Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma

Simple Summary In this manuscript, we reported that a newly developed recombinant human IL15 fused with albumin binding domain (hIL15-ABD) showed superior biological half-life, pharmacokinetic and anti-tumor immunity than wild-type (WT) hIL15. Our hIL-15-ABD can effectively enhance anti-tumor efficacy of anti-PD-L1 on colon cancer and melanoma animal models. The anti-tumor potential of hIL-15-ABD was associated with tumor microenvironment (TME) regulation, including the activation of NK cells and CD8(+) T cells, the reduction of immunosuppressive cells (MDSCs and Tregs) and the suppression of immunosuppressive factors (IDO, FOXP3 and VEGF). In conclusion, our new hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME's immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy. We suggested hIL15-ABD as the potential complementary agent may effectively augment the therapeutic efficacy of anti-PD-L1 antibody in colon cancer and melanoma model. Anti-PD-L1 antibody monotherapy shows limited efficacy in a significant proportion of the patients. A common explanation for the inefficacy is a lack of anti-tumor effector cells in the tumor microenvironment (TME). Recombinant human interleukin-15 (hIL15), a potent immune stimulant, has been investigated in clinical trial with encouraging results. However, hIL15 is constrained by the short half-life of hIL15 and a relatively unfavorable pharmacokinetics profile. We developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin binding domain (hIL15-ABD) and explored the therapeutic efficacy and immune regulation of hIL-15, hIL15-ABD and/or combination with anti-PD-L1 on CT26 murine colon cancer (CC) and B16-F10 murine melanoma models. We demonstrated that hIL15-ABD has significant inhibitory effect on the CT26 and B16-F10 tumor growths as compared to hIL-15. hIL-15-ABD not only showed superior half-life and pharmacokinetics data than hIL-15, but also enhance anti-tumor efficacy of antibody against PD-L1 via suppressive effect on accumulation of Tregs and MDSCs and activation of NK and CD8+T cells. Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME's immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

Automated summary

The study introduced a newly developed recombinant human IL15 fused with an albumin binding domain (hIL15-ABD) that exhibited superior biological half-life, pharmacokinetic properties, and anti-tumor immunity compared to wild-type IL15. hIL15-ABD enhanced the anti-tumor efficacy of anti-PD-L1, leading to tumor growth inhibition and modulation of the tumor microenvironment by regulating immune cells and reducing immunosuppressive factors. Combination therapy of hIL15-ABD with anti-PD-L1 showed a greater anti-tumor effect than monotherapy by increasing the activity of anti-tumor effector cells and decreasing immunosuppressive cells in the TME.