FcRn-Targeted Alpha Therapy Using [²²⁵Ac]Ac-Macropa-Rozanolixizumab Enables Potent Antitumor Activity.

Abstract

Overexpression of FcRn in multiple hematologic and solid cancers makes it a promising target for monoclonal antibodies, though its presence in healthy tissue calls for proper assessment of toxicity. Here, we report the preclinical development and evaluation of [225Ac]Ac-Macropa-rozanolixizumab, a proof-of-concept FcRn-targeted α-radioimmunotherapeutic. Using a site-specific approach based on interchain disulfide re-bridging, rozanolixizumab was conjugated with Macropa by a PEG4 linker and radiolabeled with actinium-225 in mild aqueous conditions. FcRn binding, immunoreactivity and cytotoxicity were assessed in vitro. Following a single dose administration, biodistribution, dosimetry, and antitumor activity were studied in CHO-FcRn xenograft-bearing mice. Conjugation produced a homogeneous product (chelator-to-antibody ratio 3.3 ± 0.2; > 96% monomer). FcRn binding was retained following conjugation and radiolabeling, although affinity was reduced relative to native rozanolixizumab (Kd = 3.77 ± 0.86 nM). The immunoreactive fraction was 82.4 ± 3.1%. Radiolabeling efficiency was 98.9 ± 0.8% and serum stability exceeded 94% at 168 h. Receptor-dependent cytotoxicity was confirmed in vitro (IC50 = 4.86 ± 0.4 kBq/mL in FcRn-positive cells), with minimal effect in FcRn-negative controls. Tumor uptake peaked at 20.3 ± 1.9%ID/g at 48 h with low skeletal uptake. Absorbed dose ratios were 4.82/0.28 Gy/MBq (tumor/bone marrow; ratio 17.2). A single treatment produced significant survival benefit (log-rank P < 0.001), dose-dependent tumor control, and transient, self-limiting body weight changes. [225Ac]Ac-Macropa-rozanolixizumab demonstrated FcRn-specific α-particle cytotoxicity and favorable dosimetric properties in a proof-of-concept xenograft model. These findings support FcRn as a potential target for radioimmunotherapy. Further studies are required to evaluate toxicity, endogenous IgG competition and translational applicability.