The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

International Journal of Cancer. Journal International Du Cancer
Emanuele PucaDario Neri

Abstract

We describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 antibody in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively spliced EDB domain of fibronectin), retained the activity of the parental cytokine and was able to selectively localize to murine tumors in vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent antitumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with checkpoint blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case, cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8+ T cells for the anticancer activity observed in both tumor models. Upon L19-mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the maj...Continue Reading

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Citations

Oct 9, 2020·Science Translational Medicine·Tobias WeissPatrick Roth
Nov 27, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jacqueline MockDario Neri
Jan 22, 2021·Experimental Biology and Medicine·Baptiste GouyouMattia Matasci
Nov 13, 2020·Frontiers in Immunology·Khue G NguyenDavid A Zaharoff
Apr 3, 2021·Cancer Immunology, Immunotherapy : CII·Marco StringhiniDario Neri

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