期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26645-6
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资金
- Innovent Biologics
IBI319, a CD137/PD-1 bispecific antibody, overcomes the limitations of CD137 agonists in cancer immunotherapy by restricting T cell activation to the tumor microenvironment through coupling CD137 activation with PD-1 crosslinking, resulting in effective tumor control and reduced liver toxicity.
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.
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