Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1

Abstract

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen. Due to its expression on the cell surface of leukemia cells from patients with chronic lymphocytic leukemia (CLL), but not on normal B-cells or other post-partum tissues, ROR1 is an attractive candidate for targeted therapies. UC-961 is a first-in-class humanized monoclonal antibody (mAb) that binds the extracellular domain of ROR1. In this paper we outline some of the preclinical studies leading to an investigation new drug (IND) designation, enabling clinical studies in patients with CLL.

ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma

“…Cirmtuzumab (UC-961), a first-in-class humanized anti-ROR1 mAb, had specific antitumor effect on CLL, breast cancer and pancreas ADC cancer without any off-target activity or toxicity in preclinical tests. UC-961 has been conducted to a Phase I study in patients with relapsed or refractory CLL35. Because of its tumor-specific expression and absence on normal mature cells, ROR1 could be a potential candidate for CAR (Chimeric antigen receptor) -T cell therapy.…”

High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

“…31 Moreover, high-level expression of ROR1 also has been associated with higher levels of AKT activation, 24,30,32,33 consistent with the notion that ROR1 signaling leading to activation of AKT may serve as a driver, not just in CLL, but also in other malignancies. Because of this and its restricted postpartum expression, ROR1 may be an attractive target for therapy with either mAbs, 7,34 or other agents that specifically inhibit this orphan receptor and/or its downstream signaling pathways. designed research, analyzed data, provided patient samples, and wrote the paper.…”

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

“…[22][23][24] ROR1 mAb 2A2 was active in blocking Wnt5a binding to ROR1 and its downstream signaling in CLL. 30,31 We observed that ROR1 2A2 was effective when used at similar concentrations as other ROR1 mAbs (5-10 mg/mL) 19,23 in ROR1 Figure 2C-D).…”

“…24 Moreover, cirmtuzumab has been shown to augment the effect of ibrutinib treatment in CLL, suggesting high therapeutic potential for ROR1 mAb in combinatorial treatments. 25 The molecular mechanism underlining the oncogenic role of ROR1 in hematological malignancies is not completely understood.…”

“…19 Furthermore, high ROR1 levels on B-ALL or CLL cells can sustain prosurvival signaling through activation of MEK/ERK and AKT pathways, whereas targeting ROR1 expression efficiently induced apoptosis in malignant cells, suggesting a critical role for this molecule in maintaining cancer cell survival. [20][21][22][23][24] ROR1 monoclonal antibody (mAb) cirmtuzumab has shown excellent preclinical efficacy in directly inducing apoptosis in ROR1…”