Fusion molecules and treatment of IgE-mediated allergic diseases
View Patent ↗The invention concerns bifunctional fusion molecules for the treatment of IgE-mediated allergic conditions and FcεRI-mediated autoimmune conditions. The invention provides a new therapeutic approach for the treatment of both acute and late-phase allergic responses due to ingestion, inhalation, cutaneous and parenteral exposure to allergens, responses including asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, as well as anaphylactic reactions due to exposures such as bee stings or penicillin allergy. In addition, the invention provides for a novel, safer and more efficacious form of allergy vaccination.
1. An isolated fusion molecule comprising a human IgG heavy chain constant region sequence capable of binding to a human IgG inhibitory receptor directly functionally connected to a human IgE heavy chain constant region sequence capable of binding to a human IgE receptor wherein said fusion molecule is capable of binding both the IgG inhibitory receptor and the IgE receptor.
2. The fusion molecule of claim 1 wherein said IgG heavy chain constant region sequence and IgE heavy chain constant region sequence are connected via a polypeptide linker of 5 to 25 amino acid residues.
3. The fusion molecule of claim 2 wherein said polypeptide linker consists of 10 to 25 amino acid residues.
4. The fusion molecule of claim 3 wherein said polypeptide linker consists of 15 to 25 amino acid residues.
5. The fusion molecule of claim 1 wherein said IgG inhibitory receptor is a low affinity FcγRIIb IgG inhibitory receptor.
6. The fusion molecule of claim 1 wherein said IgE receptor is selected from a high-affinity FcεRI receptor and a low-affinity FcεRII receptor.
7. The fusion molecule of claim 1 wherein said IgG heavy chain constant region is selected from the heavy chain constant regions of IgG 1 , IgG 2 , IgG 3 and IgG 4 .
8. The fusion molecule of claim 7 wherein said IgG heavy chain constant region is an IgG 1 heavy chain constant region.
9. The fusion molecule of claim 8 wherein said IgG 1 heavy chain constant region sequence consists of the hinge-CH2-CH3 portion of an IgG 1 heavy chain constant region.
10. The fusion molecule of claim 9 wherein said hinge-CH2-CH3 portion of an IgG 1 heavy chain constant region is the amino acid sequence of SEQ ID NO:3.
11. An isolated fusion molecule comprising a human IgG heavy chain constant region sequence capable of binding to a human IgG inhibitory receptor directly functionally connected to a human IgE heavy chain constant region sequence capable of binding to a human IgE receptor wherein said fusion molecule is capable of binding to both the IgG inhibitory receptor and to the IgE receptor and wherein said IgE heavy chain constant region consists of the CH2-CH3-CH4 portion of a native human IgE heavy chain constant region.
12. The fusion molecule of claim 11 wherein said CH2-CH3-CH4 portion of a native human IgE heavy chain constant region consists of the amino acid sequence of SEQ ID NO:6.
13. A homodimer wherein said homodimer comprises the fusion molecule of claim 1 covalently linked to a second identical fusion molecule.
14. The homodimer of claim 13 wherein said linkage is through one or more disulfide bonds.
15. The fusion molecule of SEQ ID NO:7.
16. A homodimer wherein said homodimer comprises the fusion molecule of claim 15 covalently linked to a second identical fusion molecule.
17. The homodimer of claim 16 wherein said linkage is through one or more disulfide bonds.
18. An isolated fusion molecule comprising a human IgG heavy chain constant region sequence capable of binding to a human IgG inhibitory receptor directly functionally connected to a human IgE heavy chain constant region sequence capable of binding to a human IgE receptor wherein said fusion molecule is capable of binding to both the IgG inhibitory receptor and to the IgE receptor and wherein said IgG heavy chain constant region sequence consists of the hinge-CH2-CH3 portion of an IgG heavy chain constant region.