Interleukin-2 (IL-2) is a cytokine from activated T cells. IL-2 plays a critical function in the generation, differentiation, survival, and homeostasis of immune effector cells. Moreover, IL-2 functions to expand T cell populations in an autocrine fashion, differentiate antigen-activated CD4⁺/CD8⁺ T cells into effector T cell subsets and activate NK cells. However, to counteract autoimmunity, IL-2 also has immunosuppressive properties. Moreover, IL-2 is involved in peripheral immune tolerance mediated by CD4⁺ FOXP3⁺ regulatory T cells (Tregs), which constitutively express high levels of IL-2 Rα. what’s worse, Tregs suppress T cell activity, thereby compromising anti-tumor immunity. Here, we will introduce a novel immunocytokine — Simlukafusp alfa (FAP-IL2v).

Simlukafusp alfa is a humanized IgG1 Monoclonal Antibody.

Simlukafusp alfa contains the IL2v mutein and a (G4S)3 connector fused to the high-affinity FAP human IgG1 antibody 4B9 that was generated and affinity matured by phage display.

FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4⁺/CD8⁺ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory Tregs. For example, Simlukafusp alfa (0-100 nM; 5 days) activates CD4⁺/CD8⁺ T cells and NK cells in vitro, but not preferentially Tregs. In addition, Simlukafusp alfa (0-100 nM) enhances Cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC). Also, Simlukafusp alfa (0-100 nM) enhances Cibisatamab-mediated T-cell-dependent cellular cytotoxicity (TDCC). In vivo, Simlukafusp alfa (1 mg/kg; i.v.; weekly for 4 weeks) is efficacious in combination with therapeutic antibodies in murine models of human cancer.

In a word, Simlukafusp alfa is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapy.

Reference:

[1]  Waldhauer I, et al. MAbs. 2021 Jan-Dec;13(1):1913791.