IL-2

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Ligands
IL-2 (Human)

GtoPdb Ligand ID: 4985

Synonyms: aldesleukin | interleukin-2 | Proleukin®

IL-2 is an approved drug (FDA (1992))

Compound class: Endogenous peptide in human, mouse or rat

Comment: IL-2 and IL-15 are cytokines that share common biological effects, but also exhibit distinct, and sometimes competing, functions [6]. Recombinant IL-2 is used clinically with the generic name aldesleukin.
Abbas et al. (2018) have written a review of IL-2 biology and the progress that has been made in developing IL-2 therapeutics [1].

Species: Human

View more information in the IUPHAR Pharmacology Education Project: interleukin-2

Immunopharmacology Comments
IL-2 participates in activation-induced cell death (AICD) and maintenance of peripheral CD4⁺CD25⁺ regulatory T (T_reg) cells [3], two processes contributing towards the elimination of self-reactive T cells. T_reg insufficiency is associated with autoimmune disease, and clinical evaluation of the effects of low dose IL-2 to promote T_reg proliferation and function and combat immune inflammatory disorders is showing some promising results [4]. Current IL-2 therapy relies on recombinant peptide that is limited by a short half-life in vivo. To this end, drug developers are working to produce long-acting conjugates with improved pharmackokinetics. Examples include NKTR-358, a PEG-ylated IL-2 analogue that has entered Phase 1 trial in patients with systemic lupus erythematosus (SLE; NCT03556007), and AMG392 (whose recommended INN is efavaleukin alfa), which is an IL-2-IgHG1 Fc fusion protein being developed by Amgen. AMG392 is designed to exhibit improved T_reg selectivity compared to aldesleukin. In an alternative strategy, an anti-IL-2 monoclonal antibody code named F5111.2, that binds to IL-2 and stabilizes it in a conformation that induces preferential T_reg expansion, has demonstrated immunotherapeutic potential in in vivo models of autoimmune diseases and GvHD [5]. See Abbas et al. (2018) for a review of IL-2 therapeutics and their clinical prospects [1]. Developers of any successful IL-2 agent, whose goal is to boost T_reg population and function to treat autoimmune diseases, must ensure that their invention causes minimal effects on the generation of effector and memory cells, natural killer cells, and other innate lymphoid populations that are also under IL-2 regulation, and which could act to negate the desired therapeutic action.

Immunopharmacology Comments

IL-2 participates in activation-induced cell death (AICD) and maintenance of peripheral CD4⁺CD25⁺ regulatory T (T_reg) cells [3], two processes contributing towards the elimination of self-reactive T cells. T_reg insufficiency is associated with autoimmune disease, and clinical evaluation of the effects of low dose IL-2 to promote T_reg proliferation and function and combat immune inflammatory disorders is showing some promising results [4]. Current IL-2 therapy relies on recombinant peptide that is limited by a short half-life in vivo. To this end, drug developers are working to produce long-acting conjugates with improved pharmackokinetics. Examples include NKTR-358, a PEG-ylated IL-2 analogue that has entered Phase 1 trial in patients with systemic lupus erythematosus (SLE; NCT03556007), and AMG392 (whose recommended INN is efavaleukin alfa), which is an IL-2-IgHG1 Fc fusion protein being developed by Amgen. AMG392 is designed to exhibit improved T_reg selectivity compared to aldesleukin. In an alternative strategy, an anti-IL-2 monoclonal antibody code named F5111.2, that binds to IL-2 and stabilizes it in a conformation that induces preferential T_reg expansion, has demonstrated immunotherapeutic potential in in vivo models of autoimmune diseases and GvHD [5]. See Abbas et al. (2018) for a review of IL-2 therapeutics and their clinical prospects [1]. Developers of any successful IL-2 agent, whose goal is to boost T_reg population and function to treat autoimmune diseases, must ensure that their invention causes minimal effects on the generation of effector and memory cells, natural killer cells, and other innate lymphoid populations that are also under IL-2 regulation, and which could act to negate the desired therapeutic action.

Immunopharmacology Disease
Disease	X-Refs	Comment	References
non-Hodgkin lymphoma	Disease Ontology: DOID:0060060 OMIM: 605027	US FDA orphan designation only, not approved for this indication.