Pabinafusp alfa is a fusion protein comprising a humanized anti-human transferrin receptor (TfR) antibody and human iduronate-2-sulfatase. It was developed as a novel modality to target central nervous system-related symptoms observed in patients with mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome). As the fusion protein contains an entire IgG1 molecule that binds TfR, there may be specific safety concerns, such as unexpected cellular toxicity due to its effector functions or its ability to inhibit iron metabolism, in addition to general safety concerns. Here, we present the comprehensive results of a nonclinical safety assessment of pabinafusp alfa. Pabinafusp alfa did not exhibit effector functions, as assessed by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity studies in TfR-expressing hematopoietic cells. Repeat-dose toxicity studies in cynomolgus monkeys showed that pabinafusp alfa did not induce any significant toxicological changes at doses up to 30 mg/kg/week upon intravenous administration for up to 26 weeks. Interaction of transferrin with TfR was not inhibited by pabinafusp alfa, suggesting that the effect of pabinafusp alfa on the physiological iron transport system is minimal, which was confirmed by toxicity studies in cynomolgus monkeys. These findings suggest that pabinafusp alfa is expected to be safe for long-term use in individuals with MPS II.

Pabinafusp alfa是一种融合蛋白，包含人源化抗人转铁蛋白受体（TfR）抗体和人异氰酸酯-2-硫酸酯酶。它被开发为针对在II型粘多糖贮积症（MPS II，也称为Hunter综合征）患者中观察到的中枢神经系统相关症状的新型治疗手段。由于融合蛋白包含与TfR结合的完整IgG1分子，因此除一般安全性问题外，可能还存在特定的安全性问题，例如由于其效应子功能或抑制铁代谢的能力而导致的意外细胞毒性。在这里，我们介绍了pabinafusp alfa的非临床安全性评估的综合结果。Pabinafusp alfa没有显示效应子功能，如在表达TfR的造血细胞中通过抗体依赖性细胞毒性和补体依赖性细胞毒性研究评估。对食蟹猴的重复剂量毒性研究表明，在长达26周的静脉内给药剂量下，高达30 mg / kg /周的剂量，pabinafusp alfa不会引起任何明显的毒理学变化。Pabinafusp alfa并未抑制转铁蛋白与TfR的相互作用，这表明Pabinafusp alfa对生理性铁转运系统的影响微乎其微，这在食蟹猴的毒性研究中得到了证实。这些发现表明，pabinafusp alfa有望在MPS II患者中长期使用是安全的。对食蟹猴的重复剂量毒性研究表明，在长达26周的静脉内给药剂量下，高达30 mg / kg /周的剂量，pabinafusp alfa不会引起任何明显的毒理学变化。Pabinafusp alfa并未抑制转铁蛋白与TfR的相互作用，这表明Pabinafusp alfa对生理性铁转运系统的影响微乎其微，这在食蟹猴的毒性研究中得到了证实。这些发现表明，pabinafusp alfa有望在MPS II患者中长期使用是安全的。对食蟹猴的重复剂量毒性研究表明，在长达26周的静脉内给药剂量下，高达30 mg / kg /周的剂量，pabinafusp alfa不会引起任何明显的毒理学变化。Pabinafusp alfa并未抑制转铁蛋白与TfR的相互作用，这表明Pabinafusp alfa对生理性铁转运系统的影响微乎其微，这在食蟹猴的毒性研究中得到了证实。这些发现表明，pabinafusp alfa有望在MPS II患者中长期使用是安全的。食蟹猴的毒性研究证实了这一点。这些发现表明，pabinafusp alfa有望在MPS II患者中长期使用是安全的。食蟹猴的毒性研究证实了这一点。这些发现表明，pabinafusp alfa有望在MPS II患者中长期使用是安全的。