Table 1.
Preclinical and clinical engineered IL-2-based compounds discussed in this review
| Compound Type | Compound Name | Description | Development Status | Clinical Indications | References |
|---|---|---|---|---|---|
| IL-2 muteins | Proleukin (Iovance Biotherapeutics) | Recombinant human IL-2 with C125S mutation | Approved | Metastatic renal cell carcinoma, metastatic melanoma | [74] |
| M1 | Treg-biased IL-2 mutein containing mutations at V69A and Q74P to enhance affinity to IL-2Rα | Preclinical | - | [79, 80] | |
| M6 | Treg-biased IL-2 mutein containing mutations at V69A, Q74P, and I28T to enhance affinity to IL-2Rα | Preclinical | - | [79, 80] | |
| 2–4 IL-2 | Treg-biased IL-2 mutein containing mutations at N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, I89V to enhance affinity to IL-2Rα | Preclinical | - | [83] | |
| BAY 50–4798 AIC284 (Aicuris) |
Treg-biased IL-2 mutein containing N88R mutation to reduce affinity to IL-2Rβ | Phase I (terminated) | Melanoma, renal cell carcinoma | [85, 86] | |
| IgG-(IL-2N88D)2 RO7049665 (Roche) |
IgG1-conjugated, Treg-biased IL-2 mutein containing N88D mutation to reduce affinity to IL-2Rβ | Phase II (terminated) | Ulcerative colitis, autoimmune hepatitis | [87, 150, 151] | |
| Fc.Mut24 AMG 592 (Amgen) |
IgG2a Fc domain-conjugated, Treg-biased IL-2 mutein containing N88R and V91D mutations to reduce affinity to IL-2Rβ | Phase II | GVHD, SLE, rheumatoid arthritis, ulcerative colitis | [93, 153–157] | |
| H9/Super-2 | IL-2 mutein containing mutations at L80F, R81D, L85V, I86V, I92F to enhance affinity to IL-2Rβ | Preclinical | - | [22] | |
| H9-RETR | IL-2 mutein containing mutations at L80F, R81D, L85V, I86V, I92F to enhance IL-2Rβ affinity, L18R, Q22E, Q126T, S130R mutations to reduce γc affinity | Preclinical | - | [94] | |
| IL-2 muteins | IL-2-REH | IL-2 mutein containing mutations at L18R, Q22E, and Q126H to reduce γc affinity | Preclinical | - | [95] |
| orthoIL-2 + orthoIL-2Rβ STK-009+SYNCAR (Synthekine) |
Orthogonal IL-2 containing E29D, Q30N, M33V, D34L, Q36K, and E37A mutations to ablate binding wild type IL-2Rβ and preserve binding to orthogonal IL-2Rβ counterpart | Phase I | CD19+ hematologic malignancies | [96–98] | |
| V91K, D20A, M104V | IL-2 mutein containing mutations at V91K and D20A to reduce IL-2Rβ affinity, M104V mutation to reduce IL-2Rα affinity | Preclinical | - | [100] | |
| Erb-sumIL2 | Asymmetric Fc-conjugated heterodimer composed of a CD8+ T cell-biased IL-2 mutein (mutations: F42A, L80F, R81D, L85V, I86V, and I92F) and an anti-human EGFR Fab | Preclinical | - | [177] | |
| CC-92252 (Bristol-Myers Squibb, Celgene) | Treg-biased IL-2 mutein-Fc fusion protein | Phase I (terminated) | Psoriasis | [152] | |
| PT101/MK-6194 (Merck) | Treg-biased IL-2-Fc fusion protein with mutations that reduce IL-2Rβ binding affinity and enhance affinity to IL-2Rα | Phase I/II | Ulcerative colitis, atopic dermatitis | [158–162] | |
| XmAb27564 (Xencor) | Treg-biased IL-2 mutein-Fc-fusion protein with enhanced binding affinity to IL-2Rα | Phase I | - | [163, 164] | |
| mRNA 6231 (Moderna) | Lipid nanoparticle-encapsulated mRNA encoding for HSA-IL-2m, a human serum albumin (HSA)-conjugated IL-2 mutein with N88D mutation to reduce affinity to IL-2Rβ, V69A and Q74P mutations to enhance affinity to IL-Rα | Phase I | - | [101, 165] | |
| PEGylated IL-2 | NKTR-214 Bempegaldesleukin (Nektar Therapeutics) | IL-2 variant containing an average of 6 releasable PEG chains that limit binding to the heterotrimeric IL-2 receptor | Phase III (terminated) | Prostate cancer, melanoma, head and neck squamous cell cancer, metastatic renal cell carcinoma, solid tumors, sarcoma | [115, 117, 118] |
| NKTR-358 Rezpegaldesleukin (Nektar Therapeutics) |
IL-2 variant conjugated with PEG chains that attenuate binding to IL-2Rα and IL-2Rβ | Phase II | SLE, atopic dermatitis, psoriasis, ulcerative colitis | [109, 119–121, 166–169] | |
| Dual-31/51–20K | Treg-biased IL-2 variant containing 20 kDa PEG chains conjugated at residues Y31 and T51 | Preclinical | - | [110] | |
| KKC80 | Treg-biased IL-2 with 80 kDa PEG conjugated to an azide-containing lysine derivative at residue 129 | Preclinical | - | [111] | |
| THOR-809 (Synthorx) | Treg-biased IL-2 variant containing PEG conjugated to a non-proteinogenic amino acid | Phase I | - | [112] | |
| IL-2 fusion proteins | IL-2/CD25 | IL-2/IL-2Rα fusion protein via a non-cleavable amino acid linker | Preclinical | - | [122, 124, 125] |
| EHD2-scTNFR2 | Mouse IL-2 fused to an engineered tumor necrosis factor (TNF) domain | Preclinical | - | [128] | |
| IL-2/anti-IL-2 antibody complexes and fusion proteins | IL-2/JES6–1 | Treg-biased complex of mouse IL-2 and an anti-mouse IL-2 antibody | Preclinical | - | [135–140, 143, 148] |
| IL-2/F5111.2 | Treg-biased complex of human IL-2 and an anti-human IL-2 antibody | Preclinical | - | [141] | |
| IL-2/UFKA-20 | Treg-biased complex of human IL-2 and an anti-human IL-2 antibody | Preclinical | - | [142] | |
| F5111 IC | Treg-biased “immunocytokine” comprised of a single-chain human IL-2/anti-human IL-2 antibody fusion | Preclinical | - | [144] | |
| De novo IL-2 | Neo-2/15 NL-201 (Neoleukin) |
CD8+ T cell-biased de novo IL-2 with an erased IL-2Rα binding interface and enhanced interactions with IL-2Rβγc | Phase I (terminated) | Refractory cancer | [104, 105] |
| S1–S17 | CD8+ T cell-biased IL-2 muteins with enhanced IL-2Rβγc interactions | Preclinical | - | [106] | |
| Tolerogenic particles | ImmTOR+F5111 IC (Selecta Biosciences) | Biodegradable nanoparticles encapsulating rapamycin administered with a Treg-selective single-chain IL-2/anti-IL-2 antibody fusion protein | Preclinical | - | [175] |
| Tol-MPs+F5111 IC | Biodegradable microparticles loaded with rapamycin and functionalized with a biased IL-2 fusion protein and MHC class II/myelin peptide complexes | Preclinical | - | [176] | |
| IL-2 prodrugs | ProIL2 | CD8+ T cell-biased IL-2 mutein-Fc fusion protein conjugated to IL-2Rβ by a matrix metalloproteinase-cleavable linker | Preclinical | - | [178] |
| XTX202 (Xilio Therapeutics) | Masked IL-2 prodrug with bias towards IL-2Rβγc | Phase I/II | Solid tumors | [179, 180] | |
| WTX-124 (Werewolf Therapeutics) | Conditionally active IL-2 prodrug containing an inactivating Fab domain and a half-life extension domain | Phase I | Solid tumors | [181, 182] | |
| IL-2 β/γ (Ascendis Pharma) | IL-2 prodrug with a 40 kDa mPEG carrier and a methoxy polyethylene glycol moiety in the IL-2Rα binding interface | Phase I/II | Solid tumors | [183, 184] |
Note: Trade names of clinical stage IL-2-based compounds are denoted by italics and their manufacturers are indicated in parentheses