6ba5

From Proteopedia

Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1

Structural highlights

6ba5 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.62Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ROR1_HUMAN The disease is caused by mutations affecting the gene represented in this entry.

Function

ROR1_HUMAN Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350).^[1] ^[2]

Publication Abstract from PubMed

T cell-engaging bispecific antibodies (biAbs) present a promising strategy for cancer immunotherapy, and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T cell-engaging biAbs targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 x CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory t1/2 and diminished systemic T cell activation. A diverse panel of ROR1-targeting scFv derived from immune and naive rabbit antibody repertoires was compared in this bispecific format for target-dependent T cell recruitment and activation. An ROR1-targeting scFv with a membrane-proximal epitope, R11, revealed potent and selective antitumor activity in vitro, in vivo, and ex vivo and emerged as a prime candidate for further preclinical and clinical studies. To elucidate the precise location and engagement of this membrane-proximal epitope, which is conserved between human and mouse ROR1, the 3D structure of scFv R11 in complex with the kringle domain of ROR1 was determined by X-ray crystallography at 1.6-A resolution.

Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1.,Qi J, Li X, Peng H, Cook EM, Dadashian EL, Wiestner A, Park H, Rader C Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5467-E5476. doi:, 10.1073/pnas.1719905115. Epub 2018 May 29. PMID:29844189^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations

reviews cite this structure

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References

↑ Bainbridge TW, DeAlmeida VI, Izrael-Tomasevic A, Chalouni C, Pan B, Goldsmith J, Schoen AP, Quinones GA, Kelly R, Lill JR, Sandoval W, Costa M, Polakis P, Arnott D, Rubinfeld B, Ernst JA. Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. PLoS One. 2014 Jul 16;9(7):e102695. doi: 10.1371/journal.pone.0102695., eCollection 2014. PMID:25029443 doi:http://dx.doi.org/10.1371/journal.pone.0102695
↑ Diaz-Horta O, Abad C, Sennaroglu L, Foster J 2nd, DeSmidt A, Bademci G, Tokgoz-Yilmaz S, Duman D, Cengiz FB, Grati M, Fitoz S, Liu XZ, Farooq A, Imtiaz F, Currall BB, Morton CC, Nishita M, Minami Y, Lu Z, Walz K, Tekin M. ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A. 2016 May 24;113(21):5993-8. doi:, 10.1073/pnas.1522512113. Epub 2016 May 9. PMID:27162350 doi:http://dx.doi.org/10.1073/pnas.1522512113
↑ Qi J, Li X, Peng H, Cook EM, Dadashian EL, Wiestner A, Park H, Rader C. Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5467-E5476. doi:, 10.1073/pnas.1719905115. Epub 2018 May 29. PMID:29844189 doi:http://dx.doi.org/10.1073/pnas.1719905115