Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1
| Autor: | Adrian Wiestner, Xiuling Li, Haiyong Peng, Eman L. Dadashian, HaJeung Park, Junpeng Qi, Christoph Rader, Erika M. Cook |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD3 Complex medicine.medical_treatment T cell CD3 Antineoplastic Agents Biology Crystallography X-Ray Receptor Tyrosine Kinase-like Orphan Receptors Jurkat cells Receptor tyrosine kinase Epitope 03 medical and health sciences Epitopes Jurkat Cells Mice Immune system Cancer immunotherapy Cell Line Tumor Antibodies Bispecific medicine Animals Humans Multidisciplinary Immunotherapy Molecular biology Xenograft Model Antitumor Assays 030104 developmental biology medicine.anatomical_structure PNAS Plus Cancer research biology.protein Rabbits K562 Cells Single-Chain Antibodies T-Lymphocytes Cytotoxic |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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