PLoS ONE (Jan 2019)

Empowering therapeutic antibodies with IFN-α for cancer immunotherapy.

  • Jun Guo,
  • Yu Xiao,
  • Ramesh Iyer,
  • Xin Lu,
  • Marc Lake,
  • Uri Ladror,
  • John Harlan,
  • Tanushree Samanta,
  • Medha Tomlinson,
  • Gail Bukofzer,
  • Cherrie Donawho,
  • Alex Shoemaker,
  • Tzu-Hsuan Huang

DOI
https://doi.org/10.1371/journal.pone.0219829
Journal volume & issue
Vol. 14, no. 8
p. e0219829

Abstract

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Type 1 IFNs stimulate secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells to the tumor microenvironment and IP-10 knockout mice exhibit a phenotype with compromised effector T cell generation and trafficking. Type 1 IFNs also induce MHC class 1 upregulation on tumor cells which can enhance anti-tumor CD8 T cell effector response in the tumor microenvironment. Although type 1 IFNs show great promise in potentiating anti-tumor immune response, systemic delivery of type 1 IFNs is associated with toxicity thereby limiting clinical application. In this study, we fused tumor targeting antibodies with IFN-α and showed that the fusion proteins can be produced with high yields and purity. IFN fusions selectively induced IP-10 secretion from antigen positive tumor cells, which was critical in recruiting the effector T cells to the tumor microenvironment. Further, we found that treatment with the anti-PDL1-IFN- α fusion at concentrations as low as 1 pM exhibited potent activity in mediating OT1 CD8+ T cell killing against OVA expressing tumor cells, while control IFN fusion did not exhibit any activity at the same concentration. Furthermore, the IFN-α fusion antibody was well tolerated in vivo and demonstrated anti-tumor efficacy in an anti-PD-L1 resistant syngeneic mouse tumor model. One of the potential mechanisms for the enhanced CD8 T cell killing by anti-PD-L1 IFN fusion was up-regulation of MHC class I/tumor antigen complex. Our data supports the hypothesis of targeting type 1 IFN to the tumor microenvironment may enhance effector T cell functions for anti-tumor immune response.