ALT-803   Click here for help

GtoPdb Ligand ID: 9615

Synonyms: IL-15 N72D:IL-15RαSu/Fc | IL-15SA | N-803
Immunopharmacology Ligand
Compound class: Antibody
Comment: ALT-803 (N-803) is an IL-15 superagonist developed to promote immune activation [1]. It is being investigated as an immuno-oncology agent [2,6,8-9], as immunotherapy post-allogeneic transplantation for hematological malignancies [7], and as an HIV therapy.
ALT-803 is produced from a high-yield recombinant mammalian cell line which co-expresses an IL-15 activation mutant, IL-15N72D (nogapendekin alfa) and IL-15Rαsushi domain/Fc fusion protein (inbakicept) as a stable soluble complex. The sushi domain increases transpresentation of the ALT-803 complex to the IL-2β/γ dimer which is the signal transducing component of the IL-15 receptor. The IgG Fc domain increases in vivo half-life [1].
Image re-produced from Altor BioScience Corporation's ALT-803 fact sheet (download the pdf here).

COVID-19: ALT-803 is being evaluated for safety and efficacy as an immunostimulatory agent in patients with COVID-19. This study is predicated upon the hypothesis that activating NK and T cells, via the IL-15 pathway, in patients with mild-to-moderate stage COVID-19, might reduce viral load and protect against disease progression.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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References
1. Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, Vyas VV, Marcus WD, Chavaillaz PA, Romero CA et al.. (2011)
IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization.
Cytokine, 56 (3): 804-10. [PMID:22019703]
2. Huang J, Shiao SL, Furuya H, Rosser CJ. (2019)
Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature.
J Immunother, 42 (9): 354-358. [PMID:31107371]
3. Margolin K, Morishima C, Velcheti V, Miller JS, Lee SM, Silk AW, Holtan SG, Lacroix AM, Fling SP, Kaiser JC et al.. (2018)
Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors.
Clin Cancer Res, 24 (22): 5552-5561. [PMID:30045932]
4. Miller JS, Cooley S, Holtan S, Arora M, Ustun C, Jeng E, Wong HC, Verneris MR, Wagner JE, Weisdorf DJ et al.. (2015)
'First-in-human' phase I dose escalation trial of IL-15N72D/IL-15Rα-Fc superagonist complex (ALT-803) demonstrates immune activation with anti-tumor activity in patients with relapsed hematological malignancy.
Blood, 126: 1957 Meeting poster. DOI: 10.1182/blood.V126.23.1957.1957
5. Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, Liu B, Zhu X, Wen J, You L et al.. (2016)
Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models.
Cancer Immunol Res, 4 (1): 49-60. [PMID:26511282]
6. Robinson TO, Schluns KS. (2017)
The potential and promise of IL-15 in immuno-oncogenic therapies.
Immunol Lett, 190: 159-168. [PMID:28823521]
7. Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, Weisdorf DJ, Blazar BR, Ustun C, DeFor TE et al.. (2018)
First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation.
Blood, 131 (23): 2515-2527. [PMID:29463563]
8. Van der Meer JMR, Maas RJA, Guldevall K, Klarenaar K, de Jonge PKJD, Evert JSH, van der Waart AB, Cany J, Safrit JT, Lee JH et al.. (2021)
IL-15 superagonist N-803 improves IFNγ production and killing of leukemia and ovarian cancer cells by CD34+ progenitor-derived NK cells.
Cancer Immunol Immunother, 70 (5): 1305-1321. [PMID:33140189]
9. Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller JS, Farhad M, Anderton K, Lindsey K et al.. (2018)
ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.
Lancet Oncol, 19 (5): 694-704. [PMID:29628312]
10. Zhu X, Marcus WD, Xu W, Lee HI, Han K, Egan JO, Yovandich JL, Rhode PR, Wong HC. (2009)
Novel human interleukin-15 agonists.
J Immunol, 183 (6): 3598-607. [PMID:19710453]