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ITOLIZUMAB PUBLICATIONS

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: 2021/10/25

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.

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: 2021/01/11

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.

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

Date: 2021/01/31

Link: https://www.ijrc.in/article.asp?issn=2277-9019;year=2021;volume=10;issue=1;spage=112;epage=115;aulast=Thacker

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.

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

Date: 2021/02/25

Link: https://www.ipinnovative.com/journal-article-file/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: 2021/02/25

Link: https://www.ipinnovative.com/journal-article-file/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.

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

Date: 2021/02/01

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.

Author: Subramanian Loganathan, Sandeep N. Athalye and Shashank R. Joshi

Date: 2020/06/19

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

Abstract:

  • Introduction, 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: 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: 2017/07/03

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: 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: 2016/04/01

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: 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: 2015/08/01

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

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: 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: 2014/04/02

Link: https://www.sciencedirect.com/science/article/abs/pii/S0190962214010287

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

Date: 2014/12/12

Link: https://pubmed.ncbi.nlm.nih.gov/25495868/

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.

ABSTRACT

Authors: Chakravadhanula U, Jha BK

Year: 2017

Link: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01452502/full

Abstract: –

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

Year: 2014

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).
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