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Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker

Nature Biomedical Engineering volume 6, pages 819–829 (2022)Cite this article

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Abstract

Immune-checkpoint inhibitors have shown modest efficacy against immunologically ‘cold’ tumours. Interleukin-12 (IL-12)—a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours—can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites. In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition. We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.

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Fig. 1: Masked IL-12 fully regains activity upon treatment with recombinant proteases.
Fig. 2: Masked IL-12 induces a strong antitumour response and potentiates CPI therapy.
Fig. 3: Masked IL-12 therapy elicits a wide range of inflammatory responses and causes immune cell infiltration in melanoma.
Fig. 4: Masked IL-12 eliminates side effects associated with IL-12 therapy in healthy animals.
Fig. 5: Treatment of melanoma-bearing mice with masked IL-12 does not generate systemic irAEs.
Fig. 6: Cleavage of the mask by human tumours and generation of human masked IL-12.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Additional data supporting the results of the study are also available from the corresponding authors on reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was funded by the Chicago Immunoengineering Innovation Center of the University of Chicago and NIH R01 CA219304 (to M.A.S.). We thank the University of Chicago’s Cytometry and Antibody Technology facility, particularly D. Leclerc.

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Authors and Affiliations

  1. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA

    Aslan Mansurov, Peyman Hosseinchi, Kevin Chang, Abigail L. Lauterbach, Laura T. Gray, Aaron T. Alpar, Erica Budina, Anna J. Slezak, Seounghun Kang, Shijie Cao, Suzana Gomes, John-Michael Williford, Melody A. Swartz, Juan L. Mendoza, Jun Ishihara & Jeffrey A. Hubbell

  2. Animal Resource Center, University of Chicago, Chicago, IL, USA

    Ani Solanki

  3. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA

    Melody A. Swartz

  4. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Melody A. Swartz & Jeffrey A. Hubbell

  5. Committee on Cancer Biology, University of Chicago, Chicago, IL, USA

    Melody A. Swartz & Jeffrey A. Hubbell

  6. Department of Biochemistry and Molecular Biology, Chicago, IL, USA

    Juan L. Mendoza

  7. Department of Bioengineering, Imperial College London, London, UK

    Jun Ishihara

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Contributions

A.M., J.I., M.A.S., J.L.M. and J.A.H designed the experiments and wrote the manuscript. A.M. performed the experiments. P.H. assisted with the analysis of immune cell infiltrates in B16F10 melanoma. K.C. assisted with the ex vivo tumour cleavage experiments. A.L.L. assisted with the STAT4 phosphorylation assays. L.T.G., A.J.S. and S.K. assisted with tumour experiments. A.T.A. assisted with blood chemistry analysis. E.B. assisted with protein production. S.C. assisted with the LEGENDplex assays. A.S. performed tail-vein injections. S.G. assisted with cancer-cell-line maintenance. J.-M.W. assisted with the protease-cleavage experiments.

Corresponding authors

Correspondence to Jun Ishihara or Jeffrey A. Hubbell.

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Competing interests

A.M., J.I., J.L.M. and J.A.H are inventors on a patent application (Patent number: US62/878,574, 2019) filed by the University of Chicago covering the technology described in this work. They and M.A.S. hold equity in Arrow Immune, Inc., which is developing the technology, and J.A.H. is an officer of that company. The other authors declare no competing interests.

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Nature Biomedical Engineering thanks Sunil Advani, Christian Klein and Yang-Xin Fu for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Antitumor efficacy of masked IL-12 is linker-dependent.

Mice were treated as described in Fig. 2a. Individual tumor growth curves (a) and survival (b) are shown. Statistical analysis in b was performed using log-rank (Mantel-Cox) test.

Extended Data Fig. 2 M-L6-IL12 is cleaved by mouse tumors ex vivo and in vivo.

a, Masked IL-12 variants containing linkers L2, L4, L6 and the non-cleavable LNC (0.83 μM) were incubated with EMT6 homogenate (2 mg/mL) for 6 hr at 37 °C. Samples were then diluted in media and applied to pre-activated mouse CD8+ T cells and pSTAT4 MFI was measured. b, M-L6-IL12 or non-cleavable M-LNC-IL12 were incubated in tumor-bearing serum or EMT6 homogenate for indicated times at 37 °C. Reaction mixture was analyzed via western blotting. MMP2-activated M-L6-IL12 is shown as positive control. c, B16F10-bearing mice were injected intratumorally with either M-L6-IL12 or M-LNC-IL12 (167 pmol). Tumors were collected 2 hr post injection and homogenized immediately in the presence of proteases inhibitors and EDTA to stop any further degradation and analyzed via western blotting. Experiments were performed twice with similar results.

Source data

Extended Data Fig. 3 M-L6-IL12 induces a dose-dependent antitumor efficacy in B16F10 melanoma and shows extended half-life.

a, Mice bearing B16F10 tumors were treated i.v. with either PBS (n = 5), 16.7 pmol M-L6-IL12 (n = 6), 83.3 pmol M-L6-IL12 (n = 7), 250 pmol M-L6-IL12 (n = 9), or 83.3 pmol IL-12 (n = 9) on days 7, 10 and 13 post tumor inoculation. Individual tumor growth curves (left) and survival curve (right) are shown. Statistics was performed using Mantel-Cox test. b, Healthy C57BL/6 mice were treated i.v. with 83.3 pmol of IL-12 or M-L6-IL12 (n = 3/group) and bled at the indicated time points. Plasma was analyzed for IL-12 concentration via ELISA. Experiments were performed twice with similar results.

Source data

Extended Data Fig. 4 M-L6-IL12 and unmodified IL-12 induce similar expression of proinflammatory markers and cell infiltration in B16F10 melanoma.

Mice were treated as described in Fig. 3. Intratumoral levels of CXCL-1 (a), CCL-11 (b), CCL-17 (c), IL-10 (d), IL-12 (e), IL-6 (f) were quantified using a LEGENDPlex assay and normalized by total tumor protein content. Frequency of CD3+CD4+Foxp3− T cells (g), CD11c+MHCII+ dendritic cells (h), and CD11b+F4/80+ macrophages (i) as percentage of live cells are shown. PBS, n = 8; IL-12, n = 8; M-L6-IL12, n = 7. Data are mean ± s.e.m. Statistical analyses were performed using ordinary one-way ANOVA with Tukey’s multiple comparison test. Experiment was performed twice with similar results.

Extended Data Fig. 5 Masked IL-12 minimizes systemic inflammatory response in healthy mice.

Mice were treated and analyzed as described in Fig. 4b-h. Plasma levels of IL-12 (a), IL-10 (b), IL-1a (c), IL-1b (d), and IFNb (e) were quantified using a LEGENDPlex assay. Serum levels of albumin (f), blood urea nitrogen (g), and total protein (h) were quantified using a blood chemistry analyzer. PBS, n = 5; IL-12, n = 7; M-L6-IL12, n = 6. Data are mean ± s.e.m. Statistical analyses were performed using ordinary one-way ANOVA with Tukey’s multiple comparison test. Experiments were performed twice with similar results. L.O.D = limit of detection.

Extended Data Fig. 6 Masked IL-12 reduces organ damage in MC38-bearing mice.

Mice bearing day 7 MC38 tumors were treated i.v. with either PBS (n = 6), IL-12 (83.3 pmol, n = 7) or M-L6-IL12 (250 pmol, n = 6) on days 7, 10 and 13. Plasma was collected on day 16 and levels of ALT (a), AST (b), amylase (c) and total protein (d) were quantified using a blood chemistry analyzer. Data are mean ± s.e.m. Statistical analyses were performed using ordinary one-way ANOVA with Tukey’s multiple comparison test. Experiments were performed twice with similar results.

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Mansurov, A., Hosseinchi, P., Chang, K. et al. Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker. Nat. Biomed. Eng 6, 819–829 (2022). https://doi.org/10.1038/s41551-022-00888-0

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