Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1

Qi, Junpeng; Li, Xiuling; Peng, Haiyong; Cook, Erika M.; Dadashian, Eman L.; Wiestner, Adrian; Park, HaJeung; Rader, Christoph

doi:10.1073/pnas.1719905115

Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1

Journal Article · Tue May 29 00:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1719905115· OSTI ID:1462564

Qi, Junpeng ^[1]; Li, Xiuling ^[1]; Peng, Haiyong ^[1]; Cook, Erika M. ^[2]; Dadashian, Eman L. ^[2]; Wiestner, Adrian ^[2]; Park, HaJeung ^[1]; Rader, Christoph ^[1]

The Scripps Research Inst., Jupiter, FL (United States)
National Inst. of Health (NIH), Bethesda, MD (United States)

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 t_1/2 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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH

OSTI ID:: 1462564

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 24 Vol. 115; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
ROR1
X-ray crystallography
antibody engineering
bispecific antibodies
cancer immunotherapy

Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1

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