New therapeutic strategies based on biasing IL-2 mutants for cancers and autoimmune diseases

Targeted Cytokine Delivery for Cancer Treatment: Engineering and Biological Effects

“…Other facts presented below demonstrate that IL-2 has a few protumorigenic properties, which makes its use for cancer treatment less encouraging. For example, IL-2 is an inducer of Th 9 -cell differentiation and Th 9 -mediated IL-9 production, two factors correlating with better tumor cell survival and apoptosis resistance [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. IL-2 inhibits the differentiation of Th 17 cells, a population of lymphocytes performing an important function in protecting the organism from exogenous pathogenic fungi and bacteria that makes patients less resistant to infections during therapy.…”

“…Among the CEA-targeted IL-2-based immunocytokines, cergutuzumab amunaleukin is one of the most developed, with phase 1 clinical trials already completed. It consists of anti-CEA bivalent monoclonal antibody with abolished interaction with FcγR and C1q, fused to the N-terminus of a single molecule of IL-2v variant with restricted IL-2Rα binding [ 67 ]. Cergutuzumab amunaleukin (CEA-IL-2v) was designed to increase the therapeutic index, improve the pharmacokinetics of IL-2, accumulate at CEA-expressing tumors, and induce local immune response, as well as reduce binding to CD25-expressing endothelial cells and avoid predominant activation of T regs and undesired Fc effector functions [ 47 , 68 ].…”

Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy

“…18 However, residual IL-2 not bound to Treg cells inevitably binds to moderate-affinity IL-2R (composed of IL-2Rβ and IL-2Rγ) on Teff cells, inevitably leading to the off-target activation of Teff cells, consequently aggravating the autoimmune disease. 19,20 To solve this IL-2 off-target effect, many engineering strategies have been used to modify IL-2 to increase the specific targeting of Treg cells, such as IL-2 immune complexes, 21−25 IL-2 fusion proteins, 26−29 and PEGylated IL-2. 30 For example, the IL-2/JES6-1 complex (IL2C) preferentially promotes the proliferation of Treg cells by selectively binding high-affinity IL-2R without stimulating CD8 + memory T cells and NK cells.…”

“…Interleukin-2 (IL-2) is a cytokine that regulates the homeostasis between Treg and effector T (Teff) cells. , It preferentially binds to the high-affinity IL-2 receptor (IL-2R) (composed of IL-2Rα, IL-2Rβ, and IL-2Rγ) on Treg cells, promoting their proliferation and function, thereby suppressing immunity. , Therefore, the activation of Treg cells by low-dose IL-2 may be a promising approach in the treatment of brain inflammatory diseases. − Indeed, clinical trials using low-dose IL-2 in relapsing-remitting MS have been conducted . However, residual IL-2 not bound to Treg cells inevitably binds to moderate-affinity IL-2R (composed of IL-2Rβ and IL-2Rγ) on Teff cells, inevitably leading to the off-target activation of Teff cells, consequently aggravating the autoimmune disease. , …”

“…To solve this IL-2 off-target effect, many engineering strategies have been used to modify IL-2 to increase the specific targeting of Treg cells, such as IL-2 immune complexes, − IL-2 fusion proteins, − and PEGylated IL-2 . For example, the IL-2/JES6-1 complex (IL2C) preferentially promotes the proliferation of Treg cells by selectively binding high-affinity IL-2R without stimulating CD8 + memory T cells and NK cells. − However, Treg cells represent only 1–2% of peripheral blood lymphocytes, and the probability of IL2C present in the bloodstream coming into contact with Tregs is extremely low, resulting in suboptimal IL-2 delivery efficiency and limited bioavailability.…”