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retlirafusp alfa   Click here for help

GtoPdb Ligand ID: 14515

Synonyms: Ezeli® (China) | SHR-1701 | SHR1701
Approved drug Immunopharmacology Ligand
retlirafusp alfa is an approved drug
Compound class: Antibody
Comment: Retlirafusp alfa (SHR-1701) is a bifunctional fusion protein that comprises an anti-programmed death ligand 1 (PD-L1) monoclonal antibody fused to two copies of a N-terminally truncated extracellular domain (ECD) of human transforming growth factor beta receptor type 2 (TGFBR2). The TGFβR2 domain acts as a ligand trap for the receptor's endogenous ligand. Based on evidence that both the TGFβ pathway and the PD-PD-L1/PD-1 immune checkpoint are associated with tumour immune evasion, simultaneous targeting of these pathways was predicted to control tumour growth by restoring and enhancing anti-tumour immune responses [1,5,8,10]. This mechanism is also proposed to overcome tumour resistance to PD-1/PD-L1 inhibitors [2].

Peptide sequence alignments suggest that retlirafusp alfa is one of the claims in patent US11274142B2 [4]: the heavy and light chains are 100% identical to SEQ IDs 11 and 12, the truncated TGFβR2 ECD (amino acids 22-136) is identical to SEQ ID 14, and linker used matches the structure (G4S)4G that is used for the construct named "Fusion protein 10" [structure Ab-(G4S)4G-ECD(22-136)] in the patent. Unfortunately no binding affinity values for interactions with PD-L1 or TGFβ ligands are presented for this construct in the patent data tables or figures. Retlirafusp alfa is similar in structure and function to bintrafusp alfa (M7824), and indeed M7824 is used as a comparator in the patent discussed above.
References
1. Britton WR, Cioffi I, Stonebraker C, Spence M, Okolo O, Martin C, Henick B, Nakagawa H, Parikh AS. (2024)
Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma.
Cancers (Basel), 16 (17). [PMID:39272905]
2. Cheng B, Ding K, Chen P, Ji J, Luo T, Guo X, Qiu W, Ma C, Meng X, Wang J et al.. (2022)
Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer.
Cancer Commun (Lond), 42 (1): 17-36. [PMID:34981670]
3. Feng J, Tang D, Wang J, Zhou Q, Peng J, Lou H, Sun Y, Cai Y, Chen H, Yang J et al.. (2022)
SHR-1701, a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, for Recurrent or Metastatic Cervical Cancer: A Clinical Expansion Cohort of a Phase I Study.
Clin Cancer Res, 28 (24): 5297-5305. [PMID:35653122]
4. Gu J, Luo X, Tao W. (2022)
Fusion protein containing TGF-β receptor and medicinal uses thereof.
Patent number: US11274142B2. Assignee: Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd. Priority date: 11/05/2018. Publication date: 15/03/2022.
5. Jin Y, Wang C, Zhang B, Sun Y, Ji J, Cai Q, Jiang J, Zhang Z, Zhao L, Yu B et al.. (2024)
Blocking EGR1/TGF-β1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer.
Int J Biol Sci, 20 (4): 1314-1331. [PMID:38385088]
6. Keam SJ. (2026)
Retlirafusp Alfa: First Approval.
Drugs, 86 (5): 769-775. [PMID:41862758]
7. Liu D, Zhou J, Wang Y, Li M, Jiang H, Liu Y, Yin X, Ge M, Xiang X, Ying J et al.. (2022)
Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.
BMC Med, 20 (1): 408. [PMID:36280870]
8. Miller KM, Friedman CF. (2022)
Bifunctional Blockade: A Novel Immunotherapy Approach for Cervical Cancer.
Clin Cancer Res, 28 (24): 5238-5240. [PMID:35947045]
9. Tang W, Lv Y, Xie H, Wei Y, Wang J, Yu M, Jiang Y, Mao R, Huang C, Rao S et al.. (2026)
Efficacy and safety of SHR-1701 combined with chemoradiotherapy as neoadjuvant treatment for locally advanced rectal cancer.
Cancer Lett, 636: 218006. [PMID:40876501]
10. Wen J, Cui W, Yin X, Chen Y, Liu A, Wang Q, Meng X. (2025)
Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer.
Cancer Biol Med, 22 (4): 348-75. [PMID:40192238]
11. Xue R, Wei M, Yuan J, Li Z, Zhou Y, Xue Z, Wu Y, Han H, Zhou J, Yu X et al.. (2025)
A phase 1b/2 study of first-line anti-PD-L1/ TGF-βRII fusion protein SHR-1701 combined with nab-paclitaxel and gemcitabine for advanced pancreatic ductal adenocarcinoma.
Signal Transduct Target Ther, 10 (1): 415. [PMID:41422078]
12. Zhou Q, Pan Y, Yang X, Zhao Y, Han G, Pang Q, Zhang Z, Wang Q, Yao J, Wang H et al.. (2024)
Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial.
Cancer Cell, 42 (7): 1258-1267.e2. [PMID:38906157]