CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis

Corrales, Oreste; Hernández, Lissette Pérez; Prada, Dinorah; Gómez, Jesús María Fernández; Reyes, Yusimy; López, Ana Marta; González, Luis Javier; Horta, Maria del Carmen Domínguez

doi:10.1007/s10067-018-4360-3

Cited by 21 publications

(15 citation statements)

References 24 publications

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“…While therapies using pharmacological co-inducers of Hsp70 or immunization using Hsp70 peptides are promising, the above-mentioned observations are based on preclinical studies using cell cultures or animal models of arthritis with limited data on other autoimmune-like diseases and clinical evidences. In contrast, advanced and promising clinical observations in regard to the other Hsp classes (such as Hsp40 and Hsp60), in patients with RA [ 90 , 91 , 92 ] or diabetes type I, have been already reported [ 93 , 94 ]. In fact, only a single clinical observation has been provided using an ER Hsp70 family member, BiP, in patients with RA.…”

Section: Clinical Perspectivesmentioning

confidence: 99%

Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity

Tukaj

2020

IJMS

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Heat shock proteins (Hsp) are a diverse group of constitutive and/or stress-induced molecules that are categorized into several classes on the basis of their molecular weight. Mammalian Hsp have been mostly regarded as intracellular chaperones that mediate a range of essential cellular functions, including proper folding of newly synthesized polypeptides, refolding of denatured proteins, protein transport, and stabilization of native proteins’ structures. The well-characterized and highly evolutionarily conserved, stress-inducible 70-kDa heat shock protein (Hsp70), is a key molecular chaperone that is overexpressed in the cell in response to stress of various origin. Hsp70 exhibits an immunosuppressive activity via, e.g., downregulation of the nuclear factor-kappa B (NF-κB) activation, and pharmacological induction of Hsp70 can ameliorate the autoimmune arthritis development in animal models. Moreover, Hsp70 might be passively or actively released from the necrotic or stressed cells, respectively. Highly immunogenic extracellular Hsp70 has been reported to impact both the innate and adaptive immune responses, and to be implicated in the autoimmune reaction. In addition, preclinical studies revealed that immunization with highly conserved Hsp70 peptides could be regarded as a potential treatment target for autoimmune arthritis, such as the rheumatoid arthritis, via induction of antigen-specific regulatory T helper cells (also called Treg). Here, a dual role of the intra- and extracellular Hsp70 is presented in the context of the autoimmune reaction.

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Section: Clinical Perspectivesmentioning

confidence: 99%

Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity

Tukaj

2020

IJMS

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“…In addition, CIGB 814, an APL from a CD4+ T cell epitope of human Hsp60, an auto-antigen involved in the pathogenesis of RA, has been tested in 20 patients with moderated active RA in an open-label trial. The treatment was well-tolerated and indicated preliminary evidences of clinical efficacy in RA (Corrales et al 2019 ).…”

Section: Hsp In Clinical Trialsmentioning

confidence: 84%

Heat shock proteins in the therapy of autoimmune diseases: too simple to be true?

Tukaj

Kamiński

2019

Cell Stress and Chaperones

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Autoimmune diseases are characterized by the loss of immune tolerance to self-antigens which leads to an excessive immune responses and chronic inflammation. Although much progress has been made in revealing key players in pathophysiology of various autoimmune diseases, their therapy remains challenging and consists of conventional immunosuppressive treatments, including corticosteroids and more advanced biological therapies which are targeted at molecules involved in maintaining chronic inflammation. These therapies are focused on suppressing inflammation; nevertheless, a permanent balance between protective and pathogenic immune responses is not achieved. In addition, most of currently available therapies for autoimmune diseases induce severe side effects. Consequently, more effective and safer therapies are still required to control autoimmunity. Stress-induced cell protecting heat shock proteins (HSP) have been considered as a potential treatment targets for autoimmune diseases. HSP, predominantly intracellular components, might be released from bacteria or mammalian tissues and activate immune response. This activation may lead to either production of (auto)antibodies against HSP and/or induction of immune regulatory mechanisms, including expansion of desired T regulatory (Treg) cells. Because inadequate frequency or activity of Treg is a characteristic feature of autoimmune diseases, targeting this cell population is an important focus of immunotherapy approaches in autoimmunity.

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“…On other hand, CIGB-814 induced a significant reduction of autoantibodies against cyclic citrullinated peptides (anti-CCP antibodies), this decrease correlated with clinical activity of RA (Corrales et al 2019). Results from preclinical studies and phase I clinical trial indicate that CIGB-814 induces mechanism associated with induction of tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, in a phase I clinical trial, safety and PK were evaluated as primary end points for the subcutaneous (SC) administration of CIGB-814. Preliminary evidences of efficacy were observed and documented (Koffeman et al 2009;Corrales et al 2019). In particular, PK study showed that CIGB-814 reached the maximum concentration in plasma in 30 min and was cleared mostly after 4 h (Cabrales-Rico et al…”

Section: Introductionmentioning

confidence: 98%

Biodistribution and pharmacokinetic profiles of an altered peptide ligand derived from heat-shock proteins 60 in Lewis rats

Domínguez

Cabrales

Lorenzo

et al. 2020

Cell Stress and Chaperones

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Human heat-shock protein 60 (HSP60) is an autoantigen involved in the pathogenesis of rheumatoid arthritis (RA). Epitopes derived from HSP60 can trigger activation of regulatory T cells (Treg). CIGB-814 is an altered peptide ligand (APL) derived from HSP60. In preclinical models, this peptide had anti-inflammatory effects and increased Treg. The results from phase I clinical trial indicated that CIGB-814 was safe and activated mechanisms associated with induction of tolerance. Biodistribution profile for inducers of tolerance is crucial for triggering its effects. The primary goal of this study in Lewis rats was to identify (1) the target organs of CIGB-814 and (2) the pharmacokinetics (PK) profile. 125 I-CIGB-814 administered subcutaneously at three dose levels was distributed in the thyroid gland, but also at considerable levels to the stomach and small and large intestines. In addition, concentration of CIGB-814 was increased in lymph nodes (LNs) at 24 h, compared with 4-h post-administration. Small intestine and LNs are excellent sites for induction of tolerance, due to the characteristics of dendritic cells in these tissues. Maximum concentration of CIGB-814 in blood of Lewis rats at 0.5 to 1 h agrees with PK profile determined for patients. Altogether, these results support therapeutic possibilities of CIGB-814 for RA.

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CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis

Cited by 21 publications

References 24 publications

Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity

Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity

Heat shock proteins in the therapy of autoimmune diseases: too simple to be true?

Biodistribution and pharmacokinetic profiles of an altered peptide ligand derived from heat-shock proteins 60 in Lewis rats

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