4-1BBL (Fc-Fusion)

The 4-1BBL can induce anti-tumor activities by promoting CD8 T cell expansion and protect against autoimmunity and transplantation rejection by depletion NK and B cells. The 4-1BB/4-1BBL pathway is a potential therapeutic target for oncology and autoimmune disorders.

Interacting protein(s): 4-1BB
Related products: Hexa-Ligand

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Quick Spec

Description

Murine 4-1BB ligand was initially cloned by expression cloning form a cDNA library of EL4 thymoma cells using 4-1BB-Fc fusion protein. The 4-1BB Ligand is a member of the TNF superfamily (TNFSF). It carboxyl terminal extracellular domain contains three N-glycosylation sites. In addition, its membrane proximal region is rich in threonine, serine and proline residues which is indicative of O-linked glycosylation site.

Interestingly, both human and mouse 4-1BB ligand are among the least homologous member of the TNFSF. While earlier studies indicated that 4-1BB ligand might be an exception within the TNFSF and exists as dimeric protein. Subsequent studies shows the soluble trimeric ligand interacts with 4-1BB just like other TNFSF/TNFRSF pairs.

The anti-tumor effect of the 4-1BB/4-1BBL axis is based on the observation that 4-1BBL stimulates activated T cells, particularly CD8 T cells and induces secretion of high levels of IFN-g even though the potential adverse effects of inducing autoimmune status has to be considered at all time. Interestingly, in vivo administration of agonistic anti-4-1BB antibody leads to depletion of B, NK, and CD4 T cells. Hence, 4-1BBL can promote CD8 T cell expansion as well as protect against autoimmune and transplantation rejection. The 4-1BB/4-1BBL pathway is an important therapeutic candidate for oncology.

Amino Acid Sequence

IEPRGPTIKP CPPCKCPAPN LLGGPSVFIF PPKIKDVLMI SLSPIVTCVV VDVSEDDPDV QISWFVNNVE
VHTAQTQTHR EDYNSTLRVV SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP
PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY
SCSVVHEGLH NHHTTKSFSR TPGVDPACPW AVSGARASPG SAASPRLREG PELSPDDPAG LLDLRQGMFA
QLVAQNVLLI DGPLSWYSDP GLAGVSLTGG LSYKEDTKEL VVAKAGVYYV FFQLELRRVV AGEGSGSVSL
ALHLQPLRSA AGAAALALTV DLPPASSEAR NSAFGFQGRL LHLSAGQRLG VHLHTEARAR HAWQLTQGAT
VLGLFRVTPE IPAGLPSPRS E

References

1. Salek-Ardakani S, Zajonc DM, Croft M. Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications. Front Immunol. 2023;14:1228486. Epub 20230817. doi: 10.3389/fimmu.2023.1228486. PubMed PMID: 37662949; PubMed Central PMCID: PMC10469789.

2. Molecular and biological characterization of human 4-1BB and its ligand. Alderson M.R., Smith C.A., Tough T.W., Davis-Smith T., Armitage R.J., Falk B., Roux E., Baker E., Sutherland G.R., Din W.S., Goodwin R.G. Eur. J. Immunol. 24:2219-2227 (1994) 

3. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 14:2121-2127 (2004) 

4. The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily. Won E.Y., Cha K., Byun J.S., Kim D.U., Shin S., Ahn B., Kim Y.H., Rice A.J., Walz T., Kwon B.S., Cho H.S. J. Biol. Chem. 285:9202-9210 (2010)