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Supplementary Figure S5 from XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies

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posted on 2024-04-04, 15:20 authored by Ekta Patel, Natalia V. Malkova, David Crowe, Magali Pederzoli-Ribeil, Damiano Fantini, Manoussa Fanny, Hanumantha Rao Madala, Kurt A. Jenkins, Oleg Yerov, Justin Greene, Wilson Guzman, Caitlin O'Toole, Jacob Taylor, Rebekah K. O'Donnell, Parker Johnson, Bernard B. Lanter, Brian Ames, Jia Chen, Sallyann Vu, Hsin-Jung Wu, Susan Cantin, Megan McLaughlin, Yu-Shan S. Hsiao, Dheeraj S. Tomar, Raphael Rozenfeld, Lakshmanan Thiruneelakantapillai, Ronan C. O'Hagan, Benjamin Nicholson, Jennifer O'Neil, Carl Uli Bialucha

Supplemental Figure S5: IFN-γ production in plasma: MC38 tumor-bearing mice were treated with the indicated doses of mXT301 or unmasked control. Plasma IFN-γ concentration was measured by MSD assay at indicated time points. The data represent mean ± SEM, N = 3 to 5 mice per group, and IFN-γ level was assessed by a two-way ANOVA with Bonferroni’s post-hoc pairwise comparison test compared to vehicle (PBS) treated animals (*p < 0.05, **p < 0.005, ****p < 0.0001)

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ARTICLE ABSTRACT

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment–associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial.

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    Molecular Cancer Therapeutics

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    ImmunologyCytokinesImmunotherapyTranslational ResearchTumor MicroenvironmentCytokines and the microenvironmentImmune cells and the microenvironment

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