zilovertamab (UC-961) / Oncternal Therap, Shanghai Pharma, Ho’ola Therapeutics - LARVOL DELTA

Dual targeting of ROR1 and ROR2 with glycoengineered antibodies elicits potent and selective immunotherapy in hairy cell leukemia (ASH 2025) - "Combination treatment withglycoengineered anti-ROR1 and anti-ROR2 antibodies mediated significantly higher killing of Cr51-labeledHCL cells than either agent alone, or rituximab, or the combination of the two parental antibodies. Importantly, in contrast to rituximab, GE-zilovertamab and GE-6E6 spared normal B cells, which lackexpression of ROR1 and ROR2.In summary, our findings show that dual targeting with glycoengineered anti-ROR1 and anti-ROR2antibodies achieves superior, selective ADCC against ROR1/2+ hairy cell leukemia, sparing normal B cells.This approach offers a promising and potentially safer immunotherapeutic strategy for patients with HCLor other ROR-expressing B-cell malignancy."

IO biomarker • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • CD20 • FCGR3A • ROR1 • ROR2

A tandem CD19/ROR1 CAR-NK to overcome Wnt5a-mediated apoptotic resistance in chronic lymphocytic leukemia (ASH 2025) - "Receptor tyrosine kinase-like orphan receptor (ROR1)is ubiquitously expressed on CLL cells, and signaling via its ligand Wnt5a has been associated with bothibrutinib and venetoclax resistance; however, its connection to cell therapy resistance remainsunderexplored. This dual CAR-NK also has the potential to subvertsingle antigen escape. In vivo studies are underway using NSG mice engrafted with HG3 CLL cellsengineered to express both ROR1 and constitutive Wnt5a to assess whether a novel dual CAR-NK productexpressing the D10-derived anti-ROR1 scFv (derived from zilovertamab) more effectively reduces tumorburden compared to non-ROR1-inhibiting CAR constructs."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • CD69 • ROR1

Merck…announced that new data across multiple hematologic malignancies will be presented at the American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Fla. from Dec. 6-9. (Merck (MSD) Press Release) - "Data presentations will feature Merck’s pipeline candidates, including: MK-1045, an investigational CD19xCD3 T-cell engager; bomedemstat (MK-3543), an investigational, orally available lysine-specific demethylase 1 (LSD1) inhibitor; and nemtabrutinib (MK-1026), an investigational, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. Additionally, Merck will present new and updated results highlighting zilovertamab vedotin (MK-2140), an investigational antibody-drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1)."

Clinical data • B Acute Lymphoblastic Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Essential Thrombocythemia • Follicular Lymphoma • Marginal Zone Lymphoma • Polycythemia Vera

Dual Targeting of ROR1 and BTK Augments the Anti-Lymphoma Activity in Mantle Cell Lymphoma (ASH 2023) - "In addition, a patient-derived xenograft (PDX) mouse model was also used for evaluating single agent and combination efficacy of BTKis and zilovertamab (Zilo)...Treatment with single BTKi at 2-10 µM (Ibrutinib, zanubrutinib, acalabrutinib or pirtobrutinib) significantly induced cytotoxicity in the TP53Mut MCL cells, and the cell death was remarkedly increased when BTKi was combined with Zilo at 25-50 µg/ml...Conclusion Dual targeting of BTK and ROR1 signaling pathways augmented efficacy selectively in preclinical MCL models with TP53Mut. These data provide insights to develop tailored therapeutics to improve patient outcome for patients with TP53 mutation."

IO biomarker • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • KIT • ROR1

Development and Testing of a Glycoengineered Anti-ROR1 Antibody with Enhanced Capacity for Directing Antibody-Dependent Cellular Cytotoxicity (ADCC) of Chronic Lymphocytic Leukemia Cells (ASH 2023) - "Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e. g. , inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ADAM17 • BCL2 • FCGR3A • ROR1 • TP53

Combined Therapy of Zanubrutinib and Zilovertamab in the Inhibition of Invasive Capability of Chronic Lymphocytic Leukemia Cells (ASH 2023) - "Zilovertamab could inhibit Wnt5a enhanced invasiveness of CLL cells. Moreover, the combined treatment of zanubrutinib and zilovertamab had additive activity in inhibiting Matrigel invasiveness by CLL cells, supporting potential evaluation of the combined use of zilovertamab and zanubrutinib in the treatment of patients with CLL."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CXCL12 • CXCR4 • MMP9 • RELA • ROR1 • WNT5A

Defining Signaling Interactomes Involved in Non-Canonical Wnt Signaling By ROR1 or ROR2 in Hairy Cell Leukemia That Can Influence Cell Morphology and Migration (ASH 2023) - "We developed humanized monoclonal antibodies (mAbs) each specific for ROR1 (UC-961) or ROR2 (6E6-70) and found the leukemia cells of patients with classic hairy cell leukemia (cHCL) or variant HCL (vHCL) express both ROR1 and ROR2 and that these receptors function in HCL non-canonical Wnt signaling (Widhopf, G. et al)...In contrast to wild-type ROR2, or other mutant forms of ROR2, expression of this mutant form of ROR2 could not enhance chemokine-directed migration relative to that of wild-type MEC1 cells. Collectively, our studies define signaling interactomes involved in non-canonical Wnt signaling by ROR1 and/or ROR2 in hairy cell leukemia and define a residue within ROR2 that is necessary for binding HS1 and facilitating cellular migration."

Chronic Lymphocytic Leukemia • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology • ROR1 • ROR2

Wnt5a Enhances Chemokine-Directed Migration of T-Cells Made to Express ROR1 (ASH 2024) - "Such enhanced migration could be blocked by concomitant treatment of ROR1+ T cells with zilovertamab, but not with a control IgG of irrelevant specificity. These studies demonstrate that expression of ROR1 on Jurkat or normal blood T cells markedly could enhance T-cell-chemokine-directed migration, which we propose may be exploited to enhance CAR T cell homing to target-antigen-bearing cancer tissue, which typically has high levels of Wnt5a produced by accessory cells in the tumor microenvironment."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CTTN • CXCL11 • CXCL12 • CXCL9 • RHOA • ROR1 • WNT5A

ROR1-Signaling Increases Levels of Mutant TP53 Protein and Cyclin A1 Via Activation of NRF2, Potentially Potentiating Genomic Instability in Chronic Lymphocytic Leukemia Cells with Del(17p) (ASH 2024) - "(Χ2 p values of <0.01 for both), suggesting ROR1-signaling may mitigate the genotoxic stress caused by mutant TP53, thereby enhancing survival of (del17p) CLL and potentially allowing for emergence of mutant subclones with acquired resistance to targeted therapy, e.g. BTK inhibitors (BTKi's). Conversely, concomitant treatment with agents such as zilovertamab that inhibit ROR1-signaling may mitigate the risk of developing drug-resistance to BTKi's or other targeted therapies in pts with del(17p) CLL."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CCNA1 • CCNA2 • NQO1 • ROR1 • TP53 • WNT5A

Expression of ROR1 and ROR2 in Hairy Cell Leukemia Cells Enhances Constitutive Activation of ERK1/2 and Cancer Stemness (ASH 2024) - "We generated monoclonal antibodies (mAbs) that each are highly specific for human ROR1 (zilovertamab) or ROR2 (6E6) and that respectively can block Wnt5a-induced ROR1- or ROR2-dependent signaling...In addition, we found Wnt5a can induce ROR1/2-dependent activation of targets of Oct4, Sox2, and c-Myc and cancer stemness genes signatures found expressed by embryonic stem cells. We speculate that strategies that target ROR1 and/or ROR2, or that block ROR1/2-dependent signaling, may reverse HCL cancer stemness in vivo and mitigate the risk of tumor dormancy and disease-relapse that may be seen years after apparent successful therapy."

Chronic Lymphocytic Leukemia • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • CD123 • CD19 • CD20 • CD200 • CD21 • CD5 • FCER2 • IL2RA • IL3RA • ITGAE • ITGAX • MAPK1 • MAPK3 • MME • MYC • POU5F1 • ROR1 • ROR2 • SOX2 • WNT5A

A tandem CD19/ROR1 CAR-NK to overcome apoptotic resistance in chronic lymphocytic leukemia (IWCLL 2025) - "Receptor tyrosine kinase-like orphan receptor (ROR1) is ubiquitously expressed on CLL cells, and signaling via its ligand Wnt5a has been associated with both ibrutinib and venetoclax resistance (Yu, J. et al., Oncotarget, 2018; Ghia, E. et al., Leukemia, 2022)...Dual CAR-NK cells achieved increased CD69 expression compared to single-directed or untransduced NK cells against high- and low-ROR1+ CLL samples (n=6) at 16 h. Furthermore, the Dual CAR-NK had comparable cytotoxicity to CD19 CAR-NK against CLL cells and greater cytotoxicity than ROR1 CAR-NK and untransduced NK at 16 h. Conclusion We identified Wnt5a-induced ROR1 signaling as a key pathway reducing CLL cell priming for apoptosis and enhancing their survival against NK cells, which was reversible by anti-ROR1 mAb zilovertamab. We subsequently developed a novel tandem CD19/ROR1 CAR-NK product which may potentially overcome ROR1-associated cell-mediated killing resistance and subvert single-antigen escape. Our early..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • CD69 • ROR1

ROR1-Signaling Enhances Survival and Drug-Resistance of del(17p)/TP53-Mutated CLL by Mitigating Oxidative Stress Via Activation of NRF2 (IWCLL 2025) - "This pathway underpins the association between ROR1Hi expression, CK, and poor outcomes, while zilovertamab emerges as a strategy to counteract these mechanisms. Combining ROR1 inhibition with BTKis or ROS-inducing therapies (e.g., APR-246) could mitigate resistance in high-risk CLL, offering a dual-pronged approach to target both survival signaling and genomic instability."

Oxidative stress • Chronic Lymphocytic Leukemia • Hematological Malignancies • CCNA1 • NQO1 • ROR1 • SQSTM1 • TP53 • WNT5A

Oncternal Therapeutics Announces the Sale of Select Development Programs and the Wind-Down of its Operations (GlobeNewswire) - "Oncternal Therapeutics, Inc. today announced the sale of its zilovertamab and ONCT-808 programs to Ho’ola Therapeutics, Inc. Zilovertamab is an investigational monoclonal antibody designed to inhibit the function of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), and ONCT-808 is an investigational autologous chimeric antigen receptor T (CAR T) cell therapy that targets ROR1 using the binding domain from zilovertamab...Ho’ola will pay Oncternal a $3.0 million upfront payment, with $2.25 million paid immediately and $750,000 upon resolution of certain outstanding contractual obligations with third parties. Oncternal will also be eligible to receive up to $65.0 million in development, regulatory approval and sales milestone payments for the acquired products (including any future products derived from the acquired intellectual property)...The asset sale was completed on June 27, 2025, pursuant to an asset purchase agreement as of the same date."

Commercial • Chronic Lymphocytic Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma

Cirmtuzumab Consolidation for Treatment of Patients With Detectable CLL on Venetoclax (clinicaltrials.gov) - P2 | N=5 | Active, not recruiting | Sponsor: University of California, San Diego | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Jul 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Wnt5a induces ROR1 dependent NF-κB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia. (PubMed, Leukemia) - "Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • MMP9 • ROR1

ROR1-dependent mutant TP53 and cyclin A1 increases, via NRF2 activation, potentially potentiate genomic instability in chronic lymphocytic leukemia cells with del(17p) (AACR 2025) - "Similarly, we found that culture of ROR1+ del(17p) CLL cells with Wnt5a increased expression of NQO1, cyclin A1, and p53MU, and enhanced their resistance to drug induced oxidative stress; this effect of Wnt5a could be blocked by concomitant treatment with zilovertamab. As such, inhibiting ROR1-signaling may reduce resistance to oxidative stress and prove selectively deleterious to CLL cells with del(17p) and CK, thereby mitigating their adverse prognostic implications for pts with CLL."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CCNA1 • NQO1 • ROR1 • TP53 • WNT5A

Constitutive photomorphogenesis (COP)-1 leads to apoptosis in B16F10 metastatic melanoma model (AACR 2025) - "Experiments included: activated caspase-3 by live cell imaging of A375 cells following ARSB and PBMC; ELISA assays of activated caspase-3/7, cytosolic cytochrome c, BCL2, nuclear ETS1, and phospho(Tyr)-ROR1; Western blots of phospho(Ser473)-AKT1; disaccharide analysis of A375 cells following ARSB silencing and exogenous ARSB; chromatin immunoprecipitation of nuclear FOXO3 and COP1 promoter; mRNA expression of COP1; siRNA inhibition of COP1, ARSB, Insulin Growth Factor 2 Receptor, carbohydrate sulfotransferase (CHST)15; treatment by ROR1 inhibitor cirmtuzumab; and treatment by other inhibitors of signaling pathways...Decline in CHST15, by rhARSB or CHST15 siRNA reduced phospho(Tyr)-ROR1 and phospho(Ser473)-AKT1, leading to increased nuclear FOXO3 and COP1. This series of signaling and transcriptional events in A375 cells and normal human melanocytes provides new insight into how a conserved, inhibitory response to light-stimulated growth can impact on inhibition of human..."

IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • AKT1 • BCL2 • CASP3 • CASP7 • ETS1 • FOXO3 • IGF2 • ROR1

Study of B013 and Nab-Paclitaxel for Locally Advanced or Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P2/3 | N=62 | Completed | Sponsor: Shanghai Jiaolian Drug Research and Development Co., Ltd | N=450 ➔ 62 | Trial completion date: Dec 2026 ➔ Sep 2024 | Recruiting ➔ Completed | Trial primary completion date: Jun 2025 ➔ Sep 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Blockade of Wnt5A/ROR1 Signaling Activated the Androgen Response in Metastatic Castration Resistant Prostate Cancer (mCRPC) patient-derived models. (AUA 2025) - P1 | "Our data suggest that targeting ROR1 may overcome critical therapeutic resistance mechanisms in mCRPC by re-sensitizing tumors to androgen receptor signaling and chemotherapy. The combination of Zilovertamab and docetaxel showed promising synergy in preclinical models, supporting its potential as a novel treatment strategy for neuroendocrine mCRPC. A phase 1b clinical trial evaluating zilovertamab plus docetaxel in patients with metastatic CRPC (CirmD, NCT05156905, PI R Mckay) is in progress."

Clinical • Metastases • Breast Cancer • Castration-Resistant Prostate Cancer • Chronic Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CTCs • ROR1

Study of B013 and Nab-Paclitaxel for Locally Advanced or Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P2/3 | N=450 | Recruiting | Sponsor: Shanghai Jiaolian Drug Research and Development Co., Ltd | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Analysis of Wnt5A/ROR1 Signaling Inhibition as Cancer Stem Cell Targeting Therapy for Metastatic Prostate Cancer Using Live Organoid Time Lapse Microscope Imaging. (PCF 2024) - P1 | "We showed synergistic response in our PDX and cell line models with Zilovertamab plus docetaxel. A phase 1b clinical trial with zilovertamab plus docetaxel in patients with metastatic CRPC (CirmD, NCT05156905, PI R Mckay) is in progress."

Cancer stem • Metastases • Breast Cancer • Castration-Resistant Prostate Cancer • Chronic Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Oncology • Prostate Cancer • Solid Tumor • CTCs • ROR1

CirmD: Study of Docetaxel Combined with Cirmtuzumab in Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1 | N=6 | Terminated | Sponsor: University of California, San Diego | N=32 ➔ 6 | Trial completion date: Feb 2026 ➔ Oct 2024 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2025 ➔ Oct 2024; Oncternal closing clinical trial operations.

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Oncternal Therapeutics Announces Termination of its Clinical Studies and Exploration of Strategic Alternatives (GlobeNewswire) - P1 | N=57 | NCT05588440 | Sponsor: Oncternal Therapeutics Inc. | "Oncternal Therapeutics...announced its decision to discontinue its clinical trials evaluating...ONCT-808, its ROR1-targeting autologous CAR T program for the treatment of patients with aggressive B-cell lymphoma, and to explore strategic alternatives...The results with ONCT-808 at an interim Phase 1 analysis showed anti-tumor activity at every dose tested, including a complete metabolic response lasting eight months and long-term persistence of the CAR-T cells, with expected treatment emergent adverse events for a CAR-T therapy, and one death due to complications of shock at the highest dose tested...Company will discontinue all product development activities....'In light of these data and the challenging financing environment, we intend to explore strategic options with the hope of advancing and realizing value from our pipeline including ONCT-534, ONCT-808, zilovertamab and ONCT-216.'"

Discontinued • P1 data • Pipeline update • Trial termination • Castration-Resistant Prostate Cancer • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Mediastinal B Cell Lymphoma • Metastatic Castration-Resistant Prostate Cancer • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=102 | Completed | Sponsor: Oncternal Therapeutics, Inc | Active, not recruiting ➔ Completed

Trial completion • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • BCL2

A Study of B013 in Combination With Paclitaxel in Patients With Platinum-resistant Recurrent Ovarian Cancer. (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Shanghai Jiaolian Drug Research and Development Co., Ltd | Not yet recruiting ➔ Recruiting

Enrollment open • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor