COVID-19: Introduction immunosenescence, ARDS, Hyperinflammation and mortality Cytokine storm , Inflammatory storm, Treatment of COVID-19, Acalabrunitib, Tocilizumab, Anakinra and Itolizumab, Roleof itolizumab in suppressing the cytokine storm. Approval status of Itolizumab. Treatment with the anti-CD6 MAb Itolizumab. Current status of itolizumab in the treatment of COVID-19, Common side effects of itolizumab. Expert opinion

1. Introduction
Severe acute respiratory syndrome Coronavirus 2 (SARS-
CoV-2) has caused a recent outbreak of coronavirus
disease (COVID-19) [1, 2]. As of December 2019, the
first cases of 2019 coronavirus pneumonia (COVID-19)
were recorded in the Chinese city of Wuhan. A month
later, the World Health Organization (WHO) confirmed
that the cause of this pneumonia was the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) [3].
To date (November 30, 2021), 185 countries have reported cases of COVID-19, reaching a total
of 262,512,547confirmed cases, 5,227,204 deaths, and a lethality rate of 1.99% [4].
Although most cases are mild to moderate, some patients developed severe symptoms
characterized by respiratory dysfunction and / or multiple organ failure that causes death in most
cases [5]. Previous studies have showed that patients with old age and comorbidities as
hypertension and diabetes are more likely to aggravated [6, 7].
COVID-19 can range from asymptomatic illness to
critical illness. Many patients, mostly younger people,
they are asymptomatic or minimally symptomatic. Old
man people with pre-existing co-morbidities are at
higher risk of serious illness and fatal outcome [8].
Changes that occur in the immune system with age,
called immunosenescence, as well as the chronic low-
grade inflammatory condition known as inflammatory,
characterize the immune system of the elderly.
Both processes together are suggested as the origin of
most comorbidities of older adults and their susceptibility to cancer. chronic inflammatory
diseases and new infections [9]

2. Health systems are now focused on addressing this segment of patients predisposed to severe
ARDS and are also seeking to understand causation and treatment modalities in the medical
arsenal to prevent associated mortality.
Re-use of existing approved biologics that target inflammatory pathways could represent a novel
intervention to treat patients who progress to ARDS in a vaccine becomes available.
Hyperinflammation and mortality
Although the cell damage induced by viremia and the severity of the disease are known, another
causative mechanism that leads to disease severity, complications, and death is an aberrant
inflammatory response that progresses to a cytokine storm in patients with COVID-19 infection.
Several patients with severe ARDS treated in an intensive
care unit (ICU) with oxygen and supportive care have high
levels of cytokines and chemokines such as tumor necrosis
factor α (TNF-α), interleukin-2 (IL-2), IL-6, IL-10,
macrophage inflammatory protein 1α (MIP-1α), granulocyte
colony stimulating factor (G-CSF), interferon-γ-inducible
protein 10 (IP-10), interferon-γ (IFN- γ) in the blood [10].
There is a decrease in the absolute lymphocyte count and a relative increase in the proportion of
neutrophil lymphocytes (NLR) in these patients. Increased C-reactive protein (CRP) and ferritin
are also common. Other markers of coagulation and organ damage are also elevated, such as D-
dimer, lactate dehydrogenase (LDH), creatinine, and
bilirubin.
This hyperinflammatory condition leads to a deterioration in
oxygen saturation due to infiltration and pulmonary
exudation, organ damage, and dysfunction of the
coagulation pathways.
This resembles a condition called disseminated intravascular coagulation (DIC) and can lead to
multi-organ dysfunction. Here, the role of anti-inflammatory biologics such as Acalabrunitib,
Tocilizumab, Anakinra and Itolizumab may become relevant [11-16].

3. Cytokine storm / Inflammatory storm:
One of the key causes for mortality in COVID-19 is
inflammatory storms. To defend against viruses and
other pathogens humane body have developed an
elaborate and complex immune system including
various kinds of immune cells.
However, some viruses that are difficult to get rid of can
lead to over activation of immune cells. Which may recruit
more immune cells and create an inflammatory storm or
cytokine storm.
A large number of inflammatory cells and mucus gathering
in the lungs can block the gas exchange between alveoli
and capillaries, resulting in acute respiratory distress
syndrome (ARDS).
These overactive immune cells can further attack other
organs in the body, causing multiple organ failure.
Therefore, more than the virus itself the inflammatory storm
caused by an overactive immune response is the critical
cause of mortality in severe COVID-19.

4. Inflammatory storm involves many cytokines but which one is the key to trigger the
inflammatory storm in severe COVID-19 was unknown untill a comprehensive analysis of the
bloodfrom 33 patients with severe or critical COVID-19.
The reserch team of Professor Haiming Wei in the University of Science and Technology of
China (USTC) has identified that after the coronavirus infection the pathogenic T cells were
rapidly activated to produce granulocyte-macrophage colony stimulating factor (GM-CSF) and
interleukin-6 (IL-6).
GM-CSF further induced CD14 positive and CD16 positive inflammatory monocytes. Which
produced more IL-6 and other inflammatory cytokines, leading to inflammatory storms.
Therefore, IL-6 and GM-CSF are two key inflammatory cytokines in patients with severe
COVID-19 [17-19].
Itolizumab
Role in suppressing the cytokine storm
Itolizumab is a humanized anti-CD6 IgG1 mAb that binds to domain 1 of CD6, a receptor
present on Teffector cells and responsible for priming, activation, and differentiation of T cells
[20]. The binding of itolizumab to domain 1 of CD6 blocks the costimulation pathway and leads
to the inhibition of naive T cell proliferation.
This further leads to a marked reduction in pro-inflammatory cytokines involving the Th-1 and
Th-17 pathway – namely, IL-17A, TNF-α, IL-6, IFN-γ, and IL-2.

5. The microarray data also confirm the observation at the protein level and show altered
expression of other genes involved in the CD6 pathway. Itolizumab acts by immunomodulating
Tefector function and its transport to the site of inflammation, preserving Tregs and preserving
the antiviral response, and reducing associated morbidity and mortality.
Characteristic cytokines of hyperinflammation that are reduced by Itolizumab include IL-2, IFN-
γ, TNF-α through Th-1 pathway and IL-17, IL-6, TNF-α through the Th-17 pathway [20,21]. By
acting up the Th-1 and Th-17 pathways, that is,
in the Teffector cells, itolizumab reduces the
release of multiple cytokines and cell signaling
transduction factors that mainly affect the Th-
17 and Th pathways. -1 and to drugs such as
Tocilizumab or Anakinra only blocks specific
cytokines released downstream. The results for
Tocilizumab and Anakinra are encouraging and
support the hypothesis that it contains cytokine
storm syndrome, but these results are
preliminary and under further investigation.
Since itolizumab acts on Th-17 and Th-1 and
downregulates multiple cytokines and
chemokines in contrast to Toclizumab or
Anakinra, its role in reducing systemic
hyperinflammation by controlling cytokine
storm syndrome is being tested.
Table 1 shows a comparison between anti-CD6 mAb, Itolizumab, anti-IL-6 receptor mAb,
Tocilizumab and anti-IL-1 receptor antagonists, Anakinra on a mechanical level.
Function Itolizumab (anti-CD6)
Tocilizumab (anti-IL-6
receptor)
Anakinra (anti-IL-1
receptor)
Mechanism of action
Binds to CD6 receptorand blocks
ALCAM mediated T-cell
activation
BindstoIL-6receptorandblocks
IL-6 mediated signalingin
immune cells
Binds to IL-1 receptor
and blocks IL-1
mediated signaling in immune
cells

6. Immuno-modulation by
regulatory T- cells
Yes No No
Reduction in pro-
inflammatory cytokines
Downregulation of IL-6
Downregulation of IL-2
Downregulation of TNF-α
Downregulation of IL-17
BlockssignalingofIL-6 alone Blocks signaling of IL-1 alone
Duration ofaction
Longer due toupstream effect
on thepathway
Shorter due to a more
downstream action on the
pathway
Short half-life of 3–4h [16]
If COVID-19 infection is
visualized as an early stage
of infection, a pulmonary
stage, and a hyper-
inflammatory stage,
itolizumab, with its above
mechanism of action, is
optimally administered
before the host's systemic
inflammatory stage begins.
Approval status of Itolizumab:
Approved by the Drug Controller General of India (DCGI) in January 2013, itolizumab has been
marketed in India since 2013 for the treatment of moderate to severe chronic plaque psoriasis.
Trials are currently being conducted in patients with COVID-19, with complications, in India
and Cuba.
Nineteen patients confirmed as positive for SARS-CoV-2 by real-time reverse transcription
polymerase chain reaction (RT-PCR) and admitted to the Nursing Home No. 3 in Santa Clara,
Villa Clara, Cuba , were enrolled in an open, multicenter and comprehensive program. access the
clinical trial (RPCEC00000311 [VICTORIA]) with the humanized MAb itolizumab. All patients
met the inclusion criteria of the protocol (http://rpcec.sld.cu/trials/RPCEC00000311-En).

7. Therapy:
Patients received standard treatment (lopinavir / ritona-vir [Kaletra], chloroquine, prophylactic
antibiotics, INF-α2B and low molecular weight heparin [LMWH]) included in the Cuban
National Protocol approved by the Ministry of Health for COVID-19 [22]. In addition, patients
received a first 200 mg intravenous dose of itolizumab (8 vials). Some patients received a second
dose (200 mg), taking into account their clinical course and the judgment of the physician.
Adverse reactions/events (AEs) associated with itolizumab have been reported. Its classification
was made according to the NIH-CTC Toxicity Criteria, Version 5.0.
Treatment with the anti-CD6 MAb Itolizumab
The patients were treated according to the protocol established in Cuba, after confirming the
presence of SARS-CoV-2. All subjects received lopinavir / ritonavir (Kaletra), 94.7% received
chloroquine, 68.4% received IFN-α2B, and 89.5% received LMWH. In addition, 63.2% received
vitamins and 31.6% antibiotics. Three patients (15.8%) were treated with recombinant human
erythropoietin at a cytoprotective dose (Table 2). All subjects received one dose of the antibody,
while 89.5% received two doses. The median time from symptom onset to itolizumab
administration was 1 day. The time between doses ranged from 1 to 7 days, with an overall
median of 2 days. In this study, 94.7% of the patients were discharged after a mean hospital stay
of 13 days, with a range of 3 to 40 days. All were negative for SARS-CoV-2 at discharge. The
median time to negative RT-PCR was 13 days. According to the national protocol [23], the
second sample was obtained 13 days after the onset of symptoms. Previous negativity was
exceptionally evaluated in patients with rapid symptoms recovery.
Only one death occurred (a 70-year-old woman). Her medical history included hypertension,
coronary artery disease, dementia, and malnutrition. Daily electrocardiograms showed left
bundle branch block without signs of acute ischemia. Doctors stated that the immediate cause of
death was pulmonary embolism.
Only one adverse reaction (1 AE) associated with the administration of itolizumab was reported.
The AE consisted of chills and occurred immediately after the first administration and lasted for
minutes.

8. Table 2: Demographic data of elderly patients with COVID-19, treatments and results
Case
No.
Age,
years
Sex Skin color Comorbidities Treatments Outcome
12 95 F White Hypertension, ischemic heart disease, Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
malnutrition, dementia chloroquine, LMWH, parenteral vitamins
13 83 M White Hypertension, chronic obstructive Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
pulmonary disease, dementia chloroquine, LMWH, parenteral vitamins
14 78 F White Malnutrition, dementia Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
chloroquine, LMWH, parenteral vitamins
15 85 F Black Hypertension, diabetes mellitus, Itolizumab (2 doses), Kaletra, chloroquine, Alive
malnutrition, dementia LMWH, parenteral vitamins, antibiotics
16 75 F White
Hypertension, diabetes mellitus,
chronic
Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
obstructive pulmonary disease,
asthma,
chloroquine, LMWH, parenteral vitamins
malnutrition
17 68 M White Hypertension, diabetes mellitus,
chronic
obstructive pulmonary disease,
dementia, smoking, hypertensive heart
disease
Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
chloroquine, LMWH, parenteral vitamins
18 78 F NA Dementia, anemia Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
chloroquine, LMWH, antibiotics
19 88 F White Hypertension, diabetes mellitus, Itolizumab (2 doses), Kaletra, chloroquine, Alive
ischemic heart disease, malnutrition LMWH, antibiotics
20 89 F White Hypertension, ischemic heart disease, Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
heart disease chloroquine, heparin, antibiotics
21 64 M
White
Hypertension, chronic obstructive
pulmonary disease
Itolizumab (2 doses), IFN-α2B, Kaletra,
chloroquine, heparin, vitamins
Alive
22 80 F White Hypertension, diabetes mellitus, Itolizumab (2 doses), Kaletra, chloroquine, Alive
ischemic heart disease, dementia LMWH, parenteral vitamins
24 79 F White
Hypertension, ischemic heart disease,
malnutrition, dementia
Itolizumab (2 doses), Kaletra, chloroquine,
LMWH, parenteral vitamins
Alive
25 64 M White Hypertension, diabetes mellitus, Itolizumab (2 doses), IFN-α2B, Kaletra, Alive
malnutrition, dementia, lower limbs chloroquine, LMWH, parenteral vitamins
amputated
26 70 F Black
Hypertension, ischemic heart disease,
malnutrition, dementia
Itolizumab (2 doses), IFN-α2B, Kaletra,
chloroquine, LMWH, parenteral vitamins
Dead
27 100 F Black Hypertension, ischemic heart disease, Itolizumab (2 doses), Kaletra, chloroquine, Alive
malnutrition, dementia LMWH, parenteral vitamins
32 81 F NA Hypertension, ischemic heart disease, Itolizumab (2 doses), IFN-α2B, Kaletra Alive
chronic obstructive pulmonary
disease,
malnutrition
40 86 M White None Itolizumab (1 dose), IFN-α2B, Kaletra, Alive
chloroquine, heparin, erythropoietin
43 67 M Brown Obesity, smoking, alcoholism, Itolizumab (2 doses), Kaletra, chloroquine, Alive
posttraumatic paraplegia heparin, erythropoietin
44 71 M White None Itolizumab (1 dose), IFN-α2B, Kaletra, Alive
chloroquine, antibiotics, erythropoietin,
steroids, omeprazole
IFN-α2B, interferon alpha 2B; LMWH, low-molecular-weight heparin; NA, not available.

9. Other indications / studies with Itolizumab:
A randomized, open-label phase 2 study conducted in India evaluated the safety and
efficacy of itolizumab in combination with methotrexate (MTX) in patients with active
rheumatoid arthritis [24]. Itolizumab has been administered and has also been shown to be
safe and effective in rheumatoid arthritis in studies conducted in Cuba [25]. Additional
studies in the US and Australia focus on acute graft versus host disease (aGVHD; US phase
1b / 2 study), uncontrolled asthma (Australian phase 1b study), and lupus nephritis (phase
1b study in Australia). USA). Trials are currently underway in COVID-19 patients, with
complications, in India and Cuba [26].
Current status of itolizumab in the treatment of COVID-19
Itolizumab has completed a study in COVID-19 patients with moderate to severe ARDS in India.
This study was a multicenter, open-label,
randomized, controlled trial to study the
efficacy and safety of itolizumab in
complications of COVID-19 (CTRI /
2020/05/024959). In Cuba, 80 COVID-19
patients with ARDS are being treated with
itolizumab in an interventional study
(WHO trial ID: RPCEC00000311).
Common side effects of itolizumab
Infusion-related reactions
Presentation of itolizumab infusion-related reactions may include chills, rigor, nausea, flushing,
hives, cough, hypersensitivity, pruritus, rash, wheezing, dyspnea, dizziness, headache, and
hypertension. In some cases, severe reactions can occur in patients infected with COVID-19,
leading to a further state of oxygen decompensation. These occur during the first dosing cycle
and tend to decrease in severity and frequency with subsequent infusions. Acute infusion
reactions should be managed according to standard of care. It is recommended that the infusion
Itolizumab

10. be administered more slowly over 5-6 hours to reduce the incidence of infusion reactions and
improve tolerability.
Important Adverse Reactions Reported in Clinical Trials of itolizumab
In previous studies with itolizumab, infusion reactions have been reported in 15% of patients. In
clinical practice, infusion reactions have been found to range from 12% to 15%.
Itolizumab contraindications and use restrictions
Itolizumab should not be administered to patients with a history of severe allergy or known
hypersensitivity reactions to any component of itolizumab or mouse proteins. The safety and
efficacy of itolizumab in pediatric patients <18 years have not been studied; patients with liver
and kidney failure; pregnant and nursing mothers.
Expert opinion
With the number of COVID-19 cases increasing around the world, hospitals and governments
are focusing on having protocols in place to treat serious complications and death from COVID-
19 infections. Hospitalized patients progressing rapidly to severe ARDS, organ damage, and
bleeding disorders due to systemic hyper-inflammation do not currently have approved
treatments. Tocilizumab has been used not indicated for the treatment of cytokine storm in these
patients.
Reusing anti-inflammatory biologics like itolizumab could play an important role in treating
cytokine storm and complications due to COVID-19 infection and reducing mortality due to
cytokine storm complications. Itolizumab is an approved drug in India for psoriasis with a
proven safety profile [27-29, 30] and has been used in a clinical trial for the treatment of
COVID-19 complications. Itolizumab is used for the compassionate treatment of patients with
moderate to severe ARDS due to COVID-19 in various hospitals in India. The results of the trial
will be published shortly.
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