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Antitumor activity of a ROR1 × CD3 bispecific antibody in non-small cell lung cancer
Yi Wang1, Yuxi Zhang1, Haoyi Sun1
1School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Abstract:
Over the last decade, immuno-oncologic drugs especially CD3-engaging bispecific antibodies (biAbs) are experiencing fast-paced evolution, but big challenges still exist in the clinical development of biAbs in solid tumors, especially non-small cell lung cancer (NSCLC). In this study, we choose a ROR1 × CD3 biAb in scFv-Fc format, named R11 × v9 biAb, to investigate its tumor-inhibiting role in NSCLC. Notably, the ROR1-engaging arm binds both human and mouse ROR1. We found that R11 × v9 biAb specifically binds T cells and tumor cells simultaneously, and dose-dependent cytotoxicity was detected for various ROR1+ NSCLC cell lines. Further, R11 × v9 biAb mediated T-cell derived proinflammatory cytokine secretion, boosted granzyme B and perforin production from CD8+ T cells, and recruited more CD4+ T cells and CD8+ T cells into the tumor tissues. The antitumor activity of R11 × v9 biAb was confirmed in two xenograft mouse models of ROR1+ NSCLC. Importantly, no harmful side effects were observed in these in vivo studies, warranting further preclinical and clinical studies of R11 × v9 biAb in NSCLC.
Insights
A novel bispecific antibody targeting ROR1 and CD3 effectively eliminates non-small cell lung cancer (NSCLC) cells. This ROR1 x CD3 bispecific antibody (biAb) shows potent anti-tumor activity in preclinical models with no observed side effects.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Bispecific antibodies (biAbs) targeting CD3 are evolving rapidly for immuno-oncology.
- Clinical development of biAbs in solid tumors like non-small cell lung cancer (NSCLC) faces significant challenges.
- Targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a potential strategy for NSCLC treatment.
Purpose of the Study:
- To investigate the tumor-inhibiting potential of a novel ROR1 × CD3 bispecific antibody (biAb) in NSCLC.
- To evaluate the efficacy and safety of the R11 × v9 biAb in ROR1-positive NSCLC models.
Main Methods:
- Development of a ROR1 × CD3 biAb (R11 × v9) in scFv-Fc format, with ROR1 binding to human and mouse targets.
- Assessment of R11 × v9 biAb binding to T cells and ROR1+ NSCLC cell lines.
- In vitro evaluation of cytotoxicity, cytokine secretion, and immune cell activation (CD4+, CD8+ T cells).
- In vivo efficacy and safety studies in ROR1+ NSCLC xenograft mouse models.
Main Results:
- R11 × v9 biAb demonstrated specific binding to T cells and ROR1+ NSCLC cells.
- Dose-dependent cytotoxicity was observed against various ROR1+ NSCLC cell lines.
- The biAb induced T-cell mediated pro-inflammatory cytokine secretion and enhanced cytotoxic molecule production (granzyme B, perforin) in CD8+ T cells.
- R11 × v9 biAb promoted T-cell infiltration into tumor tissues.
- Significant antitumor activity was confirmed in vivo, with no observed adverse effects.
Conclusions:
- The R11 × v9 biAb effectively engages T cells to eliminate ROR1+ NSCLC cells.
- This novel biAb demonstrates potent preclinical anti-tumor efficacy and a favorable safety profile in NSCLC models.
- R11 × v9 biAb warrants further investigation in preclinical and clinical studies for NSCLC treatment.
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