Abstract
Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.
Highlights
Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life
The N-terminal ligand binding domain of either IFNAR1 or IFNAR2 was genetically fused to the N-terminal of IFN-I through a proteasecleavable linker
Masked human IFNa2b with IFNAR1 or IFNAR2 decreased IFN activity by 18- and 99fold, respectively (Fig. 1c). Both IFNAR1- and IFNAR2-masked mouse IFNa4 decreased IFN activity by over 1000-fold (Fig. 1d). These results suggest that the IFNAR domain can effectively block IFN-I’s activity
Summary
Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. Reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. This study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host. IFN toxicities and frequent use due to its short half-life increase the risk of poor treatment compliance, fail to reach the therapeutic window[11]. Peg-IFN has been approved to increase half-life but still lacks the tumor-targeting capabilities. It is challenging to manufacture desired Peg-IFNα-2b with precise numbers and positions of PEGylation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
