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Article: IgG Fusion Proteins for Brain Delivery of Biologics via Blood-Brain Barrier Receptor-Mediated Transport.

Boado, Ruben J

2022 Volume 14, Issue 7

Abstract: The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood-brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and ...

Abstract	The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood-brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and monoclonal antibodies (MAb), do not cross the BBB. These biotherapeutics can be re-engineered as brain-penetrating bifunctional IgG fusion proteins. These recombinant proteins comprise two domains, the transport domain and the therapeutic domain, respectively. The transport domain is an MAb that acts as a molecular Trojan horse by targeting a BBB-specific endogenous receptor that induces receptor-mediated transcytosis into the brain, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The therapeutic domain of the IgG fusion protein exerts its pharmacological effect in the brain once across the BBB. A generation of bifunctional IgG fusion proteins has been engineered using genetically engineered MAbs directed to either the BBB HIR or TfR as the transport domain. These IgG fusion proteins were validated in animal models of lysosomal storage disorders; acute brain conditions, such as stroke; or chronic neurodegeneration, such as Parkinson's disease and Alzheimer's disease. Human phase I-III clinical trials were also completed for Hurler MPSI and Hunter MPSII using brain-penetrating IgG-iduronidase and -iduronate-2-sulfatase fusion protein, respectively.
Language	English
Publishing date	2022-07-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14071476
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Article ; Online: Antisense drug delivery through the blood-brain barrier.

Boado, Ruben J

Advanced drug delivery reviews

2022 Volume 15, Issue 1-3, Page(s) 73–107

Abstract: The blood-brain barrier evolved to protect the brain against peripheral neurotransmitters, cytotoxins and microorganisms. This barrier prevents the delivery to brain of antisense oligomers and other potential therapeutics for the treatment of viral ... ...

Abstract	The blood-brain barrier evolved to protect the brain against peripheral neurotransmitters, cytotoxins and microorganisms. This barrier prevents the delivery to brain of antisense oligomers and other potential therapeutics for the treatment of viral infections, tumors, and other brain disorders. The brain represents a shelter for the human immunodeficiency virus (HIV), for low grade gliomas, and early stages of metastatic tumors to the brain. Non-invasive delivery systems for antisense oligodeoxynucleotide (ODN) therapeutics have been developed that include transcellular avidin-based delivery systems, such as conjugates of avidin analogues and the monoclonal antibody directed to the transferrin receptor (OX26), which targets all tissues expressing these receptors including the blood-brain barrier and liver. Although 3'-biotinylation of phosphodiester oligodeoxynucleotides provides complete protection against serum and cellular exonuclease-mediated degradation, the in vivo administration of unconjugated or vector-conjugated biotinylated PO-ODN results in a rapid degradation through an endonucleasemediated mechanism, thus limiting the efficacy of this potential therapeutic for the brain. This rapid in vivo degradation also occurs with phosphorothioate-ODN containing a single internal phosphodiester bond. Alternatively, a biotinylated peptide nucleic acid (PNA) conjugated to the OX26-streptavidin delivery system is metabolically stable in vivo and is transported to brain through the blood-brain barrier at a rate 28-fold higher than the oligomer alone. This results in a brain uptake comparable to that of morphine, a molecule well known for its pharmacological brain effects. In summary, this review discusses different approaches for delivery of antisense oligonucleotides to the brain and suggests that biotinylated PNA conjugated to avidin-based transcellular delivery system represents a model for the delivery of antisense therapeutics through the blood-brain barrier.
Language	English
Publishing date	2022-02-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
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Article: Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme.

Hahn, Andreas / Sato, Yuji / Ikeda, Toshiaki / Sonoda, Hiroyuki / Schmidt, Mathias / Pfrimmer, Charlotte / Boado, Ruben J / Pardridge, William M

Molecular genetics and metabolism reports

2022 Volume 33, Page(s) 100930

Abstract: Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1( ...

Abstract	Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1(
Language	English
Publishing date	2022-10-26
Publishing country	United States
Document type	Case Reports
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2022.100930
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Article ; Online: Brain and Organ Uptake in the Rhesus Monkey in Vivo of Recombinant Iduronidase Compared to an Insulin Receptor Antibody-Iduronidase Fusion Protein.

Boado, Ruben J / Pardridge, William M

Molecular pharmaceutics

2017 Volume 14, Issue 4, Page(s) 1271–1277

Abstract: Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-l-iduronidase (IDUA), and patients with MPSI are currently treated with IDUA enzyme replacement therapy (ERT). However, the majority of MPSI patients ... ...

Abstract	Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-l-iduronidase (IDUA), and patients with MPSI are currently treated with IDUA enzyme replacement therapy (ERT). However, the majority of MPSI patients have severe CNS involvement, and conventional ERT does not treat the brain. The failure of ERT to treat the brain is believed to be due to the lack of IDUA transport through the blood-brain barrier (BBB). However, BBB transport of IDUA has not been directly measured, to date. BBB transport of IDUA may be enhanced by fusion of the enzyme to a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb binds the insulin receptor on the BBB to trigger transport into the brain and acts as a molecular Trojan horse to deliver IDUA to brain cells. Therefore, the purpose of the present investigation was to compare, side-by-side, the BBB transport of IDUA alone and the HIRMAb-IDUA fusion protein in the Rhesus monkey in vivo. Each protein was radio-iodinated by conjugation with the [
MeSH term(s)	Animals ; Antibodies, Monoclonal/metabolism ; Antigens, CD/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Humans ; Iduronidase/metabolism ; Macaca mulatta ; Mucopolysaccharidosis I/metabolism ; Receptor, IGF Type 2/metabolism ; Receptor, Insulin/metabolism ; Recombinant Fusion Proteins/metabolism ; Succinimides/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, CD ; Receptor, IGF Type 2 ; Recombinant Fusion Proteins ; Succinimides ; Bolton-Hunter reagent (65114-37-6) ; INSR protein, human (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1) ; Iduronidase (EC 3.2.1.76)
Language	English
Publishing date	2017-03-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.6b01166
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Article ; Online: Plasma Pharmacokinetics of High-Affinity Transferrin Receptor Antibody-Erythropoietin Fusion Protein is a Function of Effector Attenuation in Mice.

Sun, Jiahong / Boado, Ruben J / Pardridge, William M / Sumbria, Rachita K

Molecular pharmaceutics

2019 Volume 16, Issue 8, Page(s) 3534–3543

Abstract: Erythropoietin (EPO) is a potential therapeutic for Alzheimer's disease (AD); however, limited blood-brain barrier (BBB) penetration reduces its applicability as a CNS therapeutic. Antibodies against the BBB transferrin receptor (TfRMAbs) act as ... ...

Abstract	Erythropoietin (EPO) is a potential therapeutic for Alzheimer's disease (AD); however, limited blood-brain barrier (BBB) penetration reduces its applicability as a CNS therapeutic. Antibodies against the BBB transferrin receptor (TfRMAbs) act as molecular Trojan horses for brain drug delivery, and a fusion protein of EPO and TfRMAb, designated TfRMAb-EPO, is protective in a mouse model of AD. TfRMAbs have Fc effector function side effects, and removal of the Fc N-linked glycosylation site by substituting Asn with Gly reduces the Fc effector function. However, the effect of such Fc mutations on the pharmacokinetics (PK) of plasma clearance of TfRMAb-based fusion proteins, such as TfRMAb-EPO, is unknown. To examine this, the plasma PK of TfRMAb-EPO (wild-type), which expresses the mouse IgG1 constant heavy chain region and includes the Asn residue at position 292, was compared to the mutant TfRMAb-N292G-EPO, in which the Asn residue at position 292 is mutated to Gly. Plasma PK was compared following IV, IP, and SQ administration for doses between 0.3 and 3 mg/kg in adult male C57 mice. The results show a profound increase in clearance (6- to 8-fold) of the TfRMAb-N292G-EPO compared with the wild-type TfRMAb-EPO following IV administration. The clearance of both the wild-type and mutant TfRMAb-EPO fusion proteins followed nonlinear PK, and a 10-fold increase in dose resulted in a 7- to 11-fold decrease in plasma clearance. Following IP and SQ administration, the
MeSH term(s)	Alzheimer Disease/drug therapy ; Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacokinetics ; Blood-Brain Barrier/cytology ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Cell Line ; Endothelial Cells ; Erythropoietin/administration & dosage ; Erythropoietin/genetics ; Erythropoietin/pharmacokinetics ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/genetics ; Immunoconjugates/immunology ; Immunoconjugates/pharmacokinetics ; Immunoglobulin Constant Regions/administration & dosage ; Immunoglobulin Constant Regions/genetics ; Immunoglobulin Constant Regions/immunology ; Immunoglobulin G/administration & dosage ; Immunoglobulin G/genetics ; Immunoglobulin G/immunology ; Injections, Intravenous ; Injections, Subcutaneous ; Male ; Mice ; Mutation ; Receptors, Transferrin/antagonists & inhibitors ; Receptors, Transferrin/immunology ; Receptors, Transferrin/metabolism ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/pharmacokinetics ; Reticulocytes/drug effects
Chemical Substances	Antibodies, Monoclonal ; EPO protein, human ; Immunoconjugates ; Immunoglobulin Constant Regions ; Immunoglobulin G ; Receptors, Transferrin ; Recombinant Fusion Proteins ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2019-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.9b00369
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Article ; Online: Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme

Andreas Hahn / Yuji Sato / Toshiaki Ikeda / Hiroyuki Sonoda / Mathias Schmidt / Charlotte Pfrimmer / Ruben J. Boado / William M. Pardridge

Molecular Genetics and Metabolism Reports, Vol 33, Iss , Pp 100930- (2022)

2022

Abstract: Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1(PPT1), leading to accumulation of lipofuscin granules in brain and progressive ... ...

Abstract	Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1(PPT1), leading to accumulation of lipofuscin granules in brain and progressive neurodegeneration. Psychomotor regression, seizures, loss of vision, and movement disorder begin in infancy and result in early death. Currently, no disease-modifying therapy is available.We report a 68-month-old boy with CLN1 treated on a compassionate use basis weekly for 26 months with a PPT1 enzyme fused to an anti-insulin receptor antibody (AGT-194), thereby enabling penetration of the blood-brain barrier (BBB). During treatment, no side effects were observed, while seizure frequency decreased, life quality improved, and the boy's general condition remained stable.This case documents for the first time that treatment of CLN1 is principally feasible by an intravenous BBB penetrating enzyme replacement therapy using PPT1 fused with the human insulin receptor. Monitoring of side effects raised no unacceptable or unexpected safety concerns.Observed improvement of life quality related to ameliorated epilepsy control raises hope that further robust clinical trials including patients in earlier stages of disease will show positive results.
Keywords	Neuronal ceroid lipofuscinosis type 1 ; CLN1 disease ; Enzyme replacement therapy ; PPT1 ; Blood-brain barrier ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610 ; 616
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery.

Boado, Ruben J

Drug news & perspectives

2008 Volume 21, Issue 9, Page(s) 489–503

Abstract: A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's ... ...

Abstract	A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease and inherited mucopolysaccharidosis. These biotherapeutics are engineered i) to cross the blood-brain barrier (BBB) following i.v. administration and ii) to produce a brain therapeutic effect. These fusion proteins are comprised of both a transport and a therapeutic domain. The transport domain is a monoclonal antibody (MAb) directed to an exofacial epitope of the BBB human insulin receptor (HIR), which uses the BBB endogenous insulin transport system to gain access to the brain via receptor-mediated transcytosis without interfering with the normal transport of insulin. Both human-chimeric and fully humanized versions of the anti-human HIRMAb have already been produced. The therapeutic domain of these fusion proteins consists of the peptide or protein of interest fused to the carboxyl terminus of the C(H)3 region of the heavy chain of the anti-human HIRMAb. A variety of HIRMAb fusion proteins were engineered aiming at the development of therapeutics for the central nervous system (CNS), i.e., stroke and Parkinson's disease, as in the case of HIRMAb-BDNF and HIRMAb-GDNF, respectively, HIRMAb-IDUA for the treatment of Hurler's disease, HIRMAb-A beta single chain antibody for passive immunotherapy of Alzheimer's disease, and HIRMAb-avidin as delivery system for biotinylated drugs, like siRNAs. The multifunctionality of these fusion proteins has been validated in preclinical work, including brain update in primates. Pending further development into pharmacological and toxicological studies, and clinical trials, members of the biotherapeutic family discussed in the present review, designed to overcome the brain drug delivery hurdle, are positioned to become a new generation of neuropharmaceutical drugs for the treatment of human CNS disorders.
MeSH term(s)	Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Brain Diseases/drug therapy ; Brain Diseases/metabolism ; Humans ; Protein Engineering/methods ; Receptor, Insulin/immunology ; Receptor, Insulin/metabolism ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism
Chemical Substances	Antibodies, Monoclonal ; Recombinant Fusion Proteins ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2008-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	885125-6
ISSN	2013-0139 ; 0214-0934
ISSN (online)	2013-0139
ISSN	0214-0934
DOI	10.1358/dnp.2008.21.9.1290820
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Zs.A 2393: Show issues

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Article ; Online: Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I.

Pardridge, William M / Boado, Ruben J / Giugliani, Roberto / Schmidt, Mathias

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

2018 Volume 32, Issue 2, Page(s) 169–176

Abstract: Background: Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy ( ... ...

Abstract	Background: Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood-brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. Methods: The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. Results: Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3-3 mg/kg with a stable plasma elimination half-life (t Conclusion: The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1-3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1-3 mg/kg, is comparable to that of laronidase in children with MPSI.
MeSH term(s)	Adolescent ; Adult ; Antibodies, Monoclonal/blood ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/therapeutic use ; Area Under Curve ; Child ; Child, Preschool ; Female ; Humans ; Iduronidase/blood ; Iduronidase/genetics ; Iduronidase/pharmacokinetics ; Iduronidase/therapeutic use ; Male ; Mucopolysaccharidosis I/blood ; Mucopolysaccharidosis I/drug therapy ; Receptor, Insulin/genetics ; Recombinant Fusion Proteins/blood ; Recombinant Fusion Proteins/pharmacokinetics ; Recombinant Fusion Proteins/therapeutic use
Chemical Substances	AGT-181 ; Antibodies, Monoclonal ; Recombinant Fusion Proteins ; Receptor, Insulin (EC 2.7.10.1) ; Iduronidase (EC 3.2.1.76)
Language	English
Publishing date	2018-02-13
Publishing country	New Zealand
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	1364202-9
ISSN	1179-190X ; 1173-8804
ISSN (online)	1179-190X
ISSN	1173-8804
DOI	10.1007/s40259-018-0264-7
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Zs.A 4112: Show issues

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Article: Blood-brain barrier transport of non-viral gene and RNAi therapeutics.

Boado, Ruben J

Pharmaceutical research

2007 Volume 24, Issue 9, Page(s) 1772–1787

Abstract: The development of gene- and RNA interference (RNAi)-based therapeutics represents a challenge for the drug delivery field. The global brain distribution of DNA genes, as well as the targeting of specific regions of the brain, is even more complicated ... ...

Abstract	The development of gene- and RNA interference (RNAi)-based therapeutics represents a challenge for the drug delivery field. The global brain distribution of DNA genes, as well as the targeting of specific regions of the brain, is even more complicated because conventional delivery systems, i.e. viruses, have poor diffusion in brain when injected in situ and do not cross the blood-brain barrier (BBB), which is only permeable to lipophilic molecules of less than 400 Da. Recent advances in the "Trojan Horse Liposome" (THL) technology applied to the transvascular non-viral gene therapy of brain disorders presents a promising solution to the DNA/RNAi delivery obstacle. The THL is comprised of immunoliposomes carrying either a gene for protein replacement or small hairpin RNA (shRNA) expression plasmids for RNAi effect, respectively. The THL is engineered with known lipids containing polyethyleneglycol (PEG), which stabilizes its structure in vivo in circulation. The tissue target specificity of THL is given by conjugation of approximately 1% of the PEG residues to peptidomimetic monoclonal antibodies (MAb) that bind to specific endogenous receptors (i.e. insulin and transferrin receptors) located on both the BBB and the brain cellular membranes, respectively. These MAbs mediate (a) receptor-mediated transcytosis of the THL complex through the BBB, (b) endocytosis into brain cells and (c) transport to the brain cell nuclear compartment. The present review presents an overview of the THL technology and its current application to gene therapy and RNAi, including experimental models of Parkinson's disease and brain tumors.
MeSH term(s)	Animals ; Biological Transport ; Blood-Brain Barrier ; Brain/metabolism ; Gene Transfer Techniques ; Genes, Reporter ; Genetic Therapy/methods ; Humans ; Liposomes ; RNA Interference ; RNA, Small Interfering/genetics
Chemical Substances	Liposomes ; RNA, Small Interfering
Language	English
Publishing date	2007-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-007-9321-5
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Zs.A 1937: Show issues

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Article ; Online: Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery.

Boado, Ruben J / Lu, Jeff Zhiqiang / Hui, Eric Ka-Wai / Lin, Huilan / Pardridge, William M

Scientific reports

2019 Volume 9, Issue 1, Page(s) 18632

Abstract: Most lysosomal storage disorders affect the central nervous system. However, lysosomal enzymes do not cross the blood-brain barrier (BBB), and intravenous enzyme infusion is not effective for the brain. Lysosomal enzymes can be re-engineered for BBB ... ...

Abstract	Most lysosomal storage disorders affect the central nervous system. However, lysosomal enzymes do not cross the blood-brain barrier (BBB), and intravenous enzyme infusion is not effective for the brain. Lysosomal enzymes can be re-engineered for BBB transport as IgG-enzyme fusion proteins, where the IgG domain is a monoclonal antibody (MAb) against an endogenous BBB receptor/transporter, and which acts as a molecular Trojan horse to deliver the enzyme to brain. However, the problem is retention of high enzyme activity following enzyme fusion to the IgG. The present investigation shows this is possible with a versatile approach that employs fusion of the enzyme to either the IgG heavy chain or light chain using a long flexible linker. The model IgG is a chimeric monoclonal antibody (MAb) against the human insulin receptor (HIR). The enzyme activity of the HIRMAb-enzyme fusion protein is preserved for hexosaminidase A, which is mutated in Tay Sachs disease, for protein palmitoylthioesterase-1, which is mutated in Batten disease type 1, acid sphingomyelinase, which is mutated in Niemann Pick disease type A, and beta galactosidase-1, which is mutated in GM1 gangliosidosis.
MeSH term(s)	Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Biological Transport/drug effects ; Blood-Brain Barrier/drug effects ; Brain/drug effects ; Drug Delivery Systems ; Humans ; Immunoglobulin G/chemistry ; Immunoglobulin G/pharmacology ; Lysosomes/chemistry ; Protein Engineering
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin G
Language	English
Publishing date	2019-12-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-55136-4
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