TLSA: Foralumab’s Versatile Applications
NASDAQ:TLSA
Tiziana Life Sciences PLC (NASDAQ:TLSA) recently posted a series of press releases describing findings related to foralumab in an article entitled “Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19.” The study was published in The Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS). Foralumab is a fully human anti-CD3 monoclonal antibody that is administered intranasally and being investigated in multiple domains. This includes COVID, secondary progressive multiple sclerosis (SPMS) and other neurodegenerative and autoimmune disorders. The study was conducted to investigate T cell function in patients taking foralumab and identified a complex mechanism that re-regulates the immune system.
The study employed serum proteomics and RNA-sequencing to evaluate subjects evaluated in multiple trials. The investigators observed a downregulation in several inflammatory markers and an increase in effector function, following the nasal administration of foralumab. Chronic inflammation is associated with health problems including tissue damage, impaired healing, autoimmune disorders and a variety of other conditions. Dysregulation of effector function can result in chronic inflammation, autoimmunity or other immune-related diseases. Tiziana’s anti-CD3 nasally administered foralumab dampened NKG7 and GIMAP7 expression while increasing TGFB1 mRNA expression. Investigators propose that foralumab induces a quiescence program in T cells through the modulation of these genes.
COVID Patients
Activated T cells appear in greater quantities for patients with moderate COVID and do not return to normal levels during the recovery phase, leading to respiratory distress and organ damage. Anti-CD3 has been shown to modulate the immune system and bring it back into balance. Anti-CD3 tempers the immune response by stimulating the release of T regulatory cells (Tregs).
Role of Various T Cells
T cells play a critical role in the immune response to inflammation. When there is an increase in inflammation, T cells are activated and mobilized to the site of inflammation to help control the immune response. Inflammation is a normal response of the immune system to infection, injury or other types of stress. When inflammation occurs, immune cells release pro-inflammatory cytokines, which can attract T cells to the site of inflammation. Upon arrival, they can regulate the immune response by releasing cytokines that either promote or suppress inflammation.
One type of T cell, called a cytotoxic T cell, can directly kill infected or damaged cells to prevent the spread of infection or tissue damage. Other types, such as helper T cells, can release cytokines that activate other immune cells, such as macrophages, to help clear pathogens or damaged tissue.
Tregs play a critical role in regulating inflammation. They are a type of T cell that can suppress or dampen immune responses, including inflammation. During an immune response, Tregs are activated and can migrate to the site of inflammation. Once there, they can release anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which can inhibit the activity of other immune cells and suppress the inflammatory response. Tregs can also directly interact with other immune cells, such as dendritic cells, macrophages, and T helper cells, to suppress their activity and reduce inflammation. Additionally, Tregs can help to prevent the development of autoimmune diseases by suppressing the activity of self-reactive immune cells that could potentially attack healthy tissues in the body.
Methods Used in Study
In healthy volunteers, subjects were treated with 100 µg of nasal foralumab given daily for 10 consecutive days. Blood was collected two days prior to the start of dosing and collected again 10 days after dosing began. Analysis of the T cells, B cells and monocytes in the blood showed downregulation of inflammatory pathways such as hypercytokinemia3 and interferon signaling pathway in both groups. The investigators also identified a coronavirus pathogenesis pathway that was downregulated in the foralumab group but not in untreated controls. Immunomodulatory effects were most pronounced in CD3+ T cells and additional evidence found changes indirectly affecting both monocytes and B cells.
Findings
Investigators identified several common mechanisms in this review of healthy, COVID and MS afflicted subjects. The comparison found that GIMAP7 and TGFB1 gene expression were upregulated, while NKG7 gene expression was downregulated in all three cohorts. The results were backed up with animal model studies in mice. Testing in healthy human subjects allowed the team identify common changes in people treated with foralumab.
Investigators under Tiziana’s umbrella have performed additional work using the anti-CD3 foralumab in Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS) and an undisclosed rare pediatric disease where there are no other treatments showing that there may be a benefit to patients. Others have performed studies showing that anti-CD3 may mitigate the severity of diabetes, arthritis, inflammatory bowel disease and lupus.
The press release identifies over a dozen genes that are modulated by the anti-CD3 foralumab. Many of them are involved in cancer and autoimmune pathways as well as guiding immune surveillance, apoptosis, and inflammation regulation among other functions.4 The primarily affected genes mentioned in the article are listed below with a short summary of their function.
➢ NKG7 – encodes natural killer cell group 7 protein
o Component of innate immune system recognizing & eliminating diseased cells
o NKG7 expression is reported in certain types of cancer
➢ TGFB1 – encodes transforming growth factor β-1 protein
o Role in cell proliferation, differentiation, migration & survival
o Regulates immune response & immune cells
➢ GIMAP7 – encodes GTPase IMAP family member 7 protein
o Role in lymphocyte development and function
o Role in T cell survival and apoptosis
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1. Source: Tiziana Corporate Presentation, January 2023
2. Source: Tiziana Corporate Presentation, January 2023
3. Hypercytokinemia is a condition characterized by an excessive production of cytokines, which are proteins produced by the immune system to regulate inflammation and the immune response. In hypercytokinemia, the immune system produces an excessive amount of cytokines, leading to a state of systemic inflammation that can cause tissue damage and organ dysfunction.
4. We have summarized the function of all the genes mentioned in the article and can share upon request.
5. Source: Tiziana Corporate Presentation, January 2023
