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. 2025 Dec;17(1):2490078.
doi: 10.1080/19420862.2025.2490078. Epub 2025 Apr 9.

Preclinical development of ozuriftamab vedotin (BA3021), a novel ROR2-specific conditionally active biologic antibody-drug conjugate

Hwai Wen Chang  1 , Gerhard Frey  1 , Jing Wang  1 , Haizhen Liu  1 , Charles Xing  1 , Jian Chen  1 , William J Boyle  1 , Jay M Short  1
Affiliations

Preclinical development of ozuriftamab vedotin (BA3021), a novel ROR2-specific conditionally active biologic antibody-drug conjugate

Hwai Wen Chang et al. MAbs. 2025 Dec.

Abstract

Receptor tyrosine kinase-like orphan receptor (ROR2) has been identified as a highly relevant tumor-associated antigen in a variety of cancer indications of high unmet medical need, including melanoma, renal cell carcinoma, osteosarcoma, gastrointestinal stromal tumor, colorectal cancer, pancreatic ductal adenocarcinoma, and non-small cell lung cancer. Overexpression of ROR2 often correlates with advanced disease or poor prognosis, making it an attractive target for cancer therapy. We developed a novel, conditionally active biologic (CAB) antibody-drug conjugate (ADC), ozuriftamab vedotin (BA3021), which binds to ROR2 only in the acidic tumor microenvironment. In healthy tissue, binding to ROR2 is greatly reduced by a novel selection mechanism using physiological chemicals as protein-associated chemical switches (PaCS). The CAB anti-ROR2 ADC displays the anticipated binding properties and mediates potent lysis of ROR2-positive cancer cell lines. In vivo, BA3021 has potent and durable antitumor activity in human cancer xenograft mouse models, including patient-derived xenograft models. In non-human primates, BA3021 was well tolerated at doses of up to 10 mg/kg and showed excellent stability in vivo. These preclinical results indicate that CAB anti-ROR2 ADC is efficacious and well tolerated and may be a promising treatment for cancer patients with ROR2-expressing tumors.

Keywords: ADC; ROR2; conditionally active; tumor targeting.

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Conflict of interest statement

All authors are shareholders of BioAtla, Inc., which owns intellectual property rights to CABs- and PaCS-related technology. HWC, GF, and JMS are inventors of relevant patents. JMS serves as a Director of BioAtla.

Figures

Figure 1.
Figure 1.
In vitro characterization of BA3021.
Concentration-dependent binding of BA3021 to human or cyno ROR2 expressing 293 cell lines and human cancer cell lines at pH6.0 and pH7.4 detected by FACS.
Figure 2.
FACS analysis.
a: SPR sensorgrams of BA3021 binding to human ROR2 at pH6.0, 6.5, 7.0, and 7.4.
Figure 3.
BA3021 binding kinetics measured by SPR.
a: Cell-killing activity of BA3021 and an isotype control ADC at pH6.0 and pH7.4 using human ROR2 expressing 293 cells. b: Cell-killing activity of BA3021 and an isotype control ADC at pH6.0 and pH7.4 using cynomolgus ROR2 expressing 293 cells. c: Cell-killing activity of BA3021 at pH6.0 and pH7.4 using LCLC103H cells (lung cancer cell line). d: Cell-killing activity of BA3021 at pH6.0 and pH7.4 using HT1080 cells (fibrosarcoma cell line). e: Cell-killing activity of BA3021 and an isotype control ADC at pH6.0 and pH7.4 using ROR2-negative 293 cells.
Figure 4.
In vitro cytotoxicity of BA3021 at pH6.0 and pH7.4.
a: Tumor size over time in a CDX model using SK-MEL5 cells. BA3021 was injected six times at 1, 3, 6, or 10 mg/kg. b: Tumor size over time in a CDX model using LCL103H cells. BA3021 was injected 6 times at 1, 3, or 6 mg/kg. c: Tumor size over time in a Sarcoma PDX model. BA3021 was injected 6 times at 6 mg/kg. d: Tumor size over time in a GIST PDX model. BA3021 was injected 6 times at 6 mg/kg.
Figure 5.
In vivo efficacy of BA3021in CDX and PDX models.
a: Concentration of free MMAE, total ADC, and total antibody in the serum of non-human primates after a single intravenous dose of BA3021 at 3 mg/kg monitored up to 512 h. c: Concentration of free MMAE and total ADC. BA3021 was injected on day 1 and day 22 at 1, 3, or 6 mg/kg.
Figure 6.
Pharmacokinetic and toxicokinetic analysis of BA3021 in non-human primates.
See this image and copyright information in PMC

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