A First-in-Class mAb (BI-1607) Targeting FcγRIIB: Preclinical Data and First-in-Human Studies in Patients with HER2-Positive Advanced Solid Tumors.

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.