Therapeutics
Low Dose Interleukin-2
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Overview
Name: Low Dose Interleukin-2
Synonyms: COYA-301, Aldesleukin, Proleukin, COYA-302, ld IL-2
Therapy Type: Other
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 3)
Company: Coya Therapeutics
Background
Low-dose interleukin 2 is being tested as an immunomodulatory approach in neurodegenerative diseases. It increases the number and activity of regulatory T cells (Tregs) that suppress inflammation. At high doses, IL-2 stimulates the immune response to tumors, and is approved for treating cancer.
Treg-mediated immune control appears to be compromised in people with AD (Faridar et al., 2020). In preclinical studies, Tregs that were transferred into AD mice entered the brain and stopped Aβ plaque growth (Faridar et al., 2022). Multiple labs have reported that low-dose IL-2 induces expansion of Treg cells, decreases hippocampal Aβ plaque load, and lessens memory deficits in APP/PS1 mice (Dansokho et al., 2016; Alves et al., 2017; Yuan et al., 2023).
Tregs also play a role in ALS and in Parkinson’s disease. In people with ALS, an observed decline in Tregs correlated with faster disease progression. In the SOD1 mouse model of ALS, giving IL-2 or Tregs resulted in motor neuron preservation, less spinal cord inflammation, and longer survival (Sheean et al., 2018; Banerjee et al., 2008). A Phase 1 study in ALS patients demonstrated reduction in markers of oxidative stress and inflammation after Treg infusion (Beers et al., 2022).
In PD patients, reductions in Treg number and function correlated with proinflammatory T cell activation, and increases in Tregs were associated with improved clinical measures (Thome et al., 2021; Arce-Sillas et al., 2024). Administration of low-dose IL-2 led to Treg expansion in a mouse model of PD (Markovic et al., 2022). In other preclinical studies, transplantation or expansion of Tregs was neuroprotective in rodent models of PD (Reynolds et al., 2010; Badr et al., 2022; Park et al., 2023).
Findings
In June 2019, academic investigators in Houston, Texas, began an open-label feasibility study of low-dose commercially available recombinant human IL-2 in people with AD dementia. Eight participants injected 1 million units of Aldesleukin daily for five days per month, for four months. Results are published (Faridar et al., 2023). The treatment was safe and well-tolerated. Most common adverse events were injection site reactions and mild leukopenia, each affecting one-third of patients. After each cycle, participants had increased Treg numbers and function, which returned to baseline between treatments. IL-2 treatment downregulated inflammatory cytokine expression in circulating monocytes, and some plasma pro-inflammatory markers decreased compared to baseline. The investigators claimed an improvement on the MMSE that reverted to baseline after treatment had ended. ADAS-Cog and CDR-SB scores did not change.
In 2020, COYA Therapeutics was founded by the Houston researchers to develop low-dose IL-2 under the name COYA-301. The company presented more results of the open-label AD study in May 2023, indicating a significant lowering of monocyte inflammatory mediators TNFα, IL-6, and IL-1β after treatment. In one patient, TSPO-PET scans suggested a reduction in brain inflammation two weeks after the last dose (slides).
In January 2022, Phase 2 began with support from the Gates Foundation and the Alzheimer’s Association. The Houston investigators enrolled 38 AD patients with mild to moderate dementia, for six months of Aldesleukin, given as a five-day course by subcutaneous injection once or twice per month. The primary endpoint was safety and tolerability. Change in Tregs as a percentage of total CD4 T cells served as a secondary endpoint. In May 2024, COYA announced completion of the study, with results to follow later in the year (press release).
In September 2022, an independent Phase 2 trial began enrolling 45 AD patients with mild dementia at the Centre Hospitalier St. Anne in Paris. Treatment consists of 1 million units of IL-2 or placebo, on a schedule of daily injections for five days, followed weekly injections for four months. The primary endpoint is change in Clinical Dementia Rating 18 months after the first injection. Other endpoints include the MMSE, ADAS-Cog, ADCS-ADL, CDR-SB, change in Tregs and other immune cells, PET scans for neuroinflammation, hippocampal atrophy, and safety. The trial will run until September 2025.
In March 2023, a biomarker study began to assess the effects of low-dose IL-2 on CSF and blood markers of inflammation, and on brain inflammation using the ER176 PET tracer that binds TSPO. This placebo-controlled study will enroll 40 patients in Houston, to receive IL-2 every two or four weeks for six months. The study will run until December 2025.
Testing of low-dose IL-2 for ALS began in 2015, with a Phase 2 trial by researchers in Nimes, France. Thirty-six patients received 1 or 2 million units of IL-2, or placebo, by subcutaneous injection for five days each month for three months, in addition to riluzole. IL-2 was tolerated, with mild adverse events that included injection site reactions and flu-like symptoms. The study achieved its primary outcome of increasing Tregs in the treatment groups. The plasma inflammation marker CCL2 decreased dose-dependently, but there was no change in the surrogate efficacy marker of plasma neurofilament light (Camu et al., 2020). Analysis of leucocyte gene expression showed a dose-dependent increase in Treg markers at the end of treatment (Giovanelli et al., 2021). Inhibition of inflammatory gene expression was apparent after the first cycle of treatment, and was less pronounced after three cycles. Higher baseline inflammatory gene expression predicted poorer response to treatment.
From 2017-2021, researchers followed up with a larger Phase 2 trial in France and the U.K. The MIROCALS study enrolled 220 patients newly diagnosed with ALS, for five-day courses of 2 million units Il-2 per day, or placebo, monthly for 18 months. The primary outcome was survival. Results were announced in December 2022 (press release). Treatment was safe, tolerated, and resulted in elevated Treg numbers. Treatment was associated with a non-significant 19 percent reduction in the risk of death. In a prespecified subgroup analysis, participants with low CSF phosphorylated neurofilament heavy chain and less aggressive disease had a significant 40 percent increase in survival. This subgroup included most of the participants in the trial.
From 2019-2022, investigators in Houston and Boston tested the combination of monthly injections of patient-derived Tregs with low dose IL-2 in 12 ALS patients. The treatment was safe and resulted in elevations of Treg suppressive function (Thonhoff et al., 2022).
In 2020, another open-label trial began recruiting 13 ALS patients in China; its status is unknown.
In October 2021, COYA started an open label study in people with ALS of low-dose IL-2 in combination with CTLA4-IgG. Called Abatacept, this drug suppresses the activation of monocytes and microglia; it is used to treat autoimmune diseases. The company is testing this dual immunomodulator under the name COYA-302. The study, at the Houston Methodist Research Institute, planned to treat 10 patients every two weeks for one year, and assess safety and tolerability. Secondary and exploratory outcomes include Treg function, serum biomarkers of oxidative stress, inflammation, and neurodegeneration, and clinical functioning on the ALSFRS-R scale. Results are published (Thonhoff et al., 2024). Four patients enrolled; all completed it without serious adverse events. Increases in Treg in number and function occurred over the entire treatment period, and returned to baseline levels after treatment stopped. Biomarkers showed trends to reduction in the first 16 weeks, but were not uniformly changed. ALSFRS-R scores remained stable over 48 weeks.
In May 2024, the Houston researchers began a small trial testing COYA-302, dosed every two or four weeks, in 10 frontotemporal dementia patients. The open-label treatment will run for six months with a primary outcome of safety, and a secondary outcome of blood Treg numbers. Completion is expected in April 2026.
For details on low dose IL-2 trials, see clinicaltrials.gov.
Last Updated: 28 Jun 2024
References
Paper Citations
- Faridar A, Eid AM, Thome AD, Zhao W, Beers DR, Pascual MB, Nakawah MO, Roman GC, Davis CS, Grundman M, Masdeu JC, Appel SH. A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer's disease. Transl Neurodegener. 2023 Nov 16;12(1):54. PubMed.
- Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine. 2020 Sep;59:102844. Epub 2020 Jul 7 PubMed.
- Thonhoff JR, Berry JD, Macklin EA, Beers DR, Mendoza PA, Zhao W, Thome AD, Triolo F, Moon JJ, Paganoni S, Cudkowicz M, Appel SH. Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022 Nov;9(6) Print 2022 Nov PubMed.
- Thonhoff JR, Beers DR, Zhao W, Faridar A, Thome A, Wen S, Zhang A, Wang J, Appel SH. A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis. Front Neurol. 2024;15:1415106. Epub 2024 Jun 10 PubMed.
- 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.
- 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.
- 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.
- 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.
- 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.
- Sheean RK, McKay FC, Cretney E, Bye CR, Perera ND, Tomas D, Weston RA, Scheller KJ, Djouma E, Menon P, Schibeci SD, Marmash N, Yerbury JJ, Nutt SL, Booth DR, Stewart GJ, Kiernan MC, Vucic S, Turner BJ. Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. JAMA Neurol. 2018 Jun 1;75(6):681-689. PubMed.
- Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One. 2008 Jul 23;3(7):e2740. PubMed.
- Beers DR, Thonhoff JR, Faridar A, Thome AD, Zhao W, Wen S, Appel SH. Tregs Attenuate Peripheral Oxidative Stress and Acute Phase Proteins in ALS. Ann Neurol. 2022 Aug;92(2):195-200. Epub 2022 May 7 PubMed.
- Thome AD, Atassi F, Wang J, Faridar A, Zhao W, Thonhoff JR, Beers DR, Lai EC, Appel SH. Ex vivo expansion of dysfunctional regulatory T lymphocytes restores suppressive function in Parkinson's disease. NPJ Parkinsons Dis. 2021 May 13;7(1):41. PubMed.
- Arce-Sillas A, Álvarez-Luquín DD, Leyva-Hernández J, Montes-Moratilla E, Vivas-Almazán V, Pérez-Correa C, Rodríguez-Ortiz U, Espinosa-Cárdenas R, Fragoso G, Sciutto E, Adalid-Peralta L. Increased levels of regulatory T cells and IL-10-producing regulatory B cells are linked to improved clinical outcome in Parkinson's disease: a 1-year observational study. J Neural Transm (Vienna). 2024 Jun 1; PubMed.
- Markovic M, Yeapuri P, Namminga KL, Lu Y, Saleh M, Olson KE, Gendelman HE, Mosley RL. Interleukin-2 expands neuroprotective regulatory T cells in Parkinson's disease. NeuroImmune Pharm Ther. 2022 Mar;1(1):43-50. Epub 2022 Jun 21 PubMed.
- Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. 2010 Mar 1;184(5):2261-71. PubMed.
- Badr M, McFleder RL, Wu J, Knorr S, Koprich JB, Hünig T, Brotchie JM, Volkmann J, Lutz MB, Ip CW. Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice. J Neuroinflammation. 2022 Dec 31;19(1):319. PubMed.
- Park SY, Yang H, Kim S, Yang J, Go H, Bae H. Alpha-Synuclein-Specific Regulatory T Cells Ameliorate Parkinson's Disease Progression in Mice. Int J Mol Sci. 2023 Oct 16;24(20) PubMed.
External Citations
Further Reading
Papers
- Alarcan H, Bruno C, Emond P, Raoul C, Vourc'h P, Corcia P, Camu W, Veyrune JL, Garlanda C, Locati M, Juntas-Morales R, Saker S, Suehs C, Masseguin C, Kirby J, Shaw P, Malaspina A, De Vos J, Al-Chalabi A, Leigh PN, Tree T, Bensimon G, Blasco H. Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis. Ann N Y Acad Sci. 2024 Jun;1536(1):82-91. Epub 2024 May 21 PubMed.
- Thome AD, Thonhoff JR, Zhao W, Faridar A, Wang J, Beers DR, Appel SH. Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation. Front Immunol. 2022;13:875825. Epub 2022 Jun 22 PubMed.
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