The FDA has cleared investigational new drug applications for the novel agents ZW251, an antibody-drug conjugate (ADC), and betabart (RV-01), a radiopharmaceutical.1,2 The regulatory clearances authorize the initiation of first-in-human phase 1 trials of these investigational treatments in patients with solid tumors.
ZW251: A GPC3-Targeting ADC for HCC
Thefirst-in-class ADC ZW251 is designed to selectively target glypican-3 (GPC3), a cell surface antigen expressed in over three-fourths of hepatocellular carcinoma (HCC) cases. According to Zymeworks, the developer of ZW251, the ADC consists of a humanized IgG1 monoclonal antibody conjugated to a proprietary camptothecin-based topoisomerase I inhibitor (TOPO1i) payload via a validated peptide-cleavable linker.1
Preclinical research showed that ZW251 elicited potent antitumor activity across multiple HCC models, including patient-derived xenografts with varying levels of GPC3 expression. The preclinical studies also showed that ZW251 was well tolerated at doses of up to 120 mg/kg when administered to nonhuman primates.
Zymeworks plans to launch a phase 1 clinical trial of ZW251 in HCC by the end of this year. There are currently no FDA-approved ADCs specifically for the treatment of liver cancer.
“This advancement marks the second ADC from our wholly-owned pipeline, utilizing our proprietary TOPO1i payload, to progress into clinical development, reinforcing confidence in our approach,” Paul Moore, PhD, chief scientific officer of Zymeworks, stated in a press release.1
“Like ZW191, which is currently in clinical trials, ZW251 utilizes the same payload paired with an optimized antibody. Our observations with ZW191 in the clinic to date provide a strong foundation as we initiate clinical development of this second ADC. With its novel design, unique mechanism of action, and promising preclinical activity, ZW251 offers the potential to meaningfully improve upon the current standard of care for HCC either as a monotherapy or in combination,” added Moore.1
Radiopharmaceutical Betabart in Solid Tumors
The radiopharmaceutical betabart (RV‑01) is a humanized IgG1 monoclonal antibody labeled with Lutetium‑177, specifically engineered to bind with high affinity to B7‑H3. The immune checkpoint B7-H3 is highly expressed across multiple solid tumors but does not have a high presence in healthy tissues.
Treatment with Betabart has resulted in significant tumor reduction and improved survival outcomes in animal models across multiple preclinical studies.
Betabart is being developed through a collaboration between MD Anderson Cancer Center and Radiopharm Theranostics. Radiopharm noted in a press release that a first-in-human phase 1 study of betabart is on schedule to launch this year during the fourth quarter.
“Recent reported preclinical studies demonstrated that RV-01 exhibits hepatic clearance, allowing the isotope sufficient time to effectively target tumors while potentially minimizing adverse effects such as hematological toxicities. Unlike peptides or small molecules, monoclonal antibodies are primarily cleared by the liver—an organ known for its radio-resistance. This characteristic, combined with the shortened half-life of RV-01 and the strong affinity for the target make this agent stand out and may offer a significant advantage not just over other monoclonal antibodies but also targeted radiotherapeutics with renal excretion pathway, the latter of which are often associated with higher risk of radiopharmaceutical-induced kidney toxicity,” Dimitris Voliotis, MD, chief medical officer of Radiopharm Theranostics, stated in a press release.2
Also, commenting in the press release, David Piwnica-Worms, MD, PhD, professor, MD Anderson Cancer Center, and scientific co-founder of Radiopharm Ventures, stated, “The high affinity and selectivity of RV-01 for the 4Ig isoform of B7H3 allows the antibody to bypass the soluble 2Ig isoform in the blood, boost binding of the radiopharmaceutical to tumor targets and avoid the formation of immune complexes in circulation.”2