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

Yunqian Qiao,Zhihai Wu,Min Zhang,Yisen Wang,Nana Luo,Yanpeng Liu,Wei Xu,Hao Wang,Xuan Wang,Ta Sun,Yangmin Qiu,Dongdong Wu,Jiya Sun,Jie Ding,Feifei Guo,Bingliang Chen,Wanwan Shen,Xiaomin Ling

doi:10.1038/s41467-021-26645-6

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.

Highlights

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
The anti-CD137 arm was modified from a previously generated anti-CD137 antibody with the mutations M101A and G106A in the CDR region of the heavy chain to eliminate methionine oxidation and reduce binding affinity. This engineering allowed IBI319 to maintain a high affinity for PD-1 (dissociation constants (KDs): 0.10 nM via surface plasmon resonance (SPR) and 0.632 nM via biolayer interferometry (BLI)) and a low affinity for CD137 (KDs: 394 nM via SPR and 719 nM via BLI) (Fig. 1a, b; Supplementary Fig. 1a) to achieve strong blocking of PD-1 and appropriate agonism of CD137
A ligandblocking assay revealed that IBI319 could completely block the binding of CD137 ligand (CD137L) to CD137 (Fig. 1c), indicating the antibody binding epitope overlapped with the binding site of the natural ligand

Summary

Introduction

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. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. The physiological signal transduction mediated by CD137 is induced by its natural ligand 4-1BBL, which is a type II membrane protein in the TNF superfamily (TNFSF)[4]. Reducing off-target toxicity while retaining antitumour efficacy is a continuing challenge in advancing CD137 agonists into clinical applications, and overcoming this issue will likely require consideration of the Fc function, affinity and binding epitope properties of the desired new molecule

Methods

Results

Conclusion