Authors: Raveendra KR, Chirag Rathod, Rahul Darnule, Subramanian Loganathan, Sarika Deodhar, Radhika A, Ashwani Marwah, Nitin M Chaudhari, Binay K Thakur, Sivakumar Vaidyanathan, and Sandeep Nilkanth Athalye.

Date: Apr 14th, 2023

Link: https://doi.org/10.1080/14712598.2023.2204186

Abstract –

Background: Itolizumab, an anti-CD6 monoclonal antibody, down-regulates COVID-19-mediated inflammation and the acute effects of cytokine release syndrome. This study aimed to evaluate the safety and efficacy of itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 ratio (PFR) ≤200 requiring oxygen therapy.

Research design and methods: This multicenter, single-arm, Phase 4 study enrolled 300 hospitalized adults with SARS-CoV-2 infection, PFR ≤200, oxygen saturation ≤94%, and ≥1 elevated inflammatory markers from 17 COVID-19 specific tertiary Indian hospitals. Patients received 1.6 mg/kg of itolizumab infusion, were assessed for 1 month, and followed-up to Day 90. Primary outcome measures included incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) and mortality rate at 1 month.

Results: Incidence of severe acute IRRs was 1.3% and mortality rate at 1 month was 6.7% (n = 20/300). Mortality rate at Day 90 was 8.0% (n = 24/300). By Day 7, most patients had stable/improved SpO2 without increasing FiO2 and by Day 30, 91.7% patients were off oxygen therapy. Overall, 63 and 10 patients, respectively, reported 123 and 11 treatment-emergent adverse events up to Days 30 and 90. No deaths were attributable to itolizumab. Patient-reported outcomes showed gradual and significant improvement for all five dimensions on EQ-5D-5L

Conclusion: Itolizumab demonstrated acceptable safety with a favorable prognosis in hospitalized COVID-19 patients.

Additional information: This paper was funded by Biocon Biologics Limited. The sponsors did not have any role in patient recruitment and management

Authors: Hemant P Thacker, Amit Dhekane, Nivedita Wadhwa, Shalaka Patil.

Date: Dec 6th, 2022

Link: https://www.ijrc.in/abstractArticleContentBrowse/IJRC/98/10/1/30662/abstractArticle/Article

Abstract –

In COVID-19 patients, cytokine release syndrome plays a critical role in disease progression. Itolizumab inhibits T-cell proliferation and differentiation, thereby modulating imminent cytokine storm. Here, we report a case of a 44-year-old male patient with confirmed COVID-19 and oxygen saturation (SpO2) of 88% on room air. A chest X-ray revealed dense opacification. High levels of inflammatory markers such as C-reactive protein (CRP) and ferritin were observed. The patient’s SpO2 decreased to 87% on day 4 despite the best supportive care.

Itolizumab was then administered at 1.6 mg/kg along with high flow oxygen. The patient’s SpO2 values improved to 95% and 97% on 4th- and 5th-day postinfusion, respectively. CRP and ferritin levels decreased by 85.96% and 24.48%, respectively, along with radiological improvement. The patient was discharged on the 7th day postinfusion in a clinically stable condition. This is the first report of an anti-CD6 humanized monoclonal antibody, itolizumab, given to a patient with moderate-to-severe COVID-19 disease that showed a reduction in hyperinflammation, leading to clinical and radiological improvement.

Authors: KR Raveendra, Chirag Rathod, Rahul Darnule, Subramanian Loganathan, Sarika Deodhar, A Radhika, Ashwani Marwah, Nitin M Chaudhari, Binay K Thakur, Sivakumar Vaidyanathan, Sandeep Nilkanth Athalye.

Date: Oct 28th, 2021

Link: https://www.medrxiv.org/content/10.1101/2021.10.25.21265462v2

Abstract –

Objective: To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 ratio (PFR) ≤200 requiring oxygen therapy.

Design: A multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days.

Methods: Hospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200; oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19-specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90.

Results: Day-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO2 without increasing FiO2. Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH, and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS, and respiratory failure. No deaths were attributable to Itolizumab.

Conclusion: Itolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.

Funding Statement: This study was funded by Biocon Biologics Limited

Author: Hemant P Thacker, Amit Dhekane, Nivedita Wadhwa, Shalaka Patil

Date: Feb 25th, 2021

Link: https://www.ijirm.org/article-details/13322

Abstract –

Hyperinflammation and cytokine storm have been reported in severe coronavirus disease (COVID-19) patients. Persistent elevated levels of inflammatory cytokines may lead to an increased risk of vascular hyperpermeability, multiorgan failure, and eventually death over time. Repurposed Itolizumab, a humanized recombinant anti-CD6 monoclonal antibody, is found to inhibit T-cell proliferation and reduce IFN-g , IL-6, and TNF-a production, thereby leading to reduction in the T-cell infiltration at the sites of inflammation. Here we report a case of a 69 year old COVID-19 confirmed male patient who presented with a history of fever, cough and fatigue. The patient had elevated levels of serum ferritin and CRP. His SpO2 was 80% and ground glass opacities were observed in his chest X-ray. The patient was initiated on oxygen (using HFR mask) along with best supportive care and saturation was maintained at SpO2 of 85%. Itolizumab (1.6 mg/kg) was administered as an intravenous infusion (Day 1). On Days 3 and 4, the patient continued on oxygen and maintained a SpO2 90% – 92%. On Day 7, there was a 87.86% reduction in the inflammatory marker CRP from baseline. On Day 8, the patient was off oxygen. On Day 9, there was further clinical improvement and the chest x-ray revealed reduction of opacities at the basal and hilar regions. Day 10 showed further CRP reduction of 97.69% from baseline. On Day 12, the patient was discharged. Itolizumab, along with best supportive care, shows potential to reduce hyperinflammation leading to clinical and radiological improvement in COVID-19 patients with severe disease.

Author: Hemant P Thacker, Dnyaneshwar Halnor, Amit Dhekane, Nivedita Wadhwa, Shalaka Patil, Bhavesh Gandhi, Janardan Nimbolkar, Ajit Avhad

Date: Feb 25th, 2021

Link: https://www.ijirm.org/article-details/13314

Abstract –

Introduction: Cytokine release syndrome caused by excessive release of cytokines due to activation of T-cells and monocytes is directly associated with COVID-19 disease severity. Itolizumab, an anti-CD6 monoclonal antibody, basis its mechanism of action might have a potential role in reducing inflammatory markers and thereby improving clinical outcomes in moderate to severe COVID-19.

Materials and Methods: We retrospectively examined records of patients with moderate or severe COVID-19 disease who were treated with Itolizumab. Eligible patients were those deteriorating clinically, requiring oxygen support or showing rapid rise in inflammatory markers and administered Itolizumab along with best supportive care. Clinical manifestations (oxygen requirement) and laboratory parameters (CRP and ferritin) were studied pre- and post-treatment.

Results: A total of 27 patients with mean age of 55.63 years (81.5% male) were included. Most common comorbid conditions were hypertension (48.1%), diabetes (44.4%), and coronary artery disease (11.1%). The mean CRP from baseline reduced by 52.68% (91 mg/L pre dose to 43mg/L post dose) at an average time of 6.4 ± 2.5 days. The mean Ferritin levels reduced by 17.41 % (407 ng/ml pre dose to 336 ng/ml post dose) at an average time of 4.6 ± 2.2 days. Mean baseline oxygen saturation improved from 93.4% to 96.1%. All patients showed clinical improvement and got discharged. The mean hospitalization time was 12.2 ± 3.9 days. No serious adverse events or infusion related reactions were reported.

Conclusions: Treatment of moderate to severe COVID-19 disease with Itolizumab along with best supportive care showed reduction in inflammatory markers and improvement in oxygen saturation levels. Itolizumab has shown potential to accelerate recovery time in hospitalized patients with COVID-19.

Author: Gore V, Kshirsagar DP, Bhat SM, Khatib KI, Mansukhani B

Date: Feb 1st, 2021

Link: https://europepmc.org/article/med/33527804

Abstract –

Background: Hyperinflammation, hypercoagulation and multi-organ dysfunction are life-threatening complications needing immediate attention in moderate-tosevere COVID-19 patients. We present our real world experience with Itolizumab, a repurposed immunomodulatory monoclonal antibody, administered in COVID-19 patients.

Methodology: Data from 25 confirmed moderate-to-severe COVID-19 patients, with high levels of pro-inflammatory markers and pulmonary function worsening on best supportive care and Itolizumab were included in this analysis. Patients requiring invasive mechanical ventilation were excluded. Clinical parameters (oxygen requirement) and laboratory parameters (ferritin, interleukin [IL]-6, C-reactive protein [CRP] and absolute lymphocyte count [ALC]) were studied preand post-treatment. Average total length of stay in hospital and ICU, percentage of patients requiring ICU admission and average time taken for weaning off oxygen for all patients were also reported.

Results: All Patients were in the range of 30-78 years of age, with majority being male (76%). Most prevalent comorbid conditions were diabetes (64%) and hypertension (28%). Median IL-6 value showed a decline by 85.4%. Significant reduction in median CRP (86.96%) and Ferritin (55.61%) was observed post- Itolizumab compared to pre-dose values. Median ALC improved from 1605 cells/ mm3 (pre-dose) to 2462.5 cells/mm3 (post-dose). Average recovery time, defined as time from Itolizumab infusion to discharge was 9.28 ± 4.04 days. Average duration of hospitalization and ICU admission was 14.24 ± 4.15 and 8.27 ± 4.47 days, respectively, with 76% patients recovered and discharged. Median oxygen saturation improved from 88 % (pre-dose) to 96 % (post-dose). All patients were weaned off oxygen within Avg + SD : 6.53 ± 2.09 days post-Itolizumab treatment. One and two point reduction in ordinal scale was observed in 88% and 76% patients, respectively. Three patients (12%) did not show improvement in ordinal sore of which two patients died because of complications due to pre-existing comorbidities. The all-cause mortality of 8%; was considered not related to Itolizumab. One infusion related event reported abated with infusion period extension.

Interpretation and conclusion: A single dose of Itolizumab accelerated recovery in adult patients with COVID-19 by controlling immune hyperactivation. The clinical improvement was demonstrated by reduction in inflammatory markers, weaning off oxygen, reduced length of hospital stay and improvement of ordinal score. Itolizumab was well tolerated and when administered in the early phase of the inflammatory cascade is an efficient therapeutic option for treatment of cytokine release syndrome in moderate to severe COVID-19 patients.

Authors: Suresh Kumar, Rosemarie De Souza, Milind Nadkar, Randeep Guleria, Anjan Trikha, Shashank R. Joshi, Subramanian Loganathan, Sivakumar Vaidyanathan, Ashwani Marwah and Sandeep N. Athalye

Date: Jan 11th, 2021

Link: https://www.tandfonline.com/doi/full/10.1080/14712598.2021.1905794

Abstract –

Objective: Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study.

Methods: Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment.

Results: Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = −0.3 [−0.61, −0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events.

Conclusion: Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.

Funding: The study was funded by Biocon Biologics India Limited and the funders did not have any role in patient recruitment and management.

Authors: Lázaro Manuel Filgueira, Julio Betancourt Cervantes, Orlando Adolfo Lovelle, Carlos Herrera, Carlos Figueredo, Naivy Sánchez, Jorge Berrio, Geidy Lorenzo, Meylan Cepeda, Mayra Ramos, Danay Saavedra, Ana Laura Añe-Kouri, Zaima Mazorra, Kalet Leon, Tania Crombet, Armando Caballero.

Date: Jan 5th, 2021

Link: https://www.futuremedicine.com/doi/full/10.2217/imt-2020-0235

Abstract –

In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.

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

Date: Nov 14th, 2020

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

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.

Conclusion: These findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients.

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: Oct 26th, 2020

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.

Conclusion: This study corroborates that the timely use of itolizumab in combination with other antivirals reduces COVID-19 disease worsening and mortality. The humanized antibody itolizumab emerges as a therapeutic alternative for patients with COVID-19. Our results suggest the possible use of itolizumab in patients with cytokine release syndrome from other pathologies.

Author: Shubham Atal, Zeenat Fatima, Sadasivam Balakrishnan

Date: Oct 13th, 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: Pugazhenthan Thangaraju, Nanditha Venkatesan, Eswaran Thangaraju, Sajitha Venkatesan

Date: Sep 26th, 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: Subramanian Loganathan, Sandeep N. Athalye and Shashank R. Joshi

Date: Jul 23rd, 2020

Link: https://www.tandfonline.com/doi/full/10.1080/14712598.2020.1798399

Abstract –

The globally rampant SARS CoV-2 pandemic requires novel medical strategies to control the severity of disease and death due to complications. Of the 15–20% patients that develop pulmonary symptoms, a sub-set develops an acute respiratory distress syndrome (ARDS) rapidly progressing into a critical condition. Marked elevation of cytokines/chemokines is observed with elevation of additional markers of inflammation, coagulation, and organ damage such as CRP, D-dimer, LDH, Ferritin and Troponin-I. This hyperinflammation leads to worsening of oxygen saturation due to pulmonary infiltration and exudation, organ damage, and dysfunction of coagulation pathway and may lead to multi-organ failure.

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

Date: Mar 31st, 2018

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

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

Date: Aug 23rd, 2017

Link: https://www.karger.com/Article/FullText/475519

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

Date: Jul-Aug, 2017

Link: https://journals.lww.com/idoj/Fulltext/2017/08040/A_Real_World_Study_to_Assess_the_Effectiveness_of.2.aspx

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.

Conclusion: Itolizumab is a safe and effective option in treatment-compliant patients with chronic plaque psoriasis. Effects of putative compliance-modulators such as cost, route of administration, and delayed onset of action warrant further investigation.

Author: Usha Bughani, Arindam Saha, Anshu Kuriakose, Reshmi Nair, Ravindra B. Sadashivarao, Rasika Venkataraman, Swati Patel, Anuja Tushar Deshchougule, Satish Kumar S., Enrique Montero, Harish V. Pai, Dinesh V. Palanivelu, Ramakrishnan Melarkode, Pradip Nair

Date: July 3rd, 2017

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

Abstract –

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.

Author: Shrichand G. Parasramani

Date: Jul 1st, 2017

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: Sunil Dogra, Shraddha Uprety, Swaroop Hassan Suresh

Date: Jan 9th, 2017

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.

Declaration of interest: 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: Nov 1st, 2016

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: Sunil Dogra, Krupashankar D.S., Leelavathy Budamakuntla, C. R. Srinivas, Uday Khopkar, Sandesh Gupta, Narendra Shetty, Dasiga Venkata Subrahmanya Pratap, M. G. Gopal, T. Narayana Rao, Vijay Garg.

Date: Aug 1st, 2015

Link: https://www.jaad.org/article/S0190-9622(15)01485-1/fulltext

Abstract:

• We have reported 28-week safety and efficacy results of itolizumab (anti-CD6 domain 12) in a double-blind, placebo-controlled phase 3 study (CTRI/2009/091/001009). Two hundred and twenty-five patients with moderate-to-severe psoriasis were randomized (2:2:1) to 3 arms (A: 0.4 mg/kg per week [q1w] for 4 weeks followed by 1.6 mg/kg every 2 weeks [q2w]; B: 1.6/mg q2w; C: placebo). At week 12, placebo was switched to 1.6 mg/kg itolizumab q2w.1 Here we evaluate long-term efficacy and safety in patients who completed the full 52 weeks of the study.

Author: Arvind Chopra, S Chandrashekara, Rajgopalan Iyer, Liza Rajasekhar, Naresh Shetty, Sarathchandra Mouli Veeravalli, Alakendu Ghosh, Mrugank Merchant, Jyotsna Oak, Vikram Londhey, Abhijit Barve, M S Ramakrishnan, Enrique Montero.

Date: June 7th, 2015

Link: https://pubmed.ncbi.nlm.nih.gov/26050104/

Abstract:

The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to methotrexate. In this open-label, phase 2 study, 70 patients fulfilling American College of Rheumatology (ACR) criteria and negative for latent tuberculosis were randomized to four arms: 0.2, 0.4, or 0.8 mg/kg itolizumab weekly combined with oral methotrexate, and methotrexate alone (2:2:2:1). Patients were treated for 12 weeks, followed by 12 weeks of methotrexate alone during follow-up. Twelve weeks of itolizumab therapy was well tolerated. Forty-four patients reported adverse events (AEs); except for six severe AEs, all others were mild or moderate. Infusion-related reactions mainly occurred after the first infusion, and none were reported after the 11th infusion. No serum anti-itolizumab antibodies were detected. In the full analysis set, all itolizumab doses showed evidence of efficacy. At 12 weeks, 50 % of the patients achieved ACR20, and 58.3 % moderate or good 28-joint count Disease Activity Score (DAS-28) response; at week 24, these responses were seen in 22 and 31 patients. Significant improvements were seen in Short Form-36 Health Survey and Health Assessment Questionnaire Disability Index scores. Overall, itolizumab in combination with methotrexate was well tolerated and efficacious in RA for 12 weeks, with efficacy persisting for the entire 24-week evaluation period.

Author: L Budamakuntla, M Madaiah, S Sarvajnamurthy, S Kapanigowda

Date: Dec 12th, 2014

Link: https://onlinelibrary.wiley.com/doi/10.1111/ced.12509

Abstract –

There is an unmet need for psoriasis therapies that provide long-term remission. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody shown to be effective in psoriasis. We report a patient who received itolizumab in a phase 2 clinical trial, and experienced long-term remission. At baseline, the patient’s Psoriasis Area and Severity Index (PASI) was 12.2, and Physician’s Global Assessment (PGA) score was 3. After 8 weeks of treatment, the patient achieved 97% improvement in PASI. She continued to have ≥ 90% improvement, initially for 4 weeks (follow-up phase), and later for 20 weeks (follow-up extension phase). She continued to visit the hospital after the final study visit; her most recent visit was on 10 May 2013. PGA results during the visits revealed sustained response for 4 years and 5 months after stopping itolizumab. Itolizumab could be therefore an important treatment option for moderate to severe psoriasis, with potential to provide long-lasting remission.

Author: D.S.Krupashankar, Sunil Dogra, Mahendra Kura, Abir Saraswat, Leelavathy Budamakuntla, T.K. Sumathy, Radha Shah, M.G. Gopal, T. Narayana Rao, C.R. Srinivas, Ramesh Bhat, Narendra Shetty, G Manmohan.

Date: Sep 1st, 2014

Link: https://www.jaad.org/article/S0190-9622(14)01028-7/fulltext

Abstract – 

Background: Itolizumab, a humanized monoclonal antibody to CD6, is a novel therapeutic agent evaluated in chronic plaque psoriasis.

Objective: We sought to assess the safety and efficacy of itolizumab in moderate to severe chronic plaque psoriasis.

Methods: A total of 225 patients were randomized (2:2:1) to 2 different itolizumab arms (A or B; A = 4-week loading dose of 0.4 mg/kg/wk followed by 1.6 mg/kg every 2 weeks; B = 1.6/mg every 2 weeks) or placebo. At week 12, the placebo arm was switched to 1.6 mg/kg itolizumab every 2 weeks. The primary end point was the proportion of patients with at least 75% improvement in Psoriasis Area and Severity Index score at week 12.

Results: At week 12, 27.0% in arm A (P = .0172 vs placebo), 36.4% in B (P = .0043 vs placebo), and 2.3% in the placebo arm had at least 75% improvement in Psoriasis Area and Severity Index score. At week 28, the proportion with at least 75% improvement in Psoriasis Area and Severity Index score was comparable: 46.1%, 45.5%, and 41.9% for A, B, and placebo, respectively. In weeks 1 to 12, the incidence of all adverse events was comparable across arms (A, 43%; B, 38%; placebo, 47%) and the incidence of infections was not greater than placebo (11.1%, 8.9%, and 18.6% for A, B, and placebo).

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: Nov 14th, 2012

Link: https://www.sciencedirect.com/science/article/pii/S2211283912000263

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: Apr 1st, 2011

Link: https://journals.aai.org/jimmunol/article/186/1_Supplement/52.27/49175/The-inhibition-of-T-cell-proliferation-in-a-mixed

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: Aug 19th, 2010

Link: https://academic.oup.com/cei/article/162/1/116/6438699

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: Chakravadhanula U, Chandrashekar BS, Parekh M, Krupashankar DS, Swaroop HS, Pawar D

Date: Dec 2nd, 2017

Link: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01452514/full

Abstract: –

Authors: A. Chopra, C. Srikantiah, P. Cg, E. Montero, R. Melarkode

Link: https://ard.bmj.com/content/73/suppl_2/69.3

Abstract:

• Background, Itolizumab is a first-in-class anti-CD6 monoclonal antibody with therapeutic potential in multiple autoimmune disorders including rheumatoid arthritis (RA).
• Objectives, To evaluate the safety and efficacy of itolizumab with background methotrexate (MTX) in patients with active RA who have inadequate response to MTX.
• Methods, In this 24-week, phase 2, randomized, open-label study, patients were randomized (2:2:2:1) to receive 3 different doses of itolizumab (0.2, 0.4 or 0.8 mg/kg weekly) with oral MTX, or oral MTX alone. The study included 12 weeks of treatment followed by 12 weeks of MTX-alone follow-up. Safety was assessed by adverse events (AE) and laboratory parameters. Efficacy was assessed at 12 weeks by American College of Rheumatology (ACR) criteria and Disease Activity Score in 28 joints assessed by European League against Rheumatism (DAS28-EULAR) criteria, and health-related quality of life was evaluated using SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI).