Development of new immunoassays for the diagnosis and prediction of drug-related complement pathology

Projektbeschreibung

Sicherere Pharmazeutika in Sicht

Pharmazeutika, auch therapeutische Antikörper, Proteine und nanotechnologische Formulierungen, führen manchmal zu schwerwiegenden und lebensbedrohlichen Gesundheitszuständen, die als Überempfindlichkeitsreaktionen bezeichnet werden. Diese entstehen entweder durch eine echte allergische Reaktion, die durch die Freisetzung von Immunglobulin E ausgelöst wird, oder aufgrund eines pseudoallergischen, durch die unspezifische Aktivierung des Komplementsystems ausgelösten Zustands. Letztere löst eine massive akute Entzündungsreaktion aus, die mit der Freisetzung von Zytokinen, Anaphylatoxinen und zelltötenden Komplexen assoziiert ist. Das EU-finanzierte Projekt immunoassays schlägt vor, vielversprechende Biomarker zu entwickeln und zu bewerten, die zwischen den verschiedenen Typen von Überempfindlichkeitsreaktionen unterscheiden können. Diese Biomarker könnten bei der Sicherheitsbewertung neuer Pharmazeutika eingesetzt werden.

Ziel

Infusion reactions (IRs) are complex, immune-mediated side effects, also known as hypersensitivity reactions (HSRs), that can occur upon intravenous infusion of pharmaceuticals, leading to severe and sometimes life-threatening conditions in patients. Those reactions may arise from a real allergy which is immune globulin class E (IgE) mediated or a “pseudoallergy”. The latter involves no IgEs and may arise because of activation of the complement (C) system called C activation-related pseudoallergy (CARPA). The complement (C-) system is part of the immune system called the innate immune system that is not adaptable and responds to foreign challenges in a non-specific manner. When stimulated proteases of the complement system cleave other C proteins and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is a massive acute inflammatory response caused by the release of cytokines, anaphylatoxins and the cell-killing membrane attack complex (MAC). Products triggering severe adverse events can include both traditional small molecules but also biologics such as therapeutic antibodies (Abs), fusion proteins, etc. and novel formulations using liposomes or nanotechnology. Regulatory guidance on the assessment of C-mediated infusion hypersensitivity has been published recently for the case of generic liposome production. Hemocompatibility (blood safety) testing for medical devices is requested by EMA and FDA since many years. However, regarding the potential of new pharmaceuticals causing allergies and/or CARPA remains a significant challenge for the industry during nonclinical development as no established safety biomarker nor meaningful, validated animal models are available up to date. During the project “IMMUNOASSAYS” Dr Fülöp proposes the development and quantitative evaluation of three promising specific safety biomarkers via ELISA technology.