CIGB-258 immunomodulatory peptide for the treatment of critical and severe COVID-19 patients
Keywords:
COVID-19, cytokine storm, hyperinflammation, HSP60, CIGB-258, jusvinza.Abstract
Introduction: CIGB-258 is an immunomodulatory peptide with anti-inflammatory properties.Objectives: To establish the therapeutic schedule with CIGB-258 peptide for COVID-19 critically ill patients. In addition, to define the criteria for use and schedule of this peptide for COVID-19 seriously ill patients.
Methods: 9 critically ill patients and 3 seriously ill patients were included in this study. Clinical, radiological and laboratory evaluations were recorded according to the established protocol. Serum samples were obtained before and after treatment with CIGB-258, for the determination of the inflammation biomarkers.
Results: The therapeutic protocol was established with the CIGB-258 peptide, which consists of intravenous administration of 1 mg of peptide every 12 hours for critically ill patients. The dose should be increased to 2 mg every 12 hours, for patients who do not show clinical and radiological improvement in 24 hours. After extubation, patients should receive 1 mg of CIGB-258 daily, for another three days. Seriously ill patients should receive 1 mg of CIGB-258 every 12 hours, until their clinical condition resolves.
Conclusions: CIGB-258 showed an excellent safety profile. The established therapeutic protocol contributed to all critically ill patients recovering from respiratory distress and being extubated. Seriously ill patients improved considerably. The levels of the biomarkers associated with hyperinflammation and cytokines decreased significantly during treatment.
Downloads
Download data is not yet available.
References
1. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID‐19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020[acceso: 14/08/2020]; 8:420‐422. Disponible en: https://covid-19.conacyt.mx/jspui/bitstream/1000/1079/1/105281.pdf
2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020[acceso: 29/07/2020];395(10229):1033–4. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270045/
3. Capraa R, DeRossia N, Mattiolib F, Romanelli G, Scarpazza C, Sormani MP, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European Journal of Internal Medicine. 2020[acceso: 08/06/2020]; 76: 31–35. Disponible en: https://doi.org/10.1016/j.ejim.2020.05.009
4. Peterson D, Damsky W, King B. The use of Janus kinase inhibitors in the time of SARS-CoV-2. J Am Acad Dermatol. 2020[acceso: 08/07/2020]; 82(6):e223-e226. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144601/
5. Domínguez MC, Lorenzo N, Barberá A, Darrasse-Jeze G, Hernandez MV, Torres AM, et al. An altered peptide ligand corresponding to a novel epitope from heat-shock protein 60 induces regulatory T cells and suppresses pathogenic response in an animal model of adjuvant induced arthritis. Autoimmunity. 2011[acceso: 21/12/2010]; 44(6):471-82. Disponible en: https://www.tandfonline.com/doi/abs/10.3109/08916934.2010.550590
6. van Eden W, van der Zee R and Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol. 2005[acceso: 06/10/2011]; 5(suppl 3):318–30. Disponible en: http://dx.doi.org/10.1136/ard.2006.058495
7. Barberá A, Lorenzo N, van Kooten P, van Roon, Jager W, Parda D, et al. APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4+T cells from rheumatoid arthritis patients. Cell Stress and Chaperones. 2016[acceso: 07/10/2013]; 21:735–744. Disponible en: https://doi.org/10.1007/s12192-016-0698-0
8. Lorenzo N, Altruda F, Silengo L and Dominguez MC. APL-1, an altered peptide ligand derived from heat-shock protein, alone or combined with methotrexate attenuates murine collagen induced arthritis. Clin Exp Med. 2017[acceso: 13/02/2016]; 17:209–216. Disponible en: https://doi.org/10.1007/s10238-016-0412-7
9. Prada D, Gómez J, Lorenzo N, Corrales O, Lopez A, Gonzalez E et al. 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. Journal of Clinical Trials. 2018[acceso: 08/02/2018]; 8(1):2167-0870. Disponible en: https://www.researchgate.net/profile/Maria_Dominguez_Horta/publication/323265216_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/links/5a8adef8aca272017e62ae6e/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.pdf
10. Corrales O, Hernández L, Prada D, Gómez J, Reyes Y, López AM, et al. CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis. Clinical Rheumatology. 2019[acceso: 05/11/2018]; 38(3):955–960. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30415439/
11. World Medical Association. World medical declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc. 2013[acceso: 24/07/2020]; 310(29): 2191-2194. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24141714/
12. Ministerio de Salud Pública. Protocolo de actuación nacional para la covid-19: versión 1.4. La Habana: Minsap; 2020. [acceso: 24/08/2020]. Disponible en: https://files.sld.cu/editorhome/files/2020/05/MINSAP_Protocolo-de-Actuaci%c3%b3n-Nacional-para-la-COVID-19_versi%c3%b3n-1.4_mayo-2020.pdf
13. Ministerio de Salud Pública. Regulación No. 45-2007: Requerimientos para la notificación y el reporte de eventos adversos graves e inesperados en los ensayos clínicos. La Habana: CECMED; 2007. [acceso: 24/08/2020]. Disponible en: https://www.cecmed.cu/sites/default/files/adjuntos/Reglamentacion/reg_45-07_requerimientos_para_la_notificacion_y_el_reporte_de_eventos_adversos_graves_e_inesperados_en_los_ensayos_clinicos.pdf
14. The ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012[acceso: 13/06/2020];307:2526–33. Disponible en: http://intensivo.sochipe.cl/subidos/catalogo3/ARDS%20definition.%20JAMA.%202012.pdf
15. Domínguez MC, Cabrales A, Lorenzo N, Padrón G and Gonzalez LJ. Biodistribution and pharmacokinetic profiles of an Altered Peptide Ligand derived from Heat-shock proteins 60 in Lewis rats. Cell Stress and Chaperones. 2020[acceso: 20/11/2020];25(1):133-140. Disponible en: https://pubmed.ncbi.nlm.nih.gov/31802366/
16 . Cabrales-Rico A, Ramos Y, Besada V,Dominguez M C, Lorenzo N, Garcia O, et al. Development and validation of a bioanalytical method based on LC-MS/MS analysis for the quantitation of CIGB-814 peptide in plasma from Rheumatoid Arthritis patients. J Pharm.Biomed Anal. 2017[acceso: 05/09/2017];143: 130-140. Disponible en: https://doi.org/10.1016/j.jpba.2017.05.030
17. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020[acceso: 30/06/2020];46(5): 846-848. DOI: 10.1007/s00134-020-05991-x
18. Capraa R, DeRossia N, Mattiolib F, Romanelli G, Scarpazza C, Sormani M, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European Journal of Internal Medicine. 2020[acceso: 06/08/2020]; 76: 31–35. Disponible en: https://doi.org/10.1016/j.ejim.2020.05.009
19. Bendib I, Chaisemartin l, Vanessa G, Schlemmer F, Maitre B, Hüe S, et al. Neutrophil Extracellular Traps Are Elevated in Patients with Pneumoniarelated Acute Respiratory Distress Syndrome. Anesthesiology. 2019[acceso: 05/05/2020]; 130: 4. Disponible en: https://doi.org/10.1097/ALN.0000000000002619
20. Li J, Guo M, Tian X , Wang X, Yang X, Wu P, et al. Virus-host interactome and proteomic survey reveal potential virulence factors influencing SARS-CoV-2 pathogenesis. Med. 2020[acceso: 30/04/2020]; 1:1-5. Disponible en: https://doi.org/10.1016/j.medj.2020.07.002
21. González M, González R, Hernández M, Bequet M, Rosario L, Grecesqui I, et al.CIGB-258, An Immunomodulatory Peptide for the Treatment of a COVID-19-associated Hepatic Encephalopathy: A Case Report. Preprint from Preprints. 2020[enviado: 09/09/2020; acceso: 09/09/2020]: [aprox. 10 pant.]. Disponible en: https://www.preprints.org/manuscript/202009.0240/v1
22. Gong J, Dong H, Xia Q, Huang Z, Wang D, Zhao Y, et al. Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19 pneumonia. Preprint from MedRxiv. 2020[enviado: 27/02/2020; acceso: 27/02/2020]:[aprox. 17 pant.]. Disponible en: https://doi.org/10.1101/2020.02.25.20025643
23. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front. Immunol. 2020[acceso: 20/06/2020]; 11:[aprox. 7 pant.]. Disponible en: https//doi.org/10.3389/fimmu.2020.00827
24. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020[acceso: 25/04/2020]; 130(5):2620-2629. Disponible en: https://www.jci.org/articles/view/137244
25. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 [acceso: 23/05/2020]; 71(15): 762-768. Disponible en: https://search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/es/covidwho-7937
2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020[acceso: 29/07/2020];395(10229):1033–4. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270045/
3. Capraa R, DeRossia N, Mattiolib F, Romanelli G, Scarpazza C, Sormani MP, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European Journal of Internal Medicine. 2020[acceso: 08/06/2020]; 76: 31–35. Disponible en: https://doi.org/10.1016/j.ejim.2020.05.009
4. Peterson D, Damsky W, King B. The use of Janus kinase inhibitors in the time of SARS-CoV-2. J Am Acad Dermatol. 2020[acceso: 08/07/2020]; 82(6):e223-e226. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144601/
5. Domínguez MC, Lorenzo N, Barberá A, Darrasse-Jeze G, Hernandez MV, Torres AM, et al. An altered peptide ligand corresponding to a novel epitope from heat-shock protein 60 induces regulatory T cells and suppresses pathogenic response in an animal model of adjuvant induced arthritis. Autoimmunity. 2011[acceso: 21/12/2010]; 44(6):471-82. Disponible en: https://www.tandfonline.com/doi/abs/10.3109/08916934.2010.550590
6. van Eden W, van der Zee R and Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol. 2005[acceso: 06/10/2011]; 5(suppl 3):318–30. Disponible en: http://dx.doi.org/10.1136/ard.2006.058495
7. Barberá A, Lorenzo N, van Kooten P, van Roon, Jager W, Parda D, et al. APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4+T cells from rheumatoid arthritis patients. Cell Stress and Chaperones. 2016[acceso: 07/10/2013]; 21:735–744. Disponible en: https://doi.org/10.1007/s12192-016-0698-0
8. Lorenzo N, Altruda F, Silengo L and Dominguez MC. APL-1, an altered peptide ligand derived from heat-shock protein, alone or combined with methotrexate attenuates murine collagen induced arthritis. Clin Exp Med. 2017[acceso: 13/02/2016]; 17:209–216. Disponible en: https://doi.org/10.1007/s10238-016-0412-7
9. Prada D, Gómez J, Lorenzo N, Corrales O, Lopez A, Gonzalez E et al. 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. Journal of Clinical Trials. 2018[acceso: 08/02/2018]; 8(1):2167-0870. Disponible en: https://www.researchgate.net/profile/Maria_Dominguez_Horta/publication/323265216_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/links/5a8adef8aca272017e62ae6e/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.pdf
10. Corrales O, Hernández L, Prada D, Gómez J, Reyes Y, López AM, et al. CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis. Clinical Rheumatology. 2019[acceso: 05/11/2018]; 38(3):955–960. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30415439/
11. World Medical Association. World medical declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc. 2013[acceso: 24/07/2020]; 310(29): 2191-2194. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24141714/
12. Ministerio de Salud Pública. Protocolo de actuación nacional para la covid-19: versión 1.4. La Habana: Minsap; 2020. [acceso: 24/08/2020]. Disponible en: https://files.sld.cu/editorhome/files/2020/05/MINSAP_Protocolo-de-Actuaci%c3%b3n-Nacional-para-la-COVID-19_versi%c3%b3n-1.4_mayo-2020.pdf
13. Ministerio de Salud Pública. Regulación No. 45-2007: Requerimientos para la notificación y el reporte de eventos adversos graves e inesperados en los ensayos clínicos. La Habana: CECMED; 2007. [acceso: 24/08/2020]. Disponible en: https://www.cecmed.cu/sites/default/files/adjuntos/Reglamentacion/reg_45-07_requerimientos_para_la_notificacion_y_el_reporte_de_eventos_adversos_graves_e_inesperados_en_los_ensayos_clinicos.pdf
14. The ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012[acceso: 13/06/2020];307:2526–33. Disponible en: http://intensivo.sochipe.cl/subidos/catalogo3/ARDS%20definition.%20JAMA.%202012.pdf
15. Domínguez MC, Cabrales A, Lorenzo N, Padrón G and Gonzalez LJ. Biodistribution and pharmacokinetic profiles of an Altered Peptide Ligand derived from Heat-shock proteins 60 in Lewis rats. Cell Stress and Chaperones. 2020[acceso: 20/11/2020];25(1):133-140. Disponible en: https://pubmed.ncbi.nlm.nih.gov/31802366/
16 . Cabrales-Rico A, Ramos Y, Besada V,Dominguez M C, Lorenzo N, Garcia O, et al. Development and validation of a bioanalytical method based on LC-MS/MS analysis for the quantitation of CIGB-814 peptide in plasma from Rheumatoid Arthritis patients. J Pharm.Biomed Anal. 2017[acceso: 05/09/2017];143: 130-140. Disponible en: https://doi.org/10.1016/j.jpba.2017.05.030
17. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020[acceso: 30/06/2020];46(5): 846-848. DOI: 10.1007/s00134-020-05991-x
18. Capraa R, DeRossia N, Mattiolib F, Romanelli G, Scarpazza C, Sormani M, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European Journal of Internal Medicine. 2020[acceso: 06/08/2020]; 76: 31–35. Disponible en: https://doi.org/10.1016/j.ejim.2020.05.009
19. Bendib I, Chaisemartin l, Vanessa G, Schlemmer F, Maitre B, Hüe S, et al. Neutrophil Extracellular Traps Are Elevated in Patients with Pneumoniarelated Acute Respiratory Distress Syndrome. Anesthesiology. 2019[acceso: 05/05/2020]; 130: 4. Disponible en: https://doi.org/10.1097/ALN.0000000000002619
20. Li J, Guo M, Tian X , Wang X, Yang X, Wu P, et al. Virus-host interactome and proteomic survey reveal potential virulence factors influencing SARS-CoV-2 pathogenesis. Med. 2020[acceso: 30/04/2020]; 1:1-5. Disponible en: https://doi.org/10.1016/j.medj.2020.07.002
21. González M, González R, Hernández M, Bequet M, Rosario L, Grecesqui I, et al.CIGB-258, An Immunomodulatory Peptide for the Treatment of a COVID-19-associated Hepatic Encephalopathy: A Case Report. Preprint from Preprints. 2020[enviado: 09/09/2020; acceso: 09/09/2020]: [aprox. 10 pant.]. Disponible en: https://www.preprints.org/manuscript/202009.0240/v1
22. Gong J, Dong H, Xia Q, Huang Z, Wang D, Zhao Y, et al. Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19 pneumonia. Preprint from MedRxiv. 2020[enviado: 27/02/2020; acceso: 27/02/2020]:[aprox. 17 pant.]. Disponible en: https://doi.org/10.1101/2020.02.25.20025643
23. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front. Immunol. 2020[acceso: 20/06/2020]; 11:[aprox. 7 pant.]. Disponible en: https//doi.org/10.3389/fimmu.2020.00827
24. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020[acceso: 25/04/2020]; 130(5):2620-2629. Disponible en: https://www.jci.org/articles/view/137244
25. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 [acceso: 23/05/2020]; 71(15): 762-768. Disponible en: https://search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/es/covidwho-7937
Published
2020-10-06
How to Cite
1.
Venegas Rodríguez R, Peña Ruiz R, Santana Sánchez R, Bequet-Romero M, Hernández-Cedeño M, Santiesteban Licea B, et al. CIGB-258 immunomodulatory peptide for the treatment of critical and severe COVID-19 patients. Rev Cubana Med Milit [Internet]. 2020 Oct. 6 [cited 2025 Mar. 14];49(4):e0200926. Available from: https://revmedmilitar.sld.cu/index.php/mil/article/view/926
Issue
Section
Research Article
License
Authors who have publications with this Journal accept the following terms:
- The authors will retain their copyright and guarantee the Journal the right of first publication of their work, which will simultaneously be subject to the Creative Commons Attribution License. The content presented here can be shared, copied and redistributed in any medium or format; Can be adapted, remixed, transformed or created from the material, using the following terms: Attribution (giving appropriate credit to the work, providing a link to the license, and indicating if changes have been made); non-commercial (you cannot use the material for commercial purposes) and share-alike (if you remix, transform or create new material from this work, you can distribute your contribution as long as you use the same license as the original work).
- The authors may adopt other non-exclusive license agreements for the distribution of the published version of the work (for example: depositing it in an institutional electronic archive or publishing it in a monographic volume) as long as the initial publication in this Journal is indicated.
- Authors are allowed and recommended to disseminate their work through the Internet (e.g., in institutional electronic archives or on their website) before and during the submission process, which can produce interesting exchanges and increase citations. of the published work.
