Data 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

• DOI: 10.1158/1535-7163.c.7160181.v1
• Publication Date: 2024-04-02T07:21:08Z
• Authors: Ekta Patel; Natalia V. Malkova; David Crowe; Magali Pederzoli-...; Damiano Fantini; Manoussa Fanny; Hanumantha Rao Ma...; 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 Thirun...; Ronan C. O'Hagan; Benjamin Nicholson; Jennifer O'Neil; Carl Uli Bialucha
• Keywords: Solid tumor

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