1, itolizumab, over the course of a year, the mAb was immunosuppressive; the reduction of the proliferation and production of pro‐inflammatory cytokines being statistically significant . Analysis of a similar number of rheumatoid arthritis patients also showed a suppressive effect of itolizumab, enhancing methotrexate treatment . Unlike lymphocyte numbers, which were transiently reduced, the reduction of inflammatory cytokine production was sustained, suggesting a mechanism other than depletion …”

Section: Introductionmentioning

confidence: 99%

CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action

Garner¹,

Hartland²,

Breuning³

et al. 2018

Immunology

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CD6 is a type I T-cell surface receptor that modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab™), which has reached the clinic for treatment of autoimmune disease. We characterized molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action. Epitope mapping using the crystal structure of CD6 to design mutants identified two distinct binding sites on different faces of domain 1, one containing residue R77, crucial for MT605 and T12.1 binding and the other, E63, which is crucial for itolizumab and MEM98. Analysis of binding kinetics revealed that itolizumab has a lower affinity compared with other CD6 domain 1 mAbs. We compared potential agonistic (triggering) and antagonistic (blocking) properties of CD6 mAbs in assays where the mechanism of action was well defined. CD6 domain 1 and 3 mAbs were equally effective in triggering interleukin-2 production by a cell line expressing a chimeric antigen receptor containing the extracellular region of CD6. CD6 domain 1 mAbs hindered binding of multivalent immobilized CD166 but were inferior compared with blocking by soluble CD166 or a CD6 domain 3 mAb. Characterization of CD6 mAbs provides an insight into how their functional effects in vivo may be interpreted and their therapeutic use optimized.

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Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Cited by 18 publications

References 67 publications

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study

CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action

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