Therapeutic Targeting of CD6 in Autoimmune Diseases: A Review of Cuban Clinical Studies with the Antibodies IOR-T1 and Itolizumab

Hernández, Patricia; Moreno, Ernesto; Aira, Lazaro E.; Rodríguez, Pedro C.

doi:10.2174/1389450117666160201114308

Cited by 32 publications

(45 citation statements)

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“…Nevertheless, in contrast with what we expected, the long‐term treatment performed, in terms of overall benefit, as well as the short‐treatment schedule. In particular, the ACR responses we observed at week 24 were in the same range of those reported in the previous study .…”

Section: Discussionsupporting

confidence: 89%

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: 89%

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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“…While, the clinical efficacy of Itolizumab has been proven in psoriasis and RA [15, 31, 39], in this study we report for the first time the effect of an anti CD6 domain 1 murine specific antibody in ameliorating the incidence of EAE in a mice model of the disease, Multiple Sclerosis. Therefore, our results point to an immunomodulatory role for Itolizumab and establishes the relevance of targeting CD6, to regulate autoimmune disorders.…”

Section: Introductionmentioning

confidence: 81%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15–35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORγT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab’)2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases.

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“…The latter is based on the in vitro inhibition by itolizumab of T-cell activation and differentiation to Th1 effector cells (51). However, mAb-induced CD6 cross-linking may also block CD6–CD166/ALCAM interaction by steric hindrance (52) or internalization (4), mimicking a “CD6-deficient like” phenotype. In this case, itolizumab would affect cell proliferative responses, in a similar way to what we observe in CD6 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…The fact that CD6 was preferentially expressed by all T cells, as well as by a small subset of mature B cells (B1a cells) involved in the production of low affinity polyreactive autoantibodies, soon led to early though discontinued attempts to treat certain autoimmune disorders (e.g., rheumatoid arthritis, psoriasis, and multiple sclerosis) using mouse anti-CD6 mAbs (2). The recent marketing of a humanized anti-CD6 mAb (itolizumab) (3, 4), together with the identification of CD6 gene as a multiple sclerosis susceptibility locus (5, 6), has renewed the interest in the study of this relatively neglected lymphocyte receptor. Due to the unavailability of genetically modified animal models targeting cd6 gene, the rationale for CD6-based therapeutic strategies mostly stems from in vitro data.…”

Section: Introductionmentioning

confidence: 99%

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Consuegra-Fernández¹,

Martínez-Florensa²,

Aranda³

et al. 2017

Front. Immunol.

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The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6−/−) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6−/− mice together with higher induction of regulatory T cells (Treg, CD4+CD25+FoxP3+) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6−/− mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21+CD23hi) and Treg cells. Interestingly, functional analysis of in vivo-generated CD6−/− Treg cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6−/− mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance.

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Therapeutic Targeting of CD6 in Autoimmune Diseases: A Review of Cuban Clinical Studies with the Antibodies IOR-T1 and Itolizumab

Cited by 32 publications

References 0 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

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

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