Phase I Clinical Trial with a Novel Altered Peptide Ligand Derived from Human Heat-Shock Protein 60 for Treatment of Rheumatoid Arthritis: Safety, Pharmacokinetics and Preliminary Therapeutic Effects

Prada, Dinorah; Gómez, Jesús María Fernández; Lorenzo, N. Alcorta; Corrales, Oreste; López, Ana Marta; Gonzalez, Evelio; Cabrales, Ania; Reyes, Yusimy; Bermudez, Yuliet; Avila, Yisel; Pérez, Lina; Molinero, Claudio; Martínez, O.; Oramas, Leonardo; Miñoso, Yaysel; Ramos, Yassel; Garay, Hilda; Pérez, Edwin G.; Lopez, M Granero; Reyes, Osvaldo; Cruz, Yolanda; Hernández, Alfredo; Carlos, Cabal; Besada, Vladimir; González, Luís Javier Durán; Padrón, Gabrìel; Horta, Maria del Carmen Domínguez

doi:10.4172/2167-0870.1000339

Cited by 11 publications

(13 citation statements)

References 32 publications

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“…Radioactivity was at relatively low levels in the liver, spleen, heart, and brain regardless time post-administration of [ 125 I]-labeled peptide. These experimental facts could indicate a low-toxicity of CIGB-814 seen in preclinical models (mice and dogs, manuscript in preparation) as well as the very favorable safety profile observed in phase I clinical trial (Prada et al 2018).…”

Section: Discussionmentioning

confidence: 90%

“…CIGB-814 significantly decreased IL-17 in patients treated with 2.5 mg. Therapy with 1 mg and 2.5 mg of CIGB-814 led to a significant reduction of interferon gamma (IFN-γ) (Prada et al 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, epitopes from human HSP60 were selected with the aim of inducing tolerance in patients with RA (Prakken et al 2004;Koffeman et al 2009;Prada et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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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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“…CIGB-258 induced regulatory effects that have been associated with the inhibition of inflammation in several experimental models and patients with RA. The molecular mechanism of CIGB-258 in preclinical studies has been associated with a decrease of chronic inflammation related to the regulation of the immune system (Domínguez et al 2011 ; Barberá et al 2016 ; Lorenzo et al 2017 ; Prada et al 2018 ; Corrales et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we showed that the regulatory effects induced by the CIGB-258 peptide were associated with an increase of regulatory T cells (Treg) and their suppressive capacity against the antigen responding effector CD4+T cells from patients with autoimmune diseases. Additionally, this peptide induced a decrease of several proinflammatory cytokines during preclinical studies (Domínguez et al 2011 ; Barberá et al 2016 ; Lorenzo et al 2017 ) and a phase I clinical trial with rheumatoid arthritis (RA) patients (Prada et al 2018 ). Similarly, this peptide induced a significant reduction of autoantibodies against cyclic citrullinated peptides and this decrease correlated with the clinical activity of RA (Corrales et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

CIGB-258, a peptide derived from human heat-shock protein 60, decreases hyperinflammation in COVID-19 patients

Hernández-Cedeño

Venegas-Rodriguez

Peña-Ruiz

et al. 2021

Cell Stress and Chaperones

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Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313

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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

Corrales

Hernández

Prada³

et al. 2018

Clin Rheumatol

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Phase I Clinical Trial with a Novel Altered Peptide Ligand Derived from Human Heat-Shock Protein 60 for Treatment of Rheumatoid Arthritis: Safety, Pharmacokinetics and Preliminary Therapeutic Effects

Cited by 11 publications

References 32 publications

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

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

CIGB-258, a peptide derived from human heat-shock protein 60, decreases hyperinflammation in COVID-19 patients

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

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