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Targeted Drug-Formaldehyde Conjugates And Methods Of Making And Using The Same

a technology of formaldehyde and conjugates, which is applied in the field of targeted drugformaldehyde conjugates and methods of making and using the same, can solve the problems of large socioeconomic toll, blindness, kidney disease and premature death, and places a heavy burden on healthcare facilities worldwid

Inactive Publication Date: 2007-08-30
HUTTON JOHN C +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It exacts a huge socioeconomic toll because of its devastating microvascular and macrovascular complications and the need of patients to maintain a lifetime daily therapeutic regimen.
It is a major cause of blindness, kidney disease and premature death, has immense socio-economic impact and places a heavy burden on healthcare facilities worldwide.
However the converse is not necessarily true, and attempts to define the cognate antigen of pathogenic T-cell clones in NOD mice that have been selected solely on the basis of islet reactivity have been largely unsuccessful, suggesting that these do not correspond to known serological markers.
Such studies in man are impeded by the general inability to access or image the affected organ and the questionable relevance of T-cell responses detected in the peripheral circulation to immunological events occurring within the islet.
The restricted usage of Vα chains in the TCRs of many of these clones points to the possibility that a limited number of antigenic epitopes and antigens are involved.

Method used

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  • Targeted Drug-Formaldehyde Conjugates And Methods Of Making And Using The Same
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  • Targeted Drug-Formaldehyde Conjugates And Methods Of Making And Using The Same

Examples

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Effect test

example 1

Test for T-cell Proliferation in Response to IGRP Protein and IGRP Protein Fragments

[0092] T-cell proliferative responses to recombinant IGRP (3-100 μg / ml) were observed from mixed lymphocyte preparations of pre-diabetic 12 week old female NOD mice (SImax=10). The fusion partner, β-galactosidase itself produced a minimal response in the assay as did equivalent constructs with G6Pase and UGRP. Constructs that were truncated C-terminally by 183 and 250 amino acids did not evoke a response suggesting that epitopes were confined to the C-terminal half of the molecule.

example 2

Test for antibodies to IGRP

[0093] IGRP was investigated as a humoral autoantigen in diabetic human subjects and NOD mice using a series of assays based either upon immunoprecipitation of 35S-labelled in vitro translated protein generated from reticulocyte lysates, or ELISAs based on the binding of antibodies to recombinant protein immobilized on microtiter plates or PVDF membranes. The assays easily detected antibodies from rabbits immunized with an IGRP COOH-terminal peptide or recombinant antigen (antibody dilution 1:50 to 1:8000) but failed to demonstrate the presence of autoantibodies in spontaneous diabetic or prediabetic samples, a high proportion of which were positive for one or more other autoantigens (insulin, GAD65 and ICA512). Other assays in which IGRP was translated in vitro with dog pancreatic microsomes to mimic its insertion into membranes and core glycosylation were similarly negative. Thus, any humoral autoimmune response remains to be characterized despite testi...

example 3

Identification of the Major IGRP Epitope

[0094] MHC class I tetramers were generated using the NIH tetramer facility. These were loaded with a series of peptides including the native mouse IGRP peptide (VYLKTNVFL (SEQ ID NO.: 6); peptide C, FIG. 4) corresponding to the NRP-V7 mimeotope (KYNKANVFL (SEQ ID NO.: 7)) that stimulates the NY8.3 CD8 T-cell clone. A procedure was developed for the isolation of mononuclear cells from the whole pancreas of NOD mice yielding approximately 0.5-1×106 CD45 positive cells (lymphocytes) per mouse (12-16wk females) for tetramer binding assays (FIG. 4). The lymphocyte population contained 10-15% CD8 positive cells of which 8% bound the native peptide tetramer. These assays confirm the remarkable finding that a major proportion of the CD8 cells in the NOD pancreas target one specific IGRP epitope. The procedure developed here represents a technical advance on previous tetramer studies of activated NRP reactive T-cell in NOD mice which required up to 4...

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Abstract

A method and compositions for detecting autoimmunity to islet glucose-6 phosphatase related protein (IGRP). Detection of IGRP autoantibodies alone, and in combination with other molecules such as the 65-kDa form of glutamate decarboxylase (GAD65), insulin and insulin granule membrane proteins ICA512 (IA-2) and phogrin (IA-2) auto-antigens, provides an effective and reliable chemical assay for the diagnosis of autoimmune (type 1) diabetes. Additionally, this invention provides therapeutic regimens based on IGRP and related molecules for the amelioration of the diabetic clinical condition. Therefore, IGRP alone or in combination with other autoimmune diabetes associated antigens such as insulin, IA-2 and GAD65, is useful in the prediction (diagnosis), treatment (therapy), and prevention (prophylaxis) of diabetes.

Description

FIELD OF THE INVENTION [0001] The method and compositions of this invention provide a method for detecting autoimmunity to islet glucose-6-phosphatase related protein (IGRP). Detection of IGRP autoimmunity alone, or in combination with other molecules such as the 65-kDa form of glutamate decarboxylase (GAD65), insulin and insulin granule membrane proteins ICA512 (IA-2) and phogrin (IA2β) auto-antigens, provides an effective and reliable chemical assay for the diagnosis of autoimmune (type 1) diabetes. Additionally, this invention provides therapeutic regimens based on IGRP and related molecules for the amelioration of the diabetic clinical condition. BACKGROUND OF THE INVENTION [0002] Diabetes has been termed the epidemic of the 21st century and over the past 50 years in Western societies has been doubling in incidence every 15 years. It exacts a huge socioeconomic toll because of its devastating microvascular and macrovascular complications and the need of patients to maintain a li...

Claims

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Application Information

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IPC IPC(8): A61K38/22G01N33/53A61BC07K14/00C12N9/16G01N33/564
CPCA61K38/28A61K38/51C12N9/16G01N33/564G01N33/6854G01N2333/916G01N2800/042A61K38/465A61K2300/00A61P3/10A61P31/04A61P37/04A61P37/06
Inventor HUTTON, JOHN C.O'BRIEN, RICHARDDAVIDSON, HOWARDHACKL, SEIJA
Owner HUTTON JOHN C
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