Rapid clearance of antigen complexes using novel antibodies
The present invention relates to rapid clearance molecules that bind target antigens and FcγRIIb with increased affinity as compared to parent molecules, the compositions being capable of causing accelerated clearance of such antigens. Such compositions are useful for treating a variety of disorders, including allergic diseases, atherosclerosis, and a variety of other conditions.
1. A method of treating atherosclerosis in a patient by rapidly lowering serum concentration of oxidized low-density lipoprotein (oxLDL) in said patient, said method comprising:
a) administering a rapid clearance molecule comprising:
i) a domain that binds said oxLDL; and
ii) a variant human IgG Fc domain comprising an amino acid substitution as compared to a parent human IgG Fc domain, wherein said variant Fc domain binds FcγRIIb with increased affinity as compared to said parent Fc domain;
wherein said rapid clearance molecule binds to said oxLDL to form a molecule-oxLDL complex and said complex is cleared at least two fold faster than oxLDL alone.
2. A method according to claim 1 , wherein said variant Fc domain comprises amino acid substitutions selected from the group consisting of S267E, S267D, L328F, P238D, S267E/L328F, G236N/S267E, and G236D/S267E, wherein numbering is according to EU index as in Kabat.
3. A method according to claim 1 , wherein said rapid clearance molecule is an antibody or an Fc fusion protein.
4. A method according to claim 3 , wherein said rapid clearance molecule is an anti-oxLDL antibody.
5. A method according to claim 3 , wherein said rapid clearance molecule is a LOX-1 Fc fusion protein.
6. A method according to claim 3 , wherein said rapid clearance molecule is a CD36 Fc fusion protein.
7. A method according to claim 1 , wherein said variant Fc domain comprises amino acid substitutions selected from the group consisting of: N434A, N434S, M428L, V308F, V259I, M428L/N434S, V259I/V308F, Y436I/M428L, Y436I or V/N434S, Y436V/M428L, M252Y, M252Y/S254T/T256E and V259I/V308F/M428L, wherein numbering is according to EU index as in Kabat.
8. A method according to claim 1 , wherein said variant Fc domain is a variant of a parent human IgG1 Fc domain.