INTRODUCTION:

Itolizumab is a notable therapeutic drug that targets the SRCR-D1 region of CD6 and selectively modulates stimulation of the T cell ¹. The parental antibody of Itolizumab is also known as murine antibody called ior T1 of the IgG isotope is mainly expressed on T lymphocytes which suppresses the T-cell proliferation, signalling, gene expression, cytokine secretion by binding to the domain 1 of T-cell receptor CD60². The molecular weight of Itolizumab is 148 kDa, consisting of two light chains with 214 amino acids and two heavy chains with 449 amino acids linked by a disulphide bond³. Itolizumab is commercially available under the trade name Alzumab™. It is manufactured by Bangalore, India-based Biocon Ltd. and comes in single-use, 25 mg/5 mL vials for intravenous (IV) injection that are free of preservatives. It comes in the form of a colourless buffer solution with pH 7.0±0.5 ³.

Itolizumab can be prescribed as an immunosuppressant to transplant recipients to prevent the rejection of the transplanted organ.

Pharmacokinetics and pharmacodynamics:

Pharmacokinetics and pharmacodynamics are very important as they play an important role in optimizing dosing regimens, predicting drug interactions, and ensuring safety and efficacy in clinical use ³. Itolizumab exhibits a linear, dose-dependent relationship in its maximum concentration (C_max) in the bloodstream, indicating that as the dose increases, the C_max also increases proportionally. This suggests a predictable pharmacokinetic response to varying doses of the medication. Additionally, higher frequency of Itolizumab administration leads to increased accumulation of the drug in the body, implying that dosing frequency significantly influences overall drug exposure over time. The half-life (T1⁄2) of Itolizumab ranges between 11.72 to 18.51 days, with variability likely influenced by factors such as dosing regimen, patient characteristics, and disease state. A longer half-life indicates a slower elimination rate from the body ⁴. Toxicity studies in rats have shown that Itolizumab is well tolerated at both single and multiple doses, with a NOAEL (No Observed Adverse Effect Level) determined to be 16 mg/kg/day. This suggests a relatively wide safety margin for the drug based on animal studies ³.

Dosage and administration:

The recommended dosage for Itolizumab is 1.6 milligrams per kilogram of body weight. For the first twelve weeks, it is administered biweekly. Following this period, the administration shifts to once every four weeks, continuing until the entire twenty-four-week course is completed. Itolizumab is delivered via intravenous (IV) infusion. Before preparation, the infusion solution should be allowed to reach room temperature. The prescribed dose should then be mixed with 250 mL of sterile normal saline. Using an infusion pump, the infusion should be administered gradually, 50 mL over the first hour and the remaining 200 mL during the next hour. Patients must be screened for any latent or active infections before starting treatment. The effects of Itolizumab have not been studied in patients with AIDS, tuberculosis, hepatitis B and C, neutropenia, lymphopenia, or acquired immune deficiency syndrome, so its use is not recommended for these individuals. Furthermore, the safety of Itolizumab in patients with hepatic or renal impairment, children under 18, pregnant women, and nursing mothers has not been established. Since Itolizumab can cross the placenta, caution is advised when considering its use in pregnant women ³.

Itolizumab binds to CD6, which aids in controlling T-cell activation and proliferation that are brought on by co-stimulating CD6. The regulation of immunological responses depends on this interplay. Itolizumab has been shown in pre-clinical tests to inhibit intracellular phosphoproteins, including activator of transcription 3 (STAT-3), signal transducer and mitogen-activated protein kinase (MAPK). These proteins participate in signalling cascades that CD6 initiates. Reduced inflammation can result from inhibiting these pathways, which can also attenuate the gene transcription of adhesion molecules and pro-inflammatory cytokines. Research has demonstrated that Itolizumab reduces the amounts of pro- inflammatory cytokines such TNF-α, IL-6, and IFN-γ. This drop in cytokine levels aids in the reduction of T-cell infiltration at inflammatory sites and the enhancement of inflammation.

Unlike some other immunomodulatory medications, Itolizumab does not deplete T or B cells by complement-dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC), or apoptosis, this implies that it has the ability to regulate immunological reactions without significantly reducing the number of vital immune cells ³. Itolizumab's specificity and targeted action are demonstrated by the fact that, despite CD6 being present in a variety of T and B cell types, its clinical use does not provide a broad range of immunomodulating effects. Figure 1 shows the action of the drug inside the body.

Mechanism of action:

Figure 1: Action of the drug inside the body.

COVID-19, induced by the SARS-CoV-2 virus, has a major influence on the immune system, namely T-cells, which are required for an efficient immunological response. In the absence of Itolizumab, as seen in Figure 2a, the virus infects cells, especially in the respiratory tract, activating the immune system. Dendritic cells transmit viral antigens to T-cells, triggering their activation. CD4+T-helper cells facilitate the immune response by stimulating other immune cells, whereas CD8+cytotoxic T-cells destroy infected cells directly. In severe situations, an overzealous immune response, known as a cytokine storm, can occur, producing an excess of pro-inflammatory cytokines and causing extensive tissue damage, particularly in the lungs. Prolonged activation and high viral loads can cause T-cell fatigue, in which T-cells lose functionality. Severe COVID-19 is frequently linked with lymphopenia (a decrease in lymphocyte counts, including T-cells), which impairs the body's capacity to fight the virus. Furthermore, the virus can avoid the immune system by changing T-cell communication pathways, worsening the illness. This evasion can lead to longer viral persistence and higher morbidity. In the presence of Itolizumab,as shown in Figure 2b, a monoclonal antibody targeting CD6 on T-cells and other immune cells, the immune response is modulated, reducing pro-inflammatory cytokine production and T-cell hyperactivation ⁵. Itolizumab binds to CD6 on T-cells, helping maintain a controlled and effective immuneresponse, thereby reducing the risk of T-cell exhaustion and preventing lymphopenia. This leads to a healthier T-cell population, mitigating severe inflammatory responses and improving outcomes in severe COVID-19 cases. By modulating T-cell activity and maintaining a balanced immune response, Itolizumab highlights its potential as a therapeutic option to reduce severe inflammatory responses and enhance patient outcomes. Additionally, it can improve the overall survival rate by decreasing the likelihood of complications related to hyperinflammation. Furthermore, Itolizumab's immunomodulatory effects may support faster recovery and reduce the duration of hospital stays ⁶ ⁷.

MATERIALS AND METHODS:

Production process flowchart:

The production process starts with the selection and development of a suitable cell line for producing the monoclonal antibody is depicted in Figure 3 shown below. Typically, Chinese hamster ovary (CHO) cells or other mammalia cells are used here. The gene that codes for the antibody is identified and isolated, and is then inserted into a suitable vector, often a plasmid, which acts as a carrier for the gene. Then the vector containing gene is introduced into the host cells through the process of transformation. The transformed cells are cultured in huge fermentation tanks under carefully monitored circumstances ⁸. The cells are provided with nutrients and the environment is optimized for growth and antibody production. The engineered cells express the gene encoding the monoclonal antibody, which is then secreted into the culture medium. When the antibody reaches the desired concentration in the culture medium, the cells are harvested. This involves separating the cells from the culture medium. The harvested culture medium undergoes several purification steps to isolate the monoclonal antibody from other proteins and contaminants ⁹. These purification steps often include filtration, chromatography, and other techniques ¹⁰. Once purified, the monoclonal antibody is prepared into the ultimate dose form. This may involve buffer exchange, concentration adjustment, and addition of stabilizers or other excipients to ensure stability and efficacy. Quality control procedures are used all through the production process to guarantee the end product's potency, purity, and safety. Testing for contaminants, potency, and stability is part of this. The final product is packaged into vials or other containers and labelled according to regulatory requirements. After passing quality control testing, the product is released for distribution to healthcare providers and patients ^10
11.

Role of itolizumab in psoriasis:

Itolizumab (marketed as Alzumab) has demonstrated efficacy in treating moderate to severe psoriasis, especially in patients resistant to conventional therapies. Clinical trials showcased its ability to improve Psoriasis Area and Severity Index (PASI) scores and enhance overall quality of life, with lower incidences of infections compared to similar medications². Case studies further underscored its effectiveness in patients with refractory psoriasis, including those with psoriatic arthritis and metabolic syndrome ¹². Immunological and histological analyses revealed reductions in proinflammatory cytokines and T-cell proliferation, aligning with its proposed mechanism of action ¹³. Throughout various trial phases, Itolizumab maintained a favorable safety profile. Patients inadequately responding to methotrexate and topical steroids found relief with Itolizumab infusions, including those resistant to other biologics like etanercept ¹⁴. Additionally, a direct link between psoriasis and metabolic syndrome highlights the importance of comprehensive patient assessment. In summary, Itolizumab emerges as a promising therapeutic option for psoriasis, offering significant symptom relief and potential benefits for patients with associated comorbidities ¹⁵.

Role of Itolizumab in covid – 19:

Numerous trials on Itolizumab's use in treating COVID-19 have produced significant results. It was initially shown that Itolizumab could be effective in treating mild cases of SARS-CoV by lowering the rate of fatalities and ICU hospitalizations in patients who were also getting standard COVID-19 medication ¹⁶. However, in one case, a 66-year-old COVID-19 patient had a severe hypersensitivity reaction to Itolizumab, underscoring the need of careful administration and premedication strategies to reduce adverse effects. Giving Itolizumab to COVID-19 patients who have been admitted to the intensive care unit (ICU) has also been observed to have a good effect on lowering mortality risk and inflammatory indicators ¹⁷. This effect is especially evident when the medication is started early in the lung phase of the illness. Furthermore, Itolizumab was efficient in lowering interleukin-6 levels, possibly attenuating cytokine storm effects and inflammation, thus supporting its utility in COVID-19 treatment protocols ¹⁸. Lastly, its use in younger COVID-19 patients with severe disease displayed promising prospects in reducing mortality following a single dose, underscoring its candidacy as a treatment option ¹⁹. These collective findings underscore the diverse outcomes and promise of Itolizumab in managing COVID-19, highlighting the imperative for further research and meticulous consideration of its administration protocols to ensure ideal results for patients ²⁰.

Role of Itolizumab in rheumatoid arthritis:

To assess Itolizumab's efficacy in treating moderate-to-severe active rheumatoid arthritis (RA), two clinical trials were carried out ²¹. In the first experiment, which took place in Cuba for 24 weeks, 80 RA patients were enrolled, and 30 of them had a thorough evaluation. Oral methotrexate (MTX) and weekly intravenous doses of Itolizumab or a placebo were given to the participants ²². The study employed ELISA to measure cytokine levels and included participants who had at least eight sore or swollen joints ²³. In order to evaluate Itolizumab's safety, tolerability, and efficacy in treating RA patients, a single clinical centre in Havana hosted the second trial, which ran from January 2008 to May 2009. Based on their body weight, the patients were given 12 intravenous doses of Itolizumab ²⁴. The American College of Rheumatology (ACR) criteria for RA diagnosis had to be met, and the patient had to be present with at least eight sore, swollen joints even after receiving stable anti-rheumatic medication ²⁵. Itolizumab's well-tolerated profile and possible therapeutic advantages in controlling T-cell proliferation were highlighted in both studies, providing insight into its function in CD6 regulation for autoimmune diseases ²⁶.

Role of Itolizumab in diabetes:

The purpose of the trial aimed to assess the efficacy and safety of Itolizumab when combined with insulin in persons who had just been diagnosed with type 1 diabetes (T1D). Twelve participants in the research received severe multiple-dose insulin therapy in addition to varying doses of either a placebo or Itolizumab. Phase I–IIa randomized, double-blind, placebo-controlled trials were carried out. Despite the lack of any serious side effects, after 52 weeks there were no discernible differences between the Itolizumab and placebo groups in terms of important indicators including C-peptide levels and glycemic control. One participant in the highest dose group did, however, exhibit higher C-peptide levels three years following the experiment, indicating potential long-term benefits. The study concluded that while the combination of Itolizumab and insulin appeared safe, it did not conclusively demonstrate efficacy in preserving short-term function of beta cells ²⁷. Additionally, more extensive and prolonged investigations are necessary to validate these findings and assess the impact of Itolizumab on T1D progression and beta cell preservation ²¹.

MARKET VALUE:

On July 13, 2020, Biocon's stock reached a record high following the drug company's receipt of emergency use authorization (EUA) for the use of the humanized antibody Itolizumab to stop the growth of T cells. The pharmaceutical company's shares on the BSE (Bombay Stock Exchange) surged 9.90% to a record high of ₹455, up from the previous closing of ₹414.30. A total of 8.2 lakh shares were priced at ₹34.55 crore on the BSE. The share price of Biocon has increased 41% since the start of the year and has gained 63% in a single year. The DCGI has given the company permission to sell Itolizumab injection, 25 mg/5 mL solution for use in emergency situations in India, where it is used to treat patients with moderate to severe acute respiratory distress syndrome (ARDS) associated with COVID-19 and cytokine release syndrome ²⁸. Itolizumab, known as Alzumab, has been priced at ₹8000 per vial in India, with most patients requiring four vials for COVID-19 treatment, bringing the total cost to ₹32,000. Biocon’s aggressive marketing has fetched high volume sales. Table 1 presents the various forms in which Itolizumab is produced across different industries ²⁹.

Table 1: Forms of Itolizumab and their respective price

Sl. No	Brand Name	Manufacturer	Form	Price (₹)
1	Itolizac	Sun Pharma	Liquid	29810
2	Alzumab injection	Biocon	Liquid	22000
3	Alzumab L	Sanjeevini Medical Agency	Lyophilised powder	31810
4	Alzumab L	Biocon biologics	Liquid	15000

DISCUSSIONS AND INTERPRETATION:

Psoriasis Treatment:

Itolizumab targets the CD6 pathway, a crucial mediator in the inflammatory cascade associated with psoriasis. By inhibiting CD6, it reduces the activity of pro-inflammatory cytokines such as IL-17 and TNF-alpha ¹². This dual inhibition is particularly beneficial in psoriasis, where inflammation and immune response dysregulation are significant factors ¹⁴.

Itolizumab's ability to modulate the immune system at a cellular level makes it a promising candidate for treating moderate to severe psoriasis, especially in cases where patients have not responded to standard treatments. Its targeted action on specific immune pathways suggests a potential for fewer side effects compared to broad-spectrum immunosuppressants.

COVID-19 Management:

In COVID-19, cytokine storms are a critical factor leading to severe complications and mortality. Itolizumab's role in dampening this hyperactive immune response by targeting CD6 and reducing pro-inflammatory cytokines offers a targeted approach to mitigating these life-threatening reactions. However, severe hypersensitivity reactions have been observed during infusion, highlighting the need for careful administration ³⁰.

While Itolizumab shows promise in reducing mortality and ICU admissions in severe COVID-19 cases, its use must be balanced with the risk of hypersensitivity reactions. This necessitates the development of stringent protocols and monitoring systems to ensure patient safety during treatment.

Rheumatoid Arthritis (RA):

RA is characterized by chronic inflammation and joint damage due to an overactive immune system. Itolizumab, by modulating T-cell activation and cytokine release, offers a novel mechanism of action distinct from conventional RA therapies such as TNF inhibitors ²⁴. This could provide an alternative pathway for patients who do not respond to or cannot tolerate current treatments ²⁶.

Itolizumab's potential in RA management lies in its unique mechanism of action, providing a new therapeutic avenue. Further research is essential to determine its long-term efficacy and safety, as well as to fully understand its impact on T-cell activity and cytokine modulation in RA patients ³¹.

Diabetes Management:

Type 1 diabetes involves the autoimmune destruction of beta cells, leading to insulin deficiency. Itolizumab’s role in preserving beta cell function by modulating the immune response could alter the disease's progression. Initial studies indicate its safety over the short term, but comprehensive trials are needed to assess long-term outcomes and overall efficacy ²¹. The initial promise shown by Itolizumab in type 1 diabetes management suggests that it could become a critical tool in preserving beta cell function and delaying disease progression. However, extensive studies with larger and more diverse patient populations are required to establish its long-term benefits and safety profile ³².

CONCLUSION:

In summary, Itolizumab demonstrates potential as a versatile therapeutic intervention across various medical conditions. Its mechanisms of action, safety profile, and effectiveness in conditions such as psoriasis, COVID-19, rheumatoid arthritis (RA), and diabetes justify further exploration through comprehensive clinical investigations and prolonged studies. However, a thorough investigation into the drug's mechanism of action is crucial, specifically whether it inhibits CD6 by binding to it or induces steric hindrance to interrupt interactions between CD6-CD166. Therefore, a comprehensive understanding of Itolizumab's effects in humans is paramount for ongoing research, ensuring its therapeutic promise is fully realized and prioritizing patient well-being

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

ACKNOWLEDGMENTS:

The authors would like to thank Dr. Nagashree N Rao, Head of the Department, Department of Biotechnology and Dr. K.N. Subramanya, Principal, R V College of Engineering for their encouragement in the review conducted.

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Received on 18.10.2024 Revised on 13.02.2025

Accepted on 05.05.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):319-324.

DOI: 10.52711/0974-360X.2026.00046

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