Additional Text

Gene Name

INSR

Uniprot ID

P06213

Gene ID

3643

Purification

Purified

Antibody Clonality

Recombinant Monoclonal

Storage Note

Store at 4⁰C for up to 3 months. Note, this antibody is provided without added preservatives, it is therefore recommed this antibody be handled under sterile conditions. For longer storage, aliquot and store at -20⁰C.

Short Description

This chimeric mouse antibody was made using the variable domain sequences of the original Human IgG1 format, for improved compatibility with existing reagents, assays and techniques.

Application Notes

This humanized antibody clone, optimized for minimal immunogenicity in humans while retaining binding affinity to its target receptor, utilizes the BBB's endogenous insulin transport system to access the brain via receptor-mediated transcytosis without disrupting normal insulin transport (Boado, 2008; PMID: 19180267). This antibody was used to investigate binding and transport across the BBB and its application in enzyme replacement therapy for brain diseases (US7388079B2). Avid binding to human brain capillaries in vitro, comparable to the murine form, was demonstrated via a radioreceptor assay. It also crossed the Rhesus monkey's BBB in vivo, specifically accumulating in areas of higher vascular density. Additionally, the light chain's role in binding to the human insulin receptor was explored, revealing that variations in the light chain sequence minimally affect binding affinity, as tested in an ELISA, indicating flexibility in light chain design for humanized antibodies (US7388079B2, Boado et al., 2007; PMID: 16937408). Furthermore, the antibody was fused with α-L-iduronidase (IDUA) and tested in an in vitro mammalian cell system to facilitate enzyme delivery for treating Hurler syndrome, showing promising results (Boado et al., 2007; PMID: 16937408, Boado et al., 2008; PMID: 17680664). Moreover, this antibody has successfully transported other enzymes across the BBB, such as Iduronate 2-sulfatase (IDS) (Boado et al., 2014; PMID: 24889100) and N-sulfoglucosamine sulfohydrolase (SGSH/sulfamidase) (Boado et al., 2014; PMID: 24949884), in in vivo Rhesus monkey models. Expanding on the SGSH enzyme fusion, the fusion antibody-enzyme construct retained high-affinity binding to the human insulin receptor and preserved 85% of the enzyme's activity compared to recombinant SGSH by fusing the enzyme to the carboxyl terminus of the antibody's heavy chain. The fusion protein was pharmacologically active in MPSIIIA fibroblasts, reducing lysosomal glycosaminoglycans (GAGs) by 72-83% and efficiently localizing to the lysosomal compartment, as confirmed by confocal microscopy. In Rhesus monkeys, the fusion protein crossed the BBB with approximately 1% of the injected dose per 100 g brain tissue, distributing into the brain parenchyma as demonstrated by capillary depletion and autoradiography. After intravenous administration, brain enzyme activity was predicted to match or exceed endogenous SGSH levels, indicating effective CNS delivery. Despite rapid plasma clearance due to peripheral tissue uptake, the fusion protein maintained a brain residence half-life of 16 hours, with lysosomal sequestration extending its functional activity to 3 days (Boado et al., 2014; PMID: 24949884). The previously mentioned HIRMAb-IDUA fusion antibody has demonstrated positive outcomes in clinical studies (Pardridge et al., 2018; PMID: 29442294). This antibody was used as part of antibody-enzyme fusion constructs to enable the delivery of therapeutic enzymes across the human BBB