Cortés, Javier, Priego, Araceli, Garralda, Elena, Rojas, Katerin, Lord, Simon R., Goetze, Thorsten O., Kuemmel, Sherko, Crabb, Simon J., Parra-Guillen, Zinnia P., Borggren, Marie, Karlsson, Ingrid, Lindahl, Danijela, Mårtensson, Linda, Oldham, Robert, Ropenga, Anna, Teige, Ingrid, Wallin, Johan, Frendeus, Björn and McAllister, Andres (2025) A First-in-Class mAb (BI-1607) Targeting FcγRIIB: preclinical data and first-in-human studies in patients with HER2-positive advanced solid tumors. Clinical Cancer Research, 31 (23), 4953-4963. (doi:10.1158/1078-0432.CCR-25-1348).
Abstract
Purpose: BI-1607 is a human mAb that specifically blocks FcγRIIB, the sole inhibitory Fc receptor and master regulator of humoral and innate immune homeostasis. These studies evaluated preclinical antitumor activity using a BI-1607 murine surrogate (mBI-1607) and the safety, tolerability, pharmacokinetics, and pharmacodynamics of the compound in combination with trastuzumab in patients with HER2-positive advanced solid tumors (NCT05555251).
Patients and methods: immunocompetent syngeneic mouse breast tumor (TUBO) and melanoma (B16-F10) models were used to evaluate in vivo antitumor activity in combination (anti-HER2 and anti-gp75). Ascending doses of BI-1607 administered intravenously every 3 weeks in combination with trastuzumab were evaluated in 18 patients with HER2-positive cancer. The primary objective was to assess the safety and tolerability of BI-1607 by determining dose-limiting toxicities and the maximum tolerated dose or maximum administered dose and identifying a recommended phase 2 dose.
Results: mBI-1607 enhanced tumor-targeting antibody efficacy and animal survival. BI-1607/trastuzumab was well tolerated, with dose-limiting toxicity (rash) in one patient (5.6%) at 900 mg; the maximum tolerated dose was not reached. Treatment-emergent adverse events grade ≥3 occurred in five patients (28%), including exanthema, increase in liver enzymes, urticaria, acute kidney injury, and aggravated condition. Overall best response was stable disease, observed in seven of the nine evaluable patients (78%). BI-1607 exhibits linear pharmacokinetics for doses above 500 mg, and full receptor saturation was observed throughout the 21 days at 700 mg. No antidrug antibodies were observed.
Conclusions: the enhancing effect on tumor direct-targeting antibodies observed preclinically, together with the favorable safety profile in patients, supports further investigation of BI-1607.
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