ד"ר אלה פישמן - Targeted elimination of cells expressing the high affinity receptor for IgE (FcRI) by a Pseudomonas exotoxin-based chimeric protein

מבוסס על מאמרן של ד"ר אלה פישמן ו Haya Lorberboum-Galski

Most allergic reactions like asthma, atopic dermatitis, allergic rhinitis, anaphylaxis or food allergies etc. involve interaction of mammalian antibody IgE and its high-affinity FceRI receptor, which is found on mast cells and basophils, the cells participating in an allergic response. Hence immunotherapy targetting FceRI with chimeric cytotoxins becomes an attractive therapeutic approach. Chimeric cytotoxins are generated by gene fusion techniques to target and kill cells that express specific receptors. An example is the chimeric protein produced in Escherichia coli constituting mouse IgE Fc fragment and Pseudomonas exotoxin (PE) which kills mouse mast cells effectively by inhibiting protein synthesis. A DNA sequence similar to constant region of mouse IgE was fused with truncated form of PE that lacked the cell binding domain. Thus this chimeric protein targeted mast cells and basophils expressing FceRI receptor because of the presence of its IgE part and killed them due to the presence of PE. This chimeric protein enters the target cells through an unoccupied IgE receptor. Since mast cells express these receptors in early stage, the immature target cells are eliminated in this approach before they can release allergy mediator chemicals. As these receptors are not expressed on stem cells, bone marrow is prevented from any kind of damage using these chimeric proteins. Since antibodies are supposed to generate against this chimeric protein, combining chimeric toxin therapy with low doses of immunosuppressants such as 15-deoxyspergualin is seen as an effective solution against this problem. The use of non-immunogenic human proteins like RNase or complement components etc. replacing bacterial toxins for cell-killing can also be an effective approach. The immunogenicity of the toxin moiety

of the chimeric protein can also be reduced by adapting various techniques like mutagenesis. Keeping these points in mind, the clinical application of this chimeric protein becomes an effective anti-allergy treatment. The cyto-toxicity of such fusion proteins can lead to an attractive treatment option of diseases like cancer etc.