1. Nonclinical safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II
- Author
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Tohru Hirato, Kohtaro Minami, Masafumi Kinoshita, Eiji Yoden, Atsushi Imakiire, Ryuji Yamamoto, and Noboru Tanaka
- Subjects
Medicine (General) ,Complement-dependent cytotoxicity ,MPS II, mucopolysaccharidosis type II ,MCHC, mean corpuscular hemoglobin concentration ,Pharmacology ,GAG, glycosaminoglycan ,CSF, cerebrospinal fluid ,Endocrinology ,QWBA, quantitative whole-body autoradioluminography ,Effector function ,pAb, polyclonal antibody ,Antibody-dependent cellular cytotoxicity ,Mucopolysaccharidosis type II ,Biology (General) ,TK, toxicokinetics ,chemistry.chemical_classification ,Antibody-dependent cell-mediated cytotoxicity ,Hunter syndrome ,RBC, red blood cell ,Ret, reticulocyte ,Toxicity ,ADA, anti-drug antibody ,Research Paper ,BBB, blood-brain barrier ,QH301-705.5 ,MCH, mean corpuscular hemoglobin ,IDS, iduronate-2-sulfatase ,NOAEL, no observed adverse effect level ,Transferrin receptor ,TfR, transferrin receptor ,CNS, central nervous system ,Ht, hematocrit ,R5-920 ,ERT, enzyme-replacement therapy ,Tf, transferrin ,Genetics ,medicine ,mAb, monoclonal antibody ,CDC, complement-dependent cytotoxicity ,Molecular Biology ,FOB, functional observational battery ,ADCC, antibody-dependent cellular cytotoxicity ,business.industry ,Iduronate-2-sulfatase ,medicine.disease ,Anti-transferrin receptor antibody ,chemistry ,Transferrin ,Fc, fragment crystalizable ,business ,Hb, hemoglobin - Abstract
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.
- Published
- 2021