6BAN

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

Summary for 6BAN

• Entry DOI: 10.2210/pdb6ban/pdb
• Related: 6BA5
• Descriptor: Variable domain of R11 Light Chain, Variable domain R11 Heavy chain, Inactive tyrosine-protein kinase transmembrane receptor ROR1, ... (4 entities in total)
• Functional Keywords: single chain fv, scfv, antibody, ror1, kringle domain, receptor tyrosine kinase-like orphan receptor, phage display, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 12
• Total formula weight: 135665.86

Authors

Park, H.,Rader, C. (deposition date: 2017-10-14, release date: 2018-06-13, Last modification date: 2019-12-04)

Primary citation

Qi, J.,Li, X.,Peng, H.,Cook, E.M.,Dadashian, E.L.,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., 115:E5467-E5476, 2018

PubMed Abstract: 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 × CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory and diminished systemic T cell activation. A diverse panel of ROR1-targeting scFv derived from immune and naïve 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-Å resolution.

PubMed: 29844189
DOI: 10.1073/pnas.1719905115

Experimental method

X-RAY DIFFRACTION (1.95 Å)