Therapeutics

Foralumab

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Overview

Name: Foralumab
Synonyms: TZLS-401, NI-0401, 28F11-AE
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Tiziana Life Sciences

Background

Foralumab is a human monoclonal IgG antibody to the CD3 T cell antigen receptor. It modulates the immune system to promote immunosuppressive and anti-inflammatory responses, in part by stimulating the production of regulatory T cells. This antibody, originally from Novimmune, was acquired by Tiziana. It is administered as an intranasal spray. 

Immune control by regulatory T cells (Tregs) appears to be compromised in people with AD (Faridar et al., 2020). In animal studies, Tregs that were transferred into AD mice entered the brain and stopped Aβ plaque growth (Faridar et al., 2022). Multiple labs have reported beneficial effects of Treg expansion on plaque load and memory deficits in mouse models of AD (Dansokho et al., 2016; Alves et al., 2017; Yuan et al., 2023). The rationale for foralumab is similar to that of low-dose interleukin-2, another immune modulatory therapy being tested in AD. 

In preclinical work with the 3XTg mouse model of AD, nasal administration of 1 microgram foralumab three times weekly for five months improved spatial learning and long-term memory, but caused no change in brain Aβ accumulation (Lopes et al., 2023). Treatment increased the frequency of Tregs in the periphery, and promoted infiltration of T cells into the brain, where they associated with microglia. Microglial gene expression changed in favor of a homeostatic phenotype, rather than inflammatory or neurodegenerative profiles. Previously, nasal foralumab had been shown to increase Tregs, and ameliorate autoimmune symptoms in a model of Lupus in mice (Wu eat al., 2008). In a multiple sclerosis mouse model, nasal antibody induced regulatory T cells that dampened brain microglia inflammation (Mayo et al., 2016).

Findings

A Phase 1 study involving 27 healthy volunteers tested foralumab doses of 10, 50, or 250 μg, or placebo, given daily as a nasal spray for five days. According to published results, all doses were well-tolerated, with no serous adverse events reported. No participants developed anti-drug antibodies. RNA sequence analysis of peripheral immune cells found induction of genes related to Tregs, and promotion of anti-inflammatory responses in monocytes. Effects were most prominent at 50 μg, and minimal at 10 or 250 μg. The treatment did not appear to directly expand cells with a classical Treg phenotype (Chitnis et al., 2022).

In a pilot trial in 39 mild COVID-19 patients, the antibody reduced serum markers of inflammation (Il-6 and C-reactive protein), and led to faster lung recovery (Moreira et al., 2021; Moreira et al., 2023). Treatment was tolerated, with no serious adverse events, changes in blood cell counts, or hypersensitivity reactions.

On June 26, 2024, the company announced that AD patients would be treated with nasal foralumab under an FDA-approved expanded access program (press release).

In September 2024, a small, placebo-controlled Phase 2 trial began to test foralumab in 16 people with AD. Treatment is planned to be 50 or 100 microgram three times weekly for two weeks, followed by a one-week break, for four cycles of treatment over three months. Participants must have early Alzheimer’s symptoms and a positive amyloid PET scan. Primary outcomes are safety, microglia function measured by [18F]PBR06 PET, and the ratios of T cell subsets in blood. The study, at Brigham and Women’s Hospital in Boston, is planned to finish in June 2026.

This antibody is also in development for multiple sclerosis, under an FDA fast track designation (July 2024 press release). A Phase 2a trial, slated to finish in late 2024, is assessing safety and brain microglia activation with PET. Additional patients are being treated under an expanded access program.

For details on foralumab trials, see clinicaltrials.gov

Last Updated: 10 Sep 2024

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References

Therapeutics Citations

  1. Low Dose Interleukin-2

Paper Citations

  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, Baecher-Allan CM. Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects. Front Immunol. 2022;13:956907. Epub 2022 Nov 23 PubMed.
  2. Moreira TG, Matos KT, De Paula GS, Santana TM, Da Mata RG, Pansera FC, Cortina AS, Spinola MG, Baecher-Allan CM, Keppeke GD, Jacob J, Palejwala V, Chen K, Izzy S, Healey BC, Rezende RM, Dedivitis RA, Shailubhai K, Weiner HL. Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study. Front Immunol. 2021;12:709861. Epub 2021 Aug 12 PubMed.
  3. G Moreira T, Gauthier CD, Murphy L, Lanser TB, Paul A, Matos KT, Mangani D, Izzy S, Rezende RM, Healy BC, Baecher-Allan CM, Chitnis T, Kuchroo V, Weiner HL. Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19. Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2220272120. Epub 2023 Mar 7 PubMed.
  4. Faridar A, Thome AD, Zhao W, Thonhoff JR, Beers DR, Pascual B, Masdeu JC, Appel SH. Restoring regulatory T-cell dysfunction in Alzheimer's disease through ex vivo expansion. Brain Commun. 2020;2(2):fcaa112. Epub 2020 Jul 20 PubMed.
  5. Faridar A, Vasquez M, Thome AD, Yin Z, Xuan H, Wang JH, Wen S, Li X, Thonhoff JR, Zhao W, Zhao H, Beers DR, Wong ST, Masdeu JC, Appel SH. Ex vivo expanded human regulatory T cells modify neuroinflammation in a preclinical model of Alzheimer's disease. Acta Neuropathol Commun. 2022 Sep 30;10(1):144. PubMed.
  6. Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, Cagnard N, Holzenberger M, Piaggio E, Aucouturier P, Dorothée G. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain. 2016 Apr;139(Pt 4):1237-51. Epub 2016 Feb 1 PubMed.
  7. Alves S, Churlaud G, Audrain M, Michaelsen-Preusse K, Fol R, Souchet B, Braudeau J, Korte M, Klatzmann D, Cartier N. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice. Brain. 2017 Mar 1;140(3):826-842. PubMed.
  8. Yuan L, Xie L, Zhang H, Zhang Y, Wei Y, Feng J, Cui L, Tian R, Feng J, Yu D, Lv C. Low-dose IL-2 Treatment Rescues Cognitive Deficits by Repairing the Imbalance Between Treg and Th17 Cells at the Middle Alzheimer's Disease Stage. J Neuroimmune Pharmacol. 2023 Dec;18(4):674-689. Epub 2023 Nov 14 PubMed.
  9. Lopes JR, Zhang X, Mayrink J, Tatematsu BK, Guo L, LeServe DS, Abou-El-Hassan H, Rong F, Dalton MJ, Oliveira MG, Lanser TB, Liu L, Butovsky O, Rezende RM, Weiner HL. Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2023 Sep 12;120(37):e2309221120. Epub 2023 Sep 5 PubMed.
  10. Wu HY, Quintana FJ, Weiner HL. Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. J Immunol. 2008 Nov 1;181(9):6038-50. PubMed.
  11. Mayo L, Cunha AP, Madi A, Beynon V, Yang Z, Alvarez JI, Prat A, Sobel RA, Kobzik L, Lassmann H, Quintana FJ, Weiner HL. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain. 2016 Jul;139(Pt 7):1939-57. Epub 2016 May 31 PubMed.

External Citations

  1. press release
  2. press release
  3. clinicaltrials.gov

Further Reading

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