Shi and Liu et al. develop LH05, a conditionally activated anti-PD-L1/IL-15 immunocytokine that employs steric hindrance to suppress systemic IL-15 activity and associated toxicities while maintaining high activity of the TME-released cytokine, improving the therapeutic window. In preclinical models, LH05 induced chemokines CXCL9 and CXCL10, leading to increased infiltration of CD8+ T and NK cells and superior antitumor activity. LH05 converted cold tumors into hot tumors, promoted Th1-type immune responses, and synergized with an oncolytic virus or checkpoint blockade to exert antitumor effects in advanced and metastatic tumor models.
Contributed by Shishir Pant
ABSTRACT: The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8(+) T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.
Author Info: (1) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong Unive
Author Info: (1) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (2) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. (3) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (4) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. (5) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (6) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (7) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (8) Hangzhou Converd Inc., Hangzhou, Zhejiang 311121, China. (9) Hangzhou Converd Inc., Hangzhou, Zhejiang 311121, China. (10) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (11) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (12) Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China. (13) Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200052, China. (14) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. (15) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (16) Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: jiang_long@shsmu.edu.cn. (17) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: roadeer@sjtu.edu.cn.
