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

Yunqian Qiao, Yangmin Qiu, Jie Ding, Nana Luo, Hao Wang, Xiaomin Ling, Jiya Sun, Zhihai Wu, Yisen Wang, Yanpeng Liu, Feifei Guo, Ta Sun, Wanwan Shen, Min Zhang, Dongdong Wu, Bingliang Chen, Wei Xu () and Xuan Wang ()
Additional contact information
Yunqian Qiao: Innovent Biologics (Suzhou) Co. Ltd
Yangmin Qiu: Innovent Biologics (Suzhou) Co. Ltd
Jie Ding: Innovent Biologics (Suzhou) Co. Ltd
Nana Luo: Innovent Biologics (Suzhou) Co. Ltd
Hao Wang: Innovent Biologics (Suzhou) Co. Ltd
Xiaomin Ling: Innovent Biologics (Suzhou) Co. Ltd
Jiya Sun: Innovent Biologics (Suzhou) Co. Ltd
Zhihai Wu: Innovent Biologics (Suzhou) Co. Ltd
Yisen Wang: Innovent Biologics (Suzhou) Co. Ltd
Yanpeng Liu: Innovent Biologics (Suzhou) Co. Ltd
Feifei Guo: Innovent Biologics (Suzhou) Co. Ltd
Ta Sun: Innovent Biologics (Suzhou) Co. Ltd
Wanwan Shen: Innovent Biologics (Suzhou) Co. Ltd
Min Zhang: Innovent Biologics (Suzhou) Co. Ltd
Dongdong Wu: Innovent Biologics (Suzhou) Co. Ltd
Bingliang Chen: Innovent Biologics (Suzhou) Co. Ltd
Wei Xu: Innovent Biologics (Suzhou) Co. Ltd
Xuan Wang: Innovent Biologics (Suzhou) Co. Ltd

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26645-6

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