Journal Article

A ROR1 targeted bispecific T cell engager shows high potency in the pre-clinical model of triple negative breast cancer

Han, Guohui, Xie, Jun, Wang, Fan, Bai, Xiangdong, Li, Weina

2025

Overview

Background Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized with poor prognosis and high metastatic potential. Although traditional chemotherapy, radiation, and surgical resection remain the standard treatment options for TNBC, bispecific antibody-based immunotherapy is emerging as new strategy in TNBC treatment. Here, we found that the receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) was highly expressed in TNBC but minimally expressed in normal tissue. A bispecific ROR1-targeted CD3 T cell engager (TCE) was designed in IgG-based format with extended half-life. Method The expression of ROR1 in TNBC was detected by RT-qPCR and immunohistology analysis. The killing of ROR1/CD3 antibody on TNBC cells was determined by the in vitro cytotoxicity assay and in vivo PBMC reconstituted mouse model. The activation of ROR1/CD3 on T cells was analyzed by the flow cytometry and ELISA assay. Pharmacokinetics study of ROR1/CD3 was performed in mouse. Results The ROR1/CD3 TCE triggered T cell activation and proliferation, which showed potent and specific killing to TNBC cells in ROR1-depedent manner. In vivo mouse model indicated that ROR1/CD3 TCE redirected the cytotoxic activity of T cells to lyse TNBC cells and induced significant tumor regression. Additionally, the ROR1/CD3 bispecific antibody exhibited an extended half-life in mouse, which may enable intermittent administration in clinic. Conclusions Collectively, these results demonstrated that ROR1/CD3 TCE has a promising efficacy profile in preclinical studies, which suggested it as a possible option for the treatment of ROR1-expressing TNBC.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Antibodies, Bispecific - immunology / Antibodies, Bispecific - pharmacology / Antigens / Biomedical and Life Sciences / Biomedicine / Bispecific antibodies / Breast cancer / Cancer / Cancer Research / Cancer therapies / CD3 antigen / CD3 Complex - antagonists & inhibitors / CD3 Complex - immunology / Cell activation / Cell culture / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Chemotherapy / CRISPR / Cytotoxicity / Design / Disease Models, Animal / Drug resistance / Enzyme-linked immunosorbent assay / Female / Flow cytometry / Half-life / Hematology / Humans / Immunoglobulin G / Immunotherapy / Kinases / Lymphocyte Activation - drug effects / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Lymphoma / Medical prognosis / Metastases / Mice / Oncology / Peripheral blood mononuclear cells / Pharmacokinetics / Plasmids / Prognosis / Protein-tyrosine kinase receptors / Proteins / Receptor Tyrosine Kinase-like Orphan Receptors - antagonists & inhibitors / Receptor Tyrosine Kinase-like Orphan Receptors - genetics / Receptor Tyrosine Kinase-like Orphan Receptors - immunology / Receptor Tyrosine Kinase-like Orphan Receptors - metabolism / ROR1 / Surgical Oncology / T cell engager / T cell receptors / T cells / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / TNBC / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - immunology / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Triple Negative Breast Neoplasms - therapy / Tumors / Xenograft Model Antitumor Assays