ArticleJournal for immunotherapy of cancer2025
Universal Fab-Fc masked cytokine prodrug platform: αPD-L1/IL-15 prodrug activates CD44
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Targeting cytokine/chemokine signaling to convert immunologically cold tumors into hot: Emerging strategies in cancer immunotherapy.Acta pharmaceutica Sinica. B · 2026Review
- Combination of YAP inhibition and photodynamic therapy induces dual DNA damage and activates STING pathway to enhance immunotherapy in uveal melanoma.Redox biology · 2026Article
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Authors and funding
10 authors.
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Abstract
backgroundImmunocytokines targeting immune checkpoints have shown great potential in overcoming resistance to immune checkpoint blockade (ICB), making them a major focus of development in recent years. However, severe dose-limiting toxicity hindered their clinical application. Therefore, it is vital to develop versatile strategies to improve safety and elucidate the underlying mechanisms of resistance reversal for advancing immunocytokine therapy.
methodsA general prodrug platform was established to construct interleukin (IL)-15 and IL-12-based immunocytokine prodrugs (P-T, P-Y, and P-Y-IL12). The efficacy of the masking strategy was validated by in vitro activity assays and in vivo safety evaluations. Antitumor efficacy of P-T was assessed in two murine cold tumor models. A comprehensive immune correlate analysis was conducted in the tumor and tumor-draining lymph node (TDLN) to identify key effector cells responsible for overcoming resistance, followed by further confirmation with egression of T cell blockade, surgical excision of TDLN, and adoptive transfer experiments. Finally, the synergistic antitumor effects of P-T with other ICB or HPK1 inhibitors were investigated.
resultsP-T or P-Y using steric hindrance from antibody moiety Fab and Fc shields IL-15 activity in circulation, and reactivates it on cleavage by tumor-specific proteases. The universality of this masking strategy is also applicable to IL-12. Compared with prior constructs, P-T and P-Y exhibit prolonged half-life and tumor retention, facilitating sustained intratumoral immune response. P-T demonstrates reduced systemic toxicity but better control of established tumors over the unmasked counterpart. CD44
conclusionsThe Fab and Fc-masked prodrug serves as a universal strategy for next-generation immunocytokines design, effectively addressing their dose-limiting toxicity. Additionally, leveraging immunocytokines to mobilize T cells in TDLNs offers a promising therapy option to overcome resistance to ICB and HPK1 inhibitors.
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