Advancements in ROR1-Targeted Therapies: Insights from Antibody-Drug Conjugates in Leukemia Treatment

3 June 2024
The orphan receptor 1 (ROR1) is a cell surface protein found in various blood and solid tumors, making it a promising therapeutic target for ROR1-positive cancers. This research introduces a pioneering anti-ROR1 monoclonal antibody drug conjugate (ADC) named XBR1-402 or its humanized variant, huXBR1-402. These are linked to a potent anthracycline-derived toxin, PNU-159682 (PNU), and have demonstrated efficacy in eliminating ROR1-positive chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and pre B cell acute lymphocytic leukemia (pre B cell ALL) cells.

In the study, a reduction in viability was observed in all ROR1-positive leukemic cell lines treated with the ADC. Notably, the ROR1-positive pre B cell ALL cell lines 697 and Kasumi-2 exhibited a marked decrease in viability when treated with XBR1-402-PNU compared to the control Trastuzumab-PNU. Similarly, the ROR1-positive Jeko and Mino cell lines of MCL showed decreased viability with huXBR1-402-PNU treatment, while the ROR1-negative Mec-1 cell line remained unaffected.

Although direct cytotoxicity wasn't significant in primary CLL cells, the PNU ADCs were found to mediate antibody-dependent cellular cytotoxicity and phagocytosis. The ADCs also induced a G2/M cell cycle arrest in affected cell lines, suggesting that targeting proliferating cells in lymphoid organs may be a strategy for PNU's therapeutic action.

In vivo studies on a murine 697 ALL model indicated that XBR1-402-PNU treatment significantly increased overall survival compared to the control. Additionally, in vivo CLL studies with huXBR1-402-PNU showed both a reduction in leukemia burden and an increase in overall survival.

The findings indicate that the anti-ROR1 ADC huXBR1-402-PNU is a potential and effective targeted therapy for ROR1-positive leukemic cells and warrants further exploration for clinical application in ROR1-positive leukemia and lymphomas.

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