A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control

Abstract

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

“…This result raises the possibility that the targeted delivery of IL-21 to the tumor may enhance antitumor efficacy. To evaluate the importance of tumor targeting for IL-21, we engineered several tumor cell lines expressing chimeric EGFR (cEGFR), in which 6 amino acids of mouse EGFR were replaced by the residues found in human EGFR to allow the binding of antihuman EGFR antibody (39,40). FDA-approved Erbitux (Erb) was chosen to target cEGFR.…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Thus, in more recent studies to circumvent this issue, specific mutations were introduced into IL-2 or both IL-2 and its receptor to preferentially stimulate infused CD8+ T cells, but not Tregs. These strategies resulted in high therapeutic efficacy and decreased toxicity in a mouse model [193,194].…”

Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy

“…This rendered it more potent than naturally occurring IL-2 by inducing superior expansion of cytotoxic T cells relative to Tregs, leading to improved anti-tumor responses, while reducing its toxicity [17]. In a recent study, a recombinant IL-2 immunocytokine comprising a tumortargeting antibody and a 'super mutant IL-2' was successfully constructed, with decreased CD25 binding and increased CD122 binding [18]. The IL-2 immunocytokine, in murine cancer models, significantly enhances anti-tumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes [18].…”

“…In a recent study, a recombinant IL-2 immunocytokine comprising a tumortargeting antibody and a 'super mutant IL-2' was successfully constructed, with decreased CD25 binding and increased CD122 binding [18]. The IL-2 immunocytokine, in murine cancer models, significantly enhances anti-tumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes [18]. In another study, a de novo computational approach was performed for designing mimics of IL-2 exclusively targeting the IL-2 beta receptor [19].…”