Insulin receptor antibodies

With regard to transport capacity, the introduction of the anti-human insulin receptor antibody (HIR MAb) 83-14 as a vector indicates the potential for future improvements in brain-specific delivery vectors. Compared to anti-TfR monoclonal antibodies, the brain de-hvery in primates is over 7-fold higher due to the high PS product of the HIR MAb. 

Kim CH, Park JH, Park TS, Baek HS. Autoimmune hypoglycemia in a type 2 diabetic patient with anti-insulin and insulin receptor antibodies. Diabetes Care 2004 27 228-9. 

A number of disorders are associated with the development of insulin resistance. Although some cases are due to autoimmune responses such as the development of anti-insulin or anti-insulin receptor antibodies, insulin resistance often results from defects at the cellular level in the insulin receptor or in postreceptor function. 

Uncommon forms of immune-mediated diabetes "Stiff-man" syndrome Anti-insulin receptor antibodies Others... 

Petruzzelli L, Herrera R, Arenas-Garcia R, Fernandez R, Bimbaum MJ, Rosen OM 1986 Isolation of a Drosophila genomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylated Drosophila receptor with an anti-peptide antibody. Proc Natl Acad Sci USA 83 4710-4714 Podskalny J, McElduff A, Gorden P 1984 Insulin receptors on Chinese hamster ovary (CHO) cells altered insulin binding to glycosylation mutants. Biochem Biophys Res Commun 125 70-75... 

Figure 2.8. Scheme of a chimeric peptide with examples for each of the distinct domains. 0X26, anti-rat transferrin receptor monoclonal antibody (mAh) 84-15, anti-human insulin receptor mAh cHSA, cationized human serum albumin VIP, vasoactive intestinal polypeptide DALDA, dermorphin analogue NGF, nerve growth factor BDNF, brain-derived neurotrophic factor PNA, peptide nucleic acid (3-gal, (3-galactosidase. 

Recombinant human IGF-I is used as an adjunct to insulin therapy in patients with large daily variations in insulin effect. It is sometimes given in insulin resistance syndromes caused by changes in the insulin receptor or in type B insulin resistance syndrome caused by antibodies to the insulin receptor. 

Coloma, M.J., et al. 2000. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Pharm Res 17 266. 

Vanadate stimulates protein kinases in the cytosol, as demonstrated in adipose cells and extracts. The activation of a membrane and cytosolic protein tyrosine kinase have been demonstrated in adipocytes, and the membranous enzyme has been postulated to be a way to involve PI-3K actions without activation of insulin receptor substrate-1 (IRS-1) in the insulin signal transduction pathway [140], It is always difficult to determine if protein kinase activation is direct or the result of stimulation of a protein phosphatase. The fact that kinase stimulation was seen in isolated extracts after cell disintegration in this adipocyte cell system supports the idea that vanadium addition to cells could directly stimulate kinases via an as-yet-undetermined mechanism. In other experiments with 3T3-L1 adipocytes bis(acetylacetonato)oxovana-dium (IV) BMOV and bis(l-N-oxide-pyridine-2thiolato)oxovanadium (TV) caused increased tyrosine phosphorylation of both the insulin receptor and IRS-1 in a synergistic way with insulin, as measured by antibodies to phosphotyrosine residues [141]. 

Substances also may be attached covalently to proteins for transporting the substances to targets in the body. Examples of this approach have been transporting radioactive iodine or toxic substances attached to antibodies in attempts to kill cancer cells and attaching radioactive metals to proteins and bleomycin for similar purposes (122). A recent novel approach has been that of Wu and Means (123) who have attached insulin to artificially formed liposomes by a reductive alkylation modification. The insulin-liposome aggregate reacts with insulin receptors. 

Alternatively, monoclonal antibodies (Mabs) to the relevant receptors can be used as transport vectors. Anti-insulin (Mab83-7 and Mab83-14) and anti-transferrin (0X26) receptor antibodies have been proposed as efficient and selective BBB transport vectors. The antitransferrin receptor antibody binds to a site removed from the transferrin binding site and therefore does not compete with endogenous transferrin for transport across the BBB. Studies using radiolabeled peptides have shown that significant uptake of a... 

Polyclonal antibodies have been prepared against partially purified rabbit mammary gland receptors [42-44], and have been used to demonstrate that the receptors really are involved in mediating the biological actions of prolactin. Anti-receptor antibodies that blocked binding of labelled prolactin were able to inhibit prolactin-stimulated casein synthesis and amino acid transport in rabbit mammary gland explants in vitro [43,45] (Fig. 4). They had no effect on the actions of insulin... 

In this case, which was marked by three autoimmune complications (insulin-dependent diabetes mellitus, myositis, and myasthenia gravis) in a single patient, a retrospective analysis of the patient s serum before aldesleukin therapy showed the presence of antibodies against glutamic acid decarboxylase, insulin, islet cell antigen, and striated muscle, but was negative for acetylcholine receptor antibodies. Immune stimulation by aldesleukin was... 

Usually, exogenous insulin is weakly antigenic. Insulin antibodies have been observed to neutralize the hypoglycemic effect of injected insulin. The antibody-binding sites on insulin are quite different from the sites involved in binding of insulin with its receptors. "... 

Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 1975 190 63-5. 

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