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. 2023 Sep 23;24(5):248–262. doi: 10.1038/s41435-023-00221-y

Table 1.

IL-2-based biologics evaluated for the treatment of autoimmune and inflammatory diseases.

Agent Mechanism of action Indication Treatment (n) Phase, clinical trial ID, status (completion date) Biological outcome Clinical outcome
PEGylated IL-2 variants
NKTR-358 [126–131] PEG-IL-2Rα-biased agonist Healthy volunteers

SAD: eight cohorts (0.3–28.0 μg/kg:

n = 76;

placebo: n = 24);

subcutaneous;

1st line

Phase 1;

NCT04133116,

completed (Mar 2020)

Dose-dependent increase in CD4 Treg, 12–17-fold increase at the highest dose tested and sustained over 20-30 days;

Increased expression of Ki67, HELIOS, CTLA4, ICOS;

No significant changes in CD4 and CD8 Tconv, low level increase in CD56high NK cells.

PK: dose-dependent response and prolonged half-life (mean 7.4–12.9 days);

Treatment-related AE primarily limited to mild or moderate injection site reactions;

No ADA were detected at any dose or any time point.
SLE (minimal to moderate)

MAD: four cohorts (3–24.0 μg/kg:

n = 36;

placebo: n = 12); biweekly schedule;

subcutaneous;

2nd line

Phase 1;

NCT03556007,

completed (Aug 2019)

Dose-dependent increase in the frequency of CD4 Treg, 12–17-fold increase at the highest dose tested and sustained over 20–30 days;

Increased expression of Ki67, HELIOS, CTLA4;

Hypereosinophilia at the highest doses in some patients, started after the second dose, resolved after treatment discontinuation;

No significant changes in CD4 and CD8 Tconv, low level increase in CD56high NK cells.

AE: mild or moderate (grade 1–2) in severity, primarily injection-site reactions, one patient had flu-like symptoms, 1 patient had moderate hypereosinophilia that resolved after the treatment was discontinued;

No ADA were detected at any dose or any time point;

No NKTR-358 treatment-related changes in disease activity were apparent as measured by SLEDAI or joint scores.
Atopic dermatitis

Multiple doses (12 or 24 µg/kg);

biweekly dosing;

1st line

Phase 1;

NCT04081350,

completed (Jan 2023)

 Increased total Treg and CD25bright Treg versus placebo during treatment period (12 weeks). Dose-dependent improvement was observed in disease-relevant scores (EASI, eczema area and severity index) versus placebo up to 36 weeks following end of treatment. No SAEs or severe AEs reported.
Psoriasis

Multiple doses;

1st line

Phase 1;

NCT04119557,

completed (Jul 2021)

 Increased Treg numbers versus placebo during treatment period (12 weeks). Improved disease score (PASI, psoriasis area and severity index) versus placebo, which was maintained up to week 19 post-treatment. Safety profile consistent with previous studies.
SLE N/A

Phase 2;

NCT04433585,

(ISLAND-SLE),

completed (Oct 2023)

 Dose-dependent proliferation of Treg. The primary endpoint of the study—a four-point reduction in the SLE disease activity index (SLEDAI-2K)—not achieved.
Ulcerative colitis

Multiple doses;

1st line

Phase 2;

NCT04677179,

(INSTRUCT-UC), terminated (Aug 2022)

 N/A N/A
THOR-809/ SAR444336 [134] PEG-IL-2Rα-biased agonist Healthy volunteers Single or repeated dose subcutaneous injections; versus placebo

Phase 1; NCT05876767,

ongoing (Jul 2023)

 N/A N/A
2021 Zhang et al. [113] PEG-IL-2Rα-biased agonist N/A N/A Preclinical N/A N/A
IL-2 muteins
Efavaleukin alfa (AMG592) [138–141] IL-2Rα-biased IL-2m (V91K, C125A) Fc-fusion protein Healthy volunteers

SAD: (n = 6/dose;

8 cohorts) or placebo (n = 2/dose) for 28 days;

subcutaneous

 Phase 1

Dose-dependent Treg expansion;

Increased CD25 and FOXP3 in expanded Treg;

No change in NK cell and minimal increase in Tconv numbers;

At the highest dose, increase in Treg: Tconv ratio peaked at day 8 (~4-fold vs baseline) and remained elevated up to day 29;

No increases in serum proinflammatory cytokines IL-6, TNFα, or IFNγ.

AE: grade 1 painless erythema at/near the injection site which resolved without treatment.

PK: dose-related increases in AMG 592 serum exposure.
SLE

MAD: five dosing cohorts;

every 2 weeks;

treatment for 12 weeks; subcutaneously;

2nd line

Phase 1;

NCT03451422,

completed (Oct 2021)

Peak Treg expansion at day 8 post dose sustained for up to 42 days after the last dose;

Mean peak increases in Treg 1.1-17.4-fold above the baseline depending on the dose;

Increased Helios, PD-1, ICOS, CD39, GITR in expanded Treg;

No significant changes in CD4 and CD8 T cells nor NK cells;

No changes in pro-inflammatory cytokines.

AE: mild-to-moderate injection site reactions,

No dose-limiting toxicities;

PK: linear and dose-dependent, half-life 18 −30 h.
RA MAD: multiple dosing schedules, follow-up for 12 weeks; 2nd line

Phase 1/2;

NCT03410056,

terminated (May 2020)

 N/A N/A
GvHD (chronic)

MAD: weekly or every 2 weeks;

2nd line

Phase 1/2;

NCT03422627,

terminated (Feb 2022)

 N/A N/A
SLE

Dose-ranging;

2nd line

Phase 2b;

NCT04680637,

terminated (Jun 2023)

 N/A N/A
Ulcerative colitis

Dose-finding;

2nd line

Phase 2;

NCT04987307,

recruiting (Jun 2024)

 N/A N/A
RG7835 (RO7049665) [115] IL-2Rα-biased IL-2m (T3A, N88D, C125A) IgG1-fusion protein Healthy volunteers

SAD;

subcutaneous

Phase 1;

NCT03221179,

completed (Jul 2019)

 N/A N/A
Ulcerative colitis

MAS;

subcutaneous;

1st line

Phase 1;

NCT03943550,

terminated based on the lack of robust clinical improvement in the underlying condition after 8 weeks of treatment (Jul 2021)

 N/A N/A
Autoimmune hepatitis

Every 2 weeks; subcutaneous administration;

2nd line

Phase 2;

NCT04790916,

terminated based on a lack of efficacy seen with RO7049665 in a study of ulcerative colitis (Nov 2021)

 N/A N/A
PT101/ MK-6194 [144] IL-2Rα-biased IL-2m (L118I, N88D, V69A, Q74P, C125S) Fc-fusion protein Healthy volunteers

SAD: five dose levels from 1 mg to 10 mg, subcutaneous;

PT101 (42) or placebo (14)

 Phase 1

Dose-related Treg expansion, mean max Treg expansion of 3.6-fold above the baseline on day 8-10 up to day 29;

No significant expansion of Tconv or NK cells;

Transient increases in eosinophil levels in some subjects.

AE grade 1 or 2 and self-limited, most commonly injection-site reactions;

No dose-limiting toxicities;

PK: peak levels of PT101 11.0–14.6 h after administration, mean half-life 20.4–28.3 h;

No ADA detected.
Ulcerative colitis MAD, subcutaneous, PT101 or placebo

Phase 1;

NCT04924114,

recruiting (Feb 2024)

 N/A N/A
DEL106/CC-92252 [146] IL-2Rα-biased IL-2m (T3A, N88R, C125S) Fc-fusion protein Healthy volunteers and patients with psoriasis

3-part study: SAD and MAD in healthy volunteers, MAD in psoriasis patients;

biweekly dosing for 12 weeks

Phase 1;

NCT03971825,

terminated due to a lack of progression criteria (Aug 2021)

SAD: Up to 2-fold Treg expansion on day 9-14, max Treg/Tconv 2-fold above baseline around day 10;

No changes in total CD4 and CD8 Tconv and NK cells;

Increased expression of CD25, FOXP3, CTLA-4, PD-1, ICOS, IL-10 on Treg;

Increased in vitro suppressive capacitiy of Treg from treated patients

MAD: Weekly dosing is not superior to biweekly dosing due to modest Treg increase;

MAD in participants with psoriasis:

modest Treg expansion in circulation and in skin lesions (up to 2-fold from baseline);

No increase in CD4 and CD8 Tconv and NK cells;

No change in TH17 in circulation or lesional IL-17 levels.

MAD in participants with psoriasis:

No apparent improvement compared to placebo as measured by target plaque severity score and static physician global assessment

AE: mild-to-moderate in intensity, mostly injection-site reactions;

Occasional eosinophil and C-reactive protein increases.
CUG252 (ref.147, 148) IL-2Rα-biased IL-2m (L19H, C125I, Q126E) Fc-fusion protein

Healthy volunteers,

SLE

SAD in healthy volunteers or MAD in SLE patients;

2nd line for SLE patients;

subcutaneous

Phase 1;

NCT05328557,

recruiting (Dec 2023)

 N/A N/A
MDNA209 (ref.114, 149) IL-2Rβ-antagonist IL-2m (L18R, Q22E, Q126T, S130R) Fc-fusion protein N/A N/A Preclinical N/A N/A
Other IL-2 fusion proteins
IL-2-CD25 [152, 153]

Human

IL-2/CD25 fusion protein

 Healthy volunteers, autoimmune diseases N/A Phase 1 N/A N/A
CUE-401 [154, 155] Human IL-2/TGF-β Fc-fusion protein N/A N/A Preclinical N/A N/A
IL2-EHD2-sc-mTNFR2 [157, 158] IL-2 fused to a TNFR2-selective TNF mutein N/A N/A Preclinical N/A N/A
Alternative IL-2 delivery methods
mRNA-6231 [163]

LNP-mRNA for Treg-specific

IL-2m/HSA fusion

 Healthy volunteers

2-part study:

SAD eand MAD;

subcutaneous

Phase 1;

NCT04916431,

completed (Aug 2022)

 N/A N/A
NNC0361-0041 [164] DNA plasmid encoding PPI, TGFβ, IL-10, IL-2 T1D

MAD in 4 cohorts, early-onset T1D (9) or placebo (3);

once weekly for 12w, subcutaneous

Phase 1;

NCT04279613,

recruiting (May 2024)

 N/A N/A
Viral vector-mediated gene transfer [167] Viral vector with astrocyte-specific promoter for tissue-specific IL-2 production N/A N/A Preclinical N/A N/A
IL-2/mAb complexes
F5111.2 [120] Human IL-2/anti-IL-2 mAb N/A N/A Preclinical N/A N/A
UFKA-20 [121] Human IL-2/anti-IL-2 mAb N/A N/A Preclinical N/A N/A
Single-chain hIL-2/F5111 mAb-fusion [178]

Single-chain

hIL-2/F5111 mAb-fusion protein

 N/A N/A Preclinical N/A N/A

AE adverse events, HSA human serum albumin, IL-2c IL-2/anti-IL-2 antibody complex, IL-2m IL-2 mutein, LNP lipid nanoparticle, MAS multiple ascending dose, PPI pre-proinsulin, SAD single ascending dose, RA rheumatoid arthritis, SLE systemic lupus erythmatosus, T1D type 1 diabetes, EASI eczema area and severity index, ADA anti-drug antibodies.