作者
Ekta Patel,Natalia Malkova,Dave Crowe,Magali Pederzoli-Ribeil,Damiano Fantini,Manoussa Fanny,Hanumantha Rao Madala,Kurt Jenkins,Oleg Yerov,Justin M. Greene,Wilson Guzman,Caitlin O’Toole,Jacob Taylor,Rory O’Donnell,Parker Johnson,Bernard B. Lanter,Bruce N. Ames,Jia Chen,Sallyann Vu,Hsin-Jung Wu,Susan Cantin,M McLaughlin,Y. Hsiao,Dheeraj S. Tomar,Raphaël Rozenfeld,Lakshmanan Thiruneelakantapillai,Ronan O’Hagan,Benjamin P. Nicholson,Jennifer O’Neil,Carl U. Bialucha
摘要
Abstract Interleukin-12 (IL-12) is a proinflammatory cytokine, that has shown promising anti-tumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL-12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL-12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL-12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an interleukin-12 receptor subunit beta 2 (IL-12Rβ2) masking domain. In vitro characterization demonstrates multiple matrix metalloproteases (MMPs), 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 in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating tumor growth inhibition compared to 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 interferon-gamma (IFN-) cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a non-human primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent anti-tumor activity while widening the therapeutic index of IL-12 treatment and is currently being evaluated in a Phase 1 clinical trial.