Authors: Díaz Y, Ramos-Suzarte M, Martín Y, Calderón N.A., Santiago W, Viñet O, La O Y, Oyarzábal J.P.A., Pérez Y, Lorenzo G, Cepeda M, Saavedra D, Mazorra Z, Estevez D, Lorenzo-Luaces P, Valenzuela C, Caballero A, Leon K, Crombet T, Hidalgo C.J.

Date: 2020/12/01

Link: https://www.karger.com/Article/Abstract/512210

Abstract:

• Background, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a recent outbreak of coronavirus disease (COVID-19). In Cuba, the first case of COVID-19 was reported on March 11, 2020. Elderly individuals with multiple comorbidities are particularly susceptible to adverse clinical outcomes in the course of SARS-CoV-2 infection. During the outbreak, a local transmission event took place in a nursing home in Villa Clara province, Cuba, in which 19 elderly residents tested positive for SARS-CoV-2.
• Methods, Based on the increased susceptibility to cytokine release syndrome, inducing respiratory and systemic complications in this population, 19 patients were included in an expanded access clinical trial to receive itolizumab, an anti-CD6 monoclonal antibody
• Results, All patients had underlying medical conditions. The product was well tolerated. After the first dose, the course of the disease was favorable, and 18 of the 19 patients (94.7%) were discharged clinically recovered with negative real-time reverse transcription polymerase chain reaction test results at 13 days. After one dose of itolizumab, circulating IL-6 decreased within the first 24–48 h in patients with high baseline values, whereas in patients with low levels, this concentration remained over low values. To preliminarily assess the effect of itolizumab, a control group was selected among the Cuban COVID-19 patients that did not receive immunomodulatory therapy. The control subjects were well matched regarding age, comorbidities, and severity of the disease. The percentage of itolizumab-treated, moderately ill patients who needed to be admitted to the intensive care unit was only one-third of that of the control group not treated with itolizumab. Additionally, treatment with itolizumab reduced the risk of death 10 times as compared with the control group.

Authors: Danay Saavedra, Ana Laura Añé-Kourí, Naivy Sánchez, Lázaro Manuel Filgueira, Julio Betancourt, Carlos Herrera, Leniel Manso, Elibet Chávez, Armando Caballero, Carlos Hidalgo, Geydi Lorenzo, Meylan Cepeda, Carmen Valenzuela, Mayra Ramos, Kalet León, Zaima Mazorra, Tania Crombet

Year: 2020

Link: https://immunityageing.biomedcentral.com/track/pdf/10.1186/s12979-020-00207-8.pdf

Abstract:

• Background, Since the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine
  storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients
• Results, We show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn’t rise as compared to their low baseline levels.

Author: Pugazhenthan Thangaraju, Nanditha Venkatesan, Eswaran Thangaraju, Sajitha Venkatesan

Year: 2020

Link: https://link.springer.com/article/10.1007/s42399-020-00550-3 

Abstract:

• Itolizumab, an anti-CD6 monoclonal antibody, has been recently approved for the off-label indication of cytokine release syndrome in the background of COVID-19, by the Drug Controller General of India. However, this drug has not been included in the National Clinical Management Protocol for COVID-19 yet. The limited-to-no experience of the Indian health workforce with the drug urged us to conduct a situational analysis in the pre-COVID era to analyse the degree of use of the drug and the indications for which it has been employed.

Author: Shubham Atal, Zeenat Fatima, Sadasivam Balakrishnan

Date: 2020

Link: https://link.springer.com/article/10.1007/s40259-020-00448-5

Abstract:

• Itolizumab is a first-in-class anti-CD6 monoclonal antibody that was initially developed for various cancers and was later developed and approved in India for treatment of moderate to severe chronic plaque psoriasis in 2013. This drug is now being re-purposed for COVID-19. The potential utility of itolizumab in COVID-19, based on its unique mechanism of action in ameliorating cytokine release syndrome (CRS), was proposed first in Cuba with approval of a single-arm clinical trial and expanded access use. Subsequently, a phase II, open-label, randomized, placebo-controlled trial has been conducted in 30 COVID-19 patients in India after receiving regulatory permission. Based on the results, the Indian drug regulatory agency recently approved itolizumab in July 2020 for ‘restricted emergency use’ for the treatment of CRS in moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. This has drawn sharp criticism within the scientific community, with the approval being granted on the basis of a relatively small phase II trial, without conduct of a conventional phase III trial, and lacking availability of the claimed supportive real-world evidence in the public domain to date. In a global scenario where finding a successful treatment for COVID-19 is of utmost priority, a biologic agent has been re-purposed and approved with a successfully completed RCT, in a country where cases and mortality due to COVID-19 are growing exponentially. However, instead of welcoming the approval with open arms, many doubts are being raised. This is an issue that needs to be considered and dealt with sensitively, as well as scientifically.

Author: Parasramani SG, Kunder GG, Suresh SH, Pawar DR

Year: 2017

Link: https://www.cochranelibrary.com/es/central/doi/10.1002/central/CN-01452500/full

Abstract: –

Author: Anchala Parthasaradhi, Vinay Singh, SG Parasramani, Nishi Yadav, DS Krupashankar, Manish Soni, Rakesh Bansal

Date: 2017/07/05

Link: https://www.idoj.in/article.asp?issn=2229-5178;year=2017;volume=8;issue=4;spage=246;epage=249;aulast=Parthasaradhi

Abstract:

• Background, While clinical trial data on the efficacy of itolizumab in the management of psoriasis is relatively well documented, data on the effectiveness of this humanized IgG1 monoclonal antibody in real-world settings is sparse. Aims: The current study assessed the effectiveness of itolizumab in real-world settings.
• Materials and Methods, This study assessed psoriasis area severity index (PASI), dermatology quality of life index (DLQI), safety, and tolerability data from a registry of itolizumab maintained by Syngene International, Bangalore. Registry data of 155 patients who were prescribed itolizumab at a dose of 1.6 mg/kg every 2 weeks for the first 12 weeks followed by 1.6 mg/kg every 4 weeks for up to 24 weeks for chronic plaque psoriasis.
• Results, In the study, 35.48% completed itolizumab for 12 weeks and 76.59% of these patients achieved PASI 75. Furthermore, 24.51% patients completed the full Itolizumab regimen for 24 weeks, of whom 92.01% patients achieved PASI 75. The mean percent change in DLQI scores at weeks 12 and 24 were 60.19 and 82.72, respectively. Adverse events and infusion reactions noted in the study were generally of mild to moderate severity.

Author: Shrichand G. Parasramani

Date: 2017 /07/01

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583834/

Abstract:

• Psoriasis is a chronic, relapsing, inflammatory disease that has been associated with Metabolic Syndrome (MS), a cluster of cardiovascular risk factors mainly hypertension, obesity, diabetes mellitus and hyperlipidemia. A 49-year-old male patient presented with extensive plaque psoriasis from past 13 years. Past medications included methotrexate, PUVA therapy, topical immunosuppressants and corticosteroids. His baseline Psoriasis Area and Severity Index (PASI) score was 39.8. The patient was screened and diagnosed with MS as per Alberti’s Criteria (his waist circumference was 100 cm, blood pressure was 160/100 mmHg and High Density Lipoprotein (HDL) was 30 mg/dl). Considering severity of the disease, in this case we used anti-CD6 humanized monoclonal antibody Itolizumab (1.6 mg/kg body weight) to treat psoriasis and concurrent MS. The patient achieved PASI 50 response in six months after treatment of 10 infusions of Itolizumab (First seven doses were given every fortnightly and the last three doses every month). Further, Itolizumab treatment was continued once every three months and PASI 75 response was achieved at the end of 15 months. His PASI score increased to 30.7 after 18 months. Contemplating link between psoriasis and MS due to possibility of overlapping inflammatory pathways, we instructed patient to reduce his weight and prescribed oral tablet metformin 500 mg twice a day. After losing 6 kg weight, his PASI score came down to 22.2 at the end of 21st month. This suggests that MS was a driving factor in worsening of his psoriasis. Psoriatic patients should be checked simultaneously for co-morbid disease conditions. The report indicates direct association of psoriasis and MS.

Author: Ganesh Pai, Anusha H. Pai

Year: 2017

Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180088

Abstract:

• Psoriasis is a chronic, relapsing, inflammatory, immune-mediated systemic disease with mainly skin and joint manifestations. The available treatment options to cure psoriasis include topical therapy, phototherapy, and biological therapy. Biological therapy has become a promising option due to the rapid action and less adverse effects associated with its use. The newly developed biologic itolizumab is a humanized recombinant anti-CD6 monoclonal antibody of IgG1 isotype that binds to domain 1 of CD6, thereby immunomodulating human lymphocytes without interfering with the binding of CD6 to the activated leukocyte-cell adhesion molecule. In this case series, a total of 5 patients with chronic plaque psoriasis were treated with itolizumab. They exhibited a rapid PASI 75 response after 4 doses of itolizumab infusion. The patients were poor responders to methotrexate and/or cyclosporine therapy for a long time. All infusions were well tolerated by all patients with no adverse reactions or infections during the treatment period. Itolizumab can be a good option for management of psoriasis and psoriatic arthritis.

Author: Sunil Dogra, Shraddha Uprety, Swaroop Hassan Suresh

Date: 2017/01/03

Link: https://www.tandfonline.com/doi/abs/10.1080/14712598.2017.1279601

Abstract:

• Introduction, Psoriasis, a chronic immune-mediated skin disorder is associated with significant physical, psychological, and quality of life impairments. Along with well-documented genetic and environmental factors, immunological factors also contribute to the pathogenesis of psoriasis. Among the immunological factors, CD6 – dependent T-cell proliferation to form Th1 and Th17 cells play a major role in the pathogenesis of psoriasis. Itolizumab is the first humanized IgG1 monoclonal antibody, which selectively targets CD6.
• Areas covered, The current article presents the pharmacology of itolizumab and provides a review of the currently available data on the efficacy and safety of itolizumab for management of moderate to severe plaque psoriasis.
• Expert opinion, The use of biologics to attenuate the immune-mediated pathological events in psoriasis is a relatively well-established clinical practice. However, the safety and efficacy of biologics continues to be an unsettled topic of ongoing research. While available data seems to suggest that itolizumab may be a safer option, additional studies with higher sample sizes and active comparators are needed before definitive conclusions can be drawn on the place of itolizumab in the management of psoriasis.

Author: Anchala Parthasaradhi

Date: 2016/11/01

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198440/

Abstract:

• Psoriasis is a common, chronic, relapsing/remitting, immune-mediated skin disease that causes itchy skin with silvery scales. It is characterized by thickened red erythematous plaques covered with silvery scales. Biological therapies have been recently introduced for patients with psoriasis in India. The biological therapies contain protein biomolecules which can be employed to target specific immune or genetic mediator of a pathophysiological process. Here, we share our clinical experience of managing 20 patients with moderate to severe psoriasis by itolizumab a humanized IgG1 monoclonal antibody. Eighteen patients achieved Psoriasis Area and Severity Index (PASI) 75 response after receiving 10 infusion of itolizumab (at the completion of treatment). Out of 18 patients 4 patients had achieved PASI 95 response and 10 patients had achieved PASI 90 response. There was no adverse event reported during the treatment period. Itolizumab was found effective and safe in the treatment of moderate to severe psoriasis patients.

Author: Pedro C. Rodriguez, Roberto Torres-Moya, Gil Reyes, Claudino Molinero, Dinorah Prada, Ana M. Lopez, Isabel M. Hernandez, Maria V. Hernandez, Jose P. Martinez, Xochel Hernandez, Angel Casaco, Mayra Ramos, Yisel Avila, Yinet Barrese, Enrique Montero, Patricia Hernandez

Date: 2012/11/21

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862386/

Abstract:

• T cells are involved in the pathogenesis of rheumatoid arthritis (RA). CD6 is a co-stimulatory molecule, predominantly expressed on lymphocytes, that has been linked to autoreactive responses. The purpose of this study was to evaluate the safety, immunogenicity and preliminary efficacy of itolizumab, a humanized anti-CD6 monoclonal antibody, in patients with active rheumatoid arthritis. Fifteen patients were enrolled in a phase I, open-label, dose-finding study. Five cohorts of patients received a weekly antibody monotherapy with a dose-range from 0.1 to 0.8 mg/kg. Itolizumab showed a good safety profile, with no severe or serious adverse events reported so far. No signs or symptoms associated with immunosuppression were observed in the study. Objective clinical responses were achieved in more than 80% of patients after treatment completion, and these responses tend to be sustained afterwards. This clinical study constitutes the first evidence of the safety and positive clinical effect of a monotherapy using an anti-CD6 antibody in patients with rheumatoid arthritis.

Author: Pradip Nair, Abhijit Ghorai, Laxmi Adhikary, Ramakrishnan Melarkode, Enrique Montero

Date: 2011/04/01

Link: https://www.jimmunol.org/content/186/1_supplement/52.27

Abstract:

• We have shown previously that the CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal human peripheral blood mononuclear cells (PBMCs), defined by Bliss analysis. The use of a CD6 membrane-distal domain (SRCR1)-specific non-depleting monoclonal antibody Itolizumab, inhibited the CD6-ALCAM induced proliferation of PBMCs. This is associated with reduction in pro inflammatory cytokines at the protein and mRNA level. In this study, we show that the antibody inhibits T cell proliferation in a typical mixed lymphocyte reaction wherein the matured dendritic cells over express ALCAM. The inhibition is associated with reduction in CD4 and CD25 surface expression in these T cells. A marked reduction in interferon-γ, tumour necrosis factor-α and IL-17 production is also observed. Using confocal microscopy we show that the receptor CD6 internalization occurs within minutes in T cells in the presence of Itolizumab and is not localized to the immunological synapse. Intriguingly, a deglycosylated antibody showed reduced inhibition of T cells in the mixed lymphocyte reaction. The deglycosylated antibody did not show any difference in binding to HuT 78 cell expressing CD6 as compared to the normal antibody. These results would suggest that the monoclonal antibody Itolizumab also prevents T cell proliferation induced in mixed lymphocyte reactions and there is a role for the Fc region glycosylation of the antibody to elucidate this function.

Author: P Nair, R Melarkode, D Rajkumar, E Montero

Date: 2010/08/19

Link: https://pubmed.ncbi.nlm.nih.gov/20726988/

Abstract:

• The CD6 membrane-proximal scavenger receptor cysteine-rich domain (SRCR3) includes the activated leucocyte cell adhesion molecule (ALCAM) binding site. CD6-ALCAM mediates a low-affinity interaction and their long-term engagement contributes to the immunological synapse. Their ligation may play a dual function, facilitating stable adhesion between the antigen-presenting cells and T cells during the early activation phase and later in the proliferative phase of the immune response. This study explored the strength of the CD6 co-stimulatory effect and whether CD6 co-stimulation with its natural ligand ALCAM also contributes to the lymphocyte effector differentiation. It was found that CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal human peripheral blood mononuclear cells, defined by Bliss analysis. CD6 co-stimulation enhanced the CD3 proliferative efficacy by 23-34%. Moreover, a fivefold increment in the CD25 molecules number with a distinct gene transcription profile associated with cell activation, differentiation, survival and adhesion molecules was observed over CD3 single activation. Additionally, CD6 co-stimulation in excess interleukin (IL)-2 promotes a preferentially proinflammatory response. Besides, a CD6 membrane-distal domain (SRCR1)-specific non-depleting monoclonal antibody (mAb) inhibited the induced proliferation in the presence of ALCAM, reducing interferon-γ, IL-6 and tumour necrosis factor-α production. These results suggest that CD6 co-stimulation enhances the intrinsic activity of the CD3 activation pathway and contributes to the T helper type 1 subset commitment, enhancing the IL-2 sensitivity of recent activated human lymphocytes. It supports the role of CD6 as a susceptibility gene for pathological autoimmunity leading to tissue inflammation, and its relevance for targeted therapy.

Authors: Jeanette Ampudia, Dalena Chu, Jana Badrani, Taylor Doherty, Stephen Connelly and Cherie Ng

Date: 01-03-2021

Link: https://www.jimmunol.org/content/206/1_Supplement/98.43

Abstract:

• CD6 is a T-cell costimulatory receptor predominantly expressed on T cells and promotes immune synapse formation, T-cell activation, and T-cell migration via interaction with activated leukocyte cell adhesion molecule (ALCAM). The CD6-ALCAM pathway has been linked to the pathogenesis of multiple autoimmune and inflammatory diseases. While the contribution of CD6 to T cell activation has been well described, less is known regarding the expression levels and role of CD6 on effector and memory T cells which contribute to ongoing disease. Consequently, the aim of this study was to determine the role of CD6 specifically on Th1, Th2 and Th17 effector T cells (Teff). Blockade of the CD6 pathway using itolizumab, a humanized mAb currently being tested in the clinic, during restimulation of fully differentiated Th1, Th2 or Th17 Teff cells in the presence of ALCAM inhibited multiple effector functions, including proliferation and changes in cell size. An average 40% decrease in proliferation was observed across multiple donors. Furthermore, treatment of Teff cells with itolizumab resulted in a significant decrease in relevant cytokines such as IFNγ and TNFα for Th1, IL-4 and IL-13 for Th2, TNFα and IL-17 for Th17, as well as in expression levels of T cell markers of activation and exhaustion such as CD69, CD25, and PD-1. This effect was exclusively observed in the presence of ALCAM, indicating that the effect was specific to blockade of the CD6-ALCAM pathway. This study is the first to characterize the CD6-ALCAM pathway as a key regulator of effector Teff cell function. As these are the cells that drive disease pathogenicity, these data support targeting the CD6-ALCAM pathway to inhibit effector Teff cell populations in autoimmune and inflammatory diseases.

Authors: Angelina R Bisconte, Lynn Kisselbach, Cherie Ng PhD, Jeanette Ampudia, Dalena Ngoc Chu, Natalya Belkina PhD, Stephen Connelly PhD, Deborah Phippard PhD.

Year: 2021

Link: https://www.precisionformedicine.com/wp-content/uploads/2021/10/AAI2021_PFM_EQ_ROFlowAssay_15April2021_Submitted.pdf

Abstract:

• Introduction, Itolizumab is a novel first-in-class monoclonal antibody that selectively targets the co-stimulatory molecule CD6, a receptor that is highly expressed on CD4 and CD8 T cells and plays an important role in activation and migration. Monitoring target engagement and changes in receptor levels is critically important to interpreting clinical data. To evaluate the pharmacodynamic properties of itolizumab treatment on T cells in patients including those with graft versus host disease (GvHD), Precision for Medicine has developed and validated a 10-color flow cytometry assay to assess the engagement and modulation of cell-surface CD6.
• Purpose, Measuring cell-based receptor engagement and fate in patients on immuno-modulatory therapies is very challenging. This assay was designed and validated to be both sensitive and selective in the quantification of CD6 receptor occupancy and modulation to facilitate the determination of an optimal therapeutic dose in autoimmune and inflammatory diseases. The validation parameters assessed included intra-assay, inter-assay, inter-operator precision and post-staining stability.