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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
- Source :
- Molecular Genetics and Metabolism Reports, Vol 27, Iss, Pp 100758-(2021), Molecular Genetics and Metabolism Reports
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 22144269
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism Reports
- Accession number :
- edsair.doi.dedup.....f0bad9d33274408b77250340e21baeff