Tiziana Life Sciences: News Service Announcement, dated November 23, 2022 – Form 6-K

Tiziana announces the publication of a peer-reviewed article on intranasal administration of foralumab demonstrating modulated CD8+ effector T-cell function and an induced T-cell regulatory response in human subjects

Third-party research by leading US academic institutions published in a peer-reviewed journal Frontiers in Immunology shows a favorable safety profile for intranasally administered foralumab and immunological activity in humans

Finding supports Tiziana’s foralumab intranasal monoclonal antibody platform as a new modality for the treatment of autoimmune and CNS diseases

Tiziana’s fully human foralumab is the first anti-CD3 mAb that has not shown an anti-drug antibody (immune reaction) in humans

New York, November 23, 2022 – Tiziana Life Sciences Ltd. (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company enabling innovative CNS immunomodulation approaches to improve the functionality of Treg-based therapies, announces the publication of a scientific article in peer-reviewed journal Frontiers in Immunology entitled “Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects.”(1) . The study was completed by researchers from Brigham and Womens Hospital (BWH) and Harvard Medical School. The aim of the study was to evaluate the safety and immunological effects of a previously uncharacterized fully human anti-CD3 nasal mAb (foralumab) and its in vitro stimulating properties. The findings support Tiziana’s intranasal foralumab platform as a new modality for the treatment of autoimmune and CNS diseases.

About the study

The study evaluated 27 healthy volunteers (nine per group) who received intranasal foralumab at doses of 10 ug, 50 ug, or 250 ug daily for 5 days or placebo. Safety was assessed and immune parameters were measured on day one (pretreatment) and days 7, 14 and 30 by fluorescence activated single cell sorting (FACS) and single cell RNA sequencing (cRNAseq).

No adverse events or safety signals were found when foralumab was dosed in amounts of 10 ug, 50 ug, and 250 ug administered for 5 consecutive days. Immunomodulatory effects were seen predominantly with the 50 ug dose. At the 50 ug dose, a reduction in CD8+ effector memory cells, an increase in naïve CD8+ and CD4+ T cells, and a reduction in CD8+ T cell granzyme B and perforin expression were observed. A dose effect in which 50 ug is more immunomodulatory than 250 ug is consistent with previous animal studies on mucosal tolerance in which higher doses do not induce immune regulation. This is probably due to partial signaling that occurs at intermediate doses that favors the induction of regulatory cells.

Anti-drug antibodies were not detected in humans.

conclusion

When intranasal foralumab was dosed in humans at the above levels, immunological activity and a favorable safety profile were observed. The findings present a new modality for the treatment of autoimmune and CNS diseases. Tiziana’s intranasal monoclonal antibody (mAb) technology is applicable to commercialized mAbs that are currently available only via IV and SC administration, addressing a huge market potential.

A notable finding from this investigation is that the biologic effect of intranasal anti-CD3 is different from intravenous anti-CD3. Anti-CD3 IV is associated with modulation of CD3 from the cell surface, a decrease in CD3 cells, and with side effects including cytokine release syndrome and, in some cases, EBV activation(two). EBV reactivation was observed with intravenous foralumab at doses of 500 ug and 1000 ug. In contrast, intranasal foralumab did not show EBV activation at any dose or modulation of cell surface CD3, and the investigators found no foralumab in the bloodstream. From these results it can be concluded that nasal foralumab acts locally while anti-CD3 administered IV acts systemically.

Confirming these findings, in animal studies, nasal anti-CD3 was observed to localize to cervical lymph nodes and, as with human studies, nasal anti-CD3 was not observed in the bloodstream of animals.

This article provides a wealth of scientifically rigorous immunological data on intranasal foralumab,” said Matthew Davis, MD, RPh, Tiziana’s chief medical officer. “The finding that immunological effects were seen predominantly at the 50 ug dose rather than the higher doses studied was intriguing. Our current study in non-active secondary progressive multiple sclerosis is using a 50 ug dose and our planned phase 2 multicenter placebo controlled dose-ranging study will also include a 50 ug dosing arm.”

To view the publication online, click here: https://www.frontiersin.org/articles/10.3389/fimmu.2022.956907/full

Cited references:

(1)

Chitnis T, Kaskow BJ, Case J, Hanus K, Li Z, Varghese JF, Healy BC, Gauthier C, Saraceno TJ, Saxena S, Lokhande H, Moreira TG, Zurawski J, Roditi RE, Bergmark RW, Giovannoni F, Torti MF , Li Z, Quintana F, Clementi WA, Shailubhai K, Weiner HL, and Baecher-Allan CM (2022) Nasal administration of anti-CD3 monoclonal antibodies modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects. Front. immunol. 13:956907. doi: 10.3389/fimmu.2022.956907

(two)

Kuhn C, Weiner HL. Therapeutic anti-CD3 monoclonal antibodies: from bench to bed. Immunotherapy (2016) 8(8):889-906. doi: 10.2217/imt-2016-0049

About Foralumab

Foralumab, the only fully human anti-CD3 mAb, has shown reduced cytokine release after intravenous (IV) administration in healthy volunteers and in patients with Crohn’s disease. In a humanized mouse model (NOD/SCID IL2γc-/-), it was shown that while targeting the T cell receptor, orally administered foralumab modulates T cell immune responses and enhances regulatory T cells (Tregs). ), thus providing therapy benefit in the treatment of inflammatory and autoimmune diseases without the occurrence of potential adverse events generally associated with parenterally administered mAb therapy. Once daily treatment for 10 consecutive days with intranasal foralumab was well tolerated and produced clinical responses in patients with COVID-19. Based on these studies, intranasal and oral administration of foralumab offer the potential to become a well-tolerated immunotherapy for autoimmune and inflammatory diseases through the induction of Tregs.

About Tiziana Life Sciences

Tiziana Life Sciences is a clinical stage biopharmaceutical company developing innovative immunomodulation therapies through new drug delivery routes. Tiziana’s innovative nasal, oral and inhalation approaches under development have the potential to provide improved efficacy, as well as safety and tolerability compared to intravenous (IV) administration. Tiziana’s two lead candidates, intranasal foralumab, the only fully human anti-CD3 mAb, and milciclib, a pan-CDK inhibitor, have demonstrated a favorable safety profile and clinical response in patients in studies to date. Tiziana’s technology for alternative immunotherapy routes has been patented with several pending applications and is expected to enable a broad portfolio of applications.

For further inquiries:

Tiziana Life Sciences Ltd

Hana Malik, Business Development and Investor Relations Manager

+44 (0) 207 495 2379

email: [email protected]

Investors:

irina koffler

LifeSci Advisors, LLC

646.970.4681

[email protected]

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