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4-1BB is a switch on activated T cells that makes them live longer and kill better. Rather than press it everywhere, new bispecific antibodies press it only on T cells that are already touching a tumour cell marked by PD-L1 or HER2.
TNFRSF9 (chromosome 1p36.23) encodes CD137 (4-1BB), the receptor for 4-1BB ligand (TNFSF9); its signal enhances CD8 T-cell survival, cytotoxicity and mitochondrial activity and so promotes immunity against viruses and tumours (UniProt Q07011). In OnCo it is the costimulatory arm of two tumour-anchored bispecifics: acasunlimab (PD-L1 x 4-1BB) in phase 3 for NSCLC, and cinrebafusp alfa (PRS-343), a HER2/4-1BB anticalin-antibody fusion protein that binds HER2 on tumour cells while engaging 4-1BB to costimulate T cells, in HER2-positive gastric cancer.
In plain words · 4-1BB is a switch on activated T cells that makes them live longer and kill better. Rather than press it everywhere, new bispecific antibodies press it only on T cells that are already touching a tumour cell marked by PD-L1 or HER2.
4-1BB is a switch on activated T cells that makes them live longer and kill better. Rather than press it everywhere, new bispecific antibodies press it only on T cells that are already touching a tumour cell marked by PD-L1 or HER2.
Both corpus agents cluster 4-1BB only where the other arm has bound a tumour antigen (PD-L1 or HER2), so costimulation is confined to T cells in contact with the tumour rather than delivered systemically.
2 products aim at CD137 (4-1BB, TNFRSF9): bispecific antibodies and other agents. Because it sits on the outside of the cell, it can be reached from the bloodstream: antibodies flag the cell, ADCs deliver a toxin, radioligands deliver radiation, and CAR-T or bispecifics bring a T cell.
Immune or microenvironment target: its medicines act on immune, stromal or bone cells rather than on the tumour cell (drug mechanisms in the corpus). HPA TNFRSF9: RNA tissue enhanced (lymphoid tissue 9 nTPM); blood lineage group enriched (granulocytes 9 nTPM, NK-cells 5 nTPM, T-cells 19 nTPM); no normal tissue stained high. Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Gastric & gastro-oesophageal junction cancer); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 1 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas TNFRSF9 tissue; UniProt Q07011; Open Targets ENSG00000049249 associations
First described 1993. Earliest sequence paper UniProt cites for the protein: Schwarz et al, Gene, 1993, "A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family". Source.
Both corpus agents cluster 4-1BB only where the other arm has bound a tumour antigen (PD-L1 or HER2), so costimulation is confined to T cells in contact with the tumour rather than delivered systemically.
RNA: tissue enhanced (lymphoid tissue 9 nTPM), detected in some normal tissues. Blood: group enriched (granulocytes 9 nTPM, NK-cells 5 nTPM, T-cells 19 nTPM).
No normal tissue stained high.
No cancer sample stained medium or high.
HPA TNFRSF9 tissue · HPA TNFRSF9 pathology · HPA protein class: CD markers
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
Acasunlimab is an experimental bispecific antibody from Genmab in phase 3 trials for non-small-cell lung cancer, aimed at PD-L1.
Cinrebafusp alfa is an experimental fusion protein from Pieris Pharmaceuticals in phase 2 trials for gastric & gastro-oesophageal junction cancer, aimed at HER2.
Query for this target: (TITLE:"CD137" OR ABSTRACT:"CD137" OR TITLE:"4-1BB, TNFRSF9" OR ABSTRACT:"4-1BB, TNFRSF9" OR TITLE:"TNFRSF9" OR ABSTRACT:"TNFRSF9" OR TITLE:"4-1BB" OR ABSTRACT:"4-1BB" OR TITLE:"ILA" OR ABSTRACT:"ILA" OR TITLE:"TNF receptor superfamily member 9" OR ABSTRACT:"TNF receptor superfamily member 9") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about CD137 (4-1BB, TNFRSF9), not a curated reading list.
Shares CD28, Checkpoint (two meanings), The cancer-immunity cycle, PD-1 / PD-L1 immune checkpoint & T-cell activation and the tag wave5-target.
Shares Checkpoint (two meanings), The cancer-immunity cycle, PD-L1 and the tag wave5-target.
Shares Checkpoint (two meanings), PD-1 / PD-L1 immune checkpoint & T-cell activation and the tag wave5-target.
Shares PD-1 / PD-L1 immune checkpoint & T-cell activation, Non-small-cell lung cancer and the tag wave5-target.
Shares The cancer-immunity cycle and the tag wave5-target.
Shares Non-small-cell lung cancer and the tag wave5-target.
Shares Non-small-cell lung cancer and the tag wave5-target.
Shares CD28, Checkpoint (two meanings), The cancer-immunity cycle, PD-1 / PD-L1 immune checkpoint & T-cell activation.