Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody

• Published in: Leukemia Vol. 37; no. 6; pp. 1349 - 1360
• Main Authors: Raab, Marc S., Cohen, Yael C., Schjesvold, Fredrik, Aardalen, Kimberly, Oka, Adwait, Spencer, Andrew, Wermke, Martin, Souza, Anita D., Kaufman, Jonathan L., Cafro, Anna Maria, Ocio, Enrique M., Doki, Noriko, Henson, Kristin, Trabucco, Gina, Carrion, Ana, Bender, Florent C., Juif, Pierre-Eric, Fessehatsion, Adonai, Fan, Liqiong, Stonehouse, Jeffrey P., Blankenship, John W., Granda, Brian, De Vita, Serena, Lu, Haihui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2023; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/21; 13/31; 59; 59/5; 64; 64/60; 692/308/153; 692/308/575; 82; 82/1; Antibodies; Antigens; Bispecific antibodies; Cancer Research; CD3 antigen; Cell activation; Chimeric antigen receptors; Critical Care Medicine; Dosage; Drug dosages; Hematology; Intensive; Internal Medicine; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Medicine & Public Health; Multiple myeloma; Oncology; Plasma cells; Response rates
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-023-01883-3

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48–250 µg/kg tested to date (
n
 = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6–56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2–27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.