Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity

• Published in: Nature communications 2021-11, Vol.12 (1), p.6360-6360, Article 6360
• Main Authors: Qiao, Yunqian, Qiu, Yangmin, Ding, Jie, Luo, Nana, Wang, Hao, Ling, Xiaomin, Sun, Jiya, Wu, Zhihai, Wang, Yisen, Liu, Yanpeng, Guo, Feifei, Sun, Ta, Shen, Wanwan, Zhang, Min, Wu, Dongdong, Chen, Bingliang, Xu, Wei, Wang, Xuan
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 14/32; 42/109; 45/91; 631/154/51/1568; 631/250/2520; 64/60; 692/308/153; 692/4028/67/580; Agonists; Animal models; Animals; Antibodies; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacology; Bispecific antibodies; Cancer; Cancer immunotherapy; CD137 antigen; Cell activation; Cell culture; Cell Line, Tumor; Cell surface; Crosslinking; Disease Models, Animal; Humanities and Social Sciences; Humans; Immune checkpoint; Immunoglobulin G; Immunotherapy; Immunotherapy - methods; Killer Cells, Natural - immunology; Ligands; Liver; Lymph nodes; Lymphocytes; Lymphocytes T; Metastases; Mice; Microenvironments; multidisciplinary; Natural killer cells; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; PD-1 protein; Pharmacokinetics; Programmed Cell Death 1 Receptor - immunology; Science; Science (multidisciplinary); Stimulation; T-Lymphocytes - immunology; Toxicity; Toxicology; Tumor microenvironment; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26645-6

Expression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development. The toxicity arising from generalised stimulation of T cells restricts applicability of CD137 agonists in cancer immune therapy. Here authors show that a bispecific antibody blocking PD-1 while activating CD137 efficiently restricts T cell activation to the tumour microenvironment, resulting in efficient tumour control and reduced liver toxicity.