A PD1-CD137L Fusion Protein More Potently Enhances Anti-Tumour Immune Responses Than Targeting PD-L1 and CD137 Separately.

Authors

Runze Xia, Emily Pauline Nickles, Yu Mei, Thamizhanban Manoharan, Yi Tian Png, Beijia Liu, Rui Sun, Kang Yi Lee, Gloryn Chia, Chwee Ming Lim, Herbert Schwarz

Published in

Immunology. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Tumour immune evasion frequently involves PD-L1-mediated inhibition of T cell activity, limiting the efficacy of PD1/PD-L1 blockade, particularly in PD-L1-low or immunologically 'cold' tumours. To overcome this limitation, we developed a dual targeting human PD1-CD137L (hPD1-CD137L) fusion protein that blocks PD-L1-PD1 inhibitory signalling and simultaneously delivers CD137-mediated T cell costimulation. The fusion protein was produced with high purity and demonstrated specific binding to PD-L1-expressing tumour cells and CD137-positive T cells. The hPD1-CD137L retained a stable multimeric structure under acidic conditions and during prolonged storage, supporting its suitability for systemic administration and activity within the tumour microenvironment. Functionally, hPD1-CD137L enhanced T cell activation, as evidenced by increased NF-κB signalling and activation marker expression, and promoted robust tumour cell cytolysis in both 2D and 3D co-culture systems. Anti-tumour activity was observed across multiple tumour models with varying PD-L1 expression, including nasopharyngeal carcinoma (NPC), rhabdomyosarcoma, lung carcinoma and patient-derived colorectal cancer organoids. Notably, hPD1-CD137L enhanced cytolysis of C666 NPC cells by patient-derived tumour-infiltrating lymphocytes at low effector-to-target ratios, and was more potent than a combination of an anti-PD-1 antibody and a CD137 agonist. In vivo, PBMC-humanised NSG mice tolerated hPD1-CD137L without significant weight loss, systemic inflammation or survival impact. Subsequent efficacy study in PBMC-humanised, Rd18 rhabdomyosarcoma-engrafted or C666 nasopharyngeal carcinoma-engrafted NSG mice showed tumour growth suppression without overt toxicity. This study validates a human PD1-CD137L fusion protein as a potent drug candidate for cancer immunotherapy.

PMID:
42572505
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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