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

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2026-07-15 DOI:10.1007/s11307-026-02124-6

Saba Shirin, Syed Qaiser Shah, Ralph Santos-Oliveira

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引用次数: 0

Abstract

Purpose: 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.

Procedure: 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.

Results: 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 (K_d = 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.

Conclusions: [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.

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使用[225Ac]Ac-Macropa-Rozanolixizumab进行fcrn靶向α治疗具有有效的抗肿瘤活性

目的：FcRn在多种血液学和实体癌中的过度表达使其成为单克隆抗体的一个有希望的靶点，尽管它在健康组织中的存在需要适当的毒性评估。在这里，我们报告了[225Ac]Ac-Macropa-rozanolixizumab的临床前开发和评估，这是一种概念验证的fcrn靶向α-放射免疫治疗药物。程序：采用基于链间二硫重新桥接的位点特异性方法，通过PEG4连接剂将rozanolizumab与Macropa偶联，并用锕-225在温和的水条件下进行放射性标记。体外评估FcRn结合、免疫反应性和细胞毒性。单次给药后，研究了CHO-FcRn异种移植小鼠的生物分布、剂量学和抗肿瘤活性。结果：偶联产物均质（螯合剂-抗体比3.3±0.2；单体> 96%）。在偶联和放射标记后，FcRn结合保持不变，尽管亲和力相对于天然rozanolizumab降低（Kd = 3.77±0.86 nM）。免疫反应率为82.4±3.1%。放射标记效率为98.9±0.8%，168 h血清稳定性超过94%。体外证实受体依赖性细胞毒性（在fcrn阳性细胞中IC50 = 4.86±0.4 kBq/mL），在fcrn阴性对照中影响最小。48 h时，肿瘤摄取量达到20.3±1.9%ID/g，骨骼摄取量较低。吸收剂量比为4.82/0.28 Gy/MBq（肿瘤/骨髓；比值17.2）。结论：[225Ac]Ac-Macropa-rozanolixizumab在概念验证异种移植模型中显示出fcrn特异性α-颗粒细胞毒性和良好的剂量学特性。这些发现支持FcRn作为放射免疫治疗的潜在靶点。需要进一步的研究来评估毒性、内源性IgG竞争和翻译适用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.