Targeting ROR1 with Cirmtuzumab-ADCs: A Promising Therapeutic Approach for ROR1-Positive Malignancies

ROR1 is an antigen found on the surface of various cancers, including chronic lymphocytic leukemia (CLL), but is not typically present on normal adult tissues. A humanized IgG1 monoclonal antibody named cirmtuzumab has been developed, which targets a specific ROR1 epitope and can inhibit ROR1 signaling. Cirmtuzumab has shown high specificity, a lack of reaction with normal post-partum cells, and a favorable pharmacokinetic profile in primates.

In a phase I clinical trial, cirmtuzumab was well-tolerated in patients with relapsed-refractory CLL at doses up to 20 mg/kg, with a serum half-life of 32.4 days and no observed neutralizing antibodies or off-target effects. The drug also induced partial down-modulation of leukemia-cell ROR1 in patients treated with doses of 2 mg/kg or higher, due to internalization and lysosomal compartmentalization of cirmtuzumab-ROR1 complexes.

Given its high specificity and long serum half-life, cirmtuzumab is considered an ideal candidate for use in antibody-drug conjugates (ADCs). In collaboration with VelosBio Inc., several cirmtuzumab-based ADCs were evaluated, leading to the selection of cirmtuzumab-ADC-7, an ADC conjugated with monomethyl auristatin E (MMAE) for ROR1-targeted intracellular release.

Cirmtuzumab-ADC-7 demonstrated selective cytotoxicity for ROR1-positive CLL and mantle-cell lymphoma (MCL) cell lines in vitro and caused significant in vivo clearance of ROR1-positive leukemia cells and xenograft tumors. The treatment led to dose-dependent decreases in cancer burden and complete tumor regressions in multiple animals.

Recent findings have linked miR-15a/16-1, which are commonly deleted or downregulated in CLL, to the targeting of both BCL2 and ROR1. This suggests a connection between BCL2 levels and ROR1 surface expression. Due to the potential for high BCL2/ROR1 expression to counteract the effects of venetoclax, a BCL2-antagonist, while enhancing the cytotoxicity of cirmtuzumab-ADC-7, combination treatments with these agents were tested. The combination indices indicated strong antitumor synergy, supporting the clinical development of a cirmtuzumab-based ADC for ROR1-positive malignancies.