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1091 CGC-601, a novel βγ-only IL-2 variant, enhances moderate immune activation without Treg expansion, and exhibits a superior safety evidence in vivo
  1. Lei Zhao,
  2. Rong Wang,
  3. Chuan Feng,
  4. Yongji Jiang,
  5. Patrick Liu and
  6. Yuan Liu
  1. Cure Genetics Co., LTD, Suzhou, China


Background IL-2 was first approved by FDA for the solid tumor treatment. However, the therapeutic window of IL-2 (low dose suppresses immune system by Treg activation and high dose represents toxicity) limited its clinical use. The major dose-limiting toxicity IL-2 is vascular leak syndrome (VLS). The mechanism of VLS is mainly considered as the direct interaction of IL-2 with IL-2Rα expressed on endothelial cells in vivo1, 2 or by over-stimulation of immune cells.3, 4 To get rid of the IL-2Rα interaction, non-α IL-2 muteins were designed to deplete the Treg expansion which may contributes to its anti-tumor efficacy (figure 1). However, they still remain the risk of overstimulated immune response.

Here, we introduce our IL-2 variant, CGC-601, which abolished its binding to IL-2Rα, while obtained a structural twist on four α-helix (figure 2). This brand new molecule was designed as a non-suppressive and moderate immune agonist, through the strategy of de-coupling the IL-2 binding pattern to ”βγ-only”.

Results CGC-601 does not bind to IL-2Rα or IL-2Rβ alone, while only binds to βγ complex with the similar affinity to wtIL-2 in a ”fast-on, fast-off” feature (figure 3). Moreover, CGC-601 shows a low Treg response and mild CD8 T and NK activation in human PBMC (figure 4). For T cell expansion, upon 50nM treatment, CGC-601 holds a similar T cell expansion capacity with rhIL-2 (figure 5A). Meanwhile, CGC-601 expands both CD8 T cells and NK cells, but Treg expansion dramatically constrained after PBMC ex vivo expansion (figure 5B). Thus, compare with rhIL-2, CGC-601 gives ”young” and less differentiated T cells after expansion (figure 6).

In the toxicity test, CGC-601 dose as high as 30 mg/kg, mice stay in good health conditions, while 10 mg/kg rhIL-2 showed a severe weight loss and a reduced activity since Day 3, suggesting CGC-601 has a much safer profile than rhIL-2 (figure 7A). Pulmonary edema is significantly reduced even CGC-601 dose reached 30mg/kg (figure 7B). CGC-601 treatment did not elevate serum IL-5 levels 6 hrs after the first dose (Fig. 7C). CGC-601 prefers C8 T cells and NK cells expansion, on the contrary, CGC-601 does not expand Tregs in vivo (figure 8).

Conclusions CGC-601 with a unique βγ-only binding property, promotes moderate CD8 T and NK expansion and diminishes immunosuppressive Tregs in vivo, has a great potential in immune-stimulation indications. CGC-601’s safety evidence sets up a platform allowing multiple application scenarios (figure 9).


  1. Boyman O, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311:1924–1927.

  2. Krieg C, et al. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci U S A. 2010;107:11906–11911.

  3. Li Y, et al. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nat Commun. 2017;8:1762.

  4. Shanafelt AB, et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nat Biotechnol. 2000;18:1197–1202.

Abstract 1091 Figure 1

Schematic of IL-2 and no-α IL-2 variants in immuno-regulation

Abstract 1091 Figure 2

The design of CGC-601

Abstract 1091 Figure 3

CGC-601 has a distinct IL-2 receptor binding profile

Abstract 1091 Figure 4

CGC-601 has a no IL-2Rαβγ preferable signaling activation

Abstract 1091 Figure 5

CGC-601 retains T cell proliferation activity

Abstract 1091 Figure 6

CGC-601 presents a high potential in T cell expansion

Abstract 1091 Figure 7

CGC-601 exhibits an excellent in vivo safety profile

Abstract 1091 Figure 8

CGC-601 effectively expand CD8 T and NK cells, but not Tregs in vivo

Abstract 1091 Figure 9

CGC-601 sets up a platform allowing multiple application scenarios

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