Methods of treating sickle cell disease with anti-P-selectin antibodies
The invention features antibodies, e.g., chimeric and humanized antibodies, that recognize (i.e., bind) P-selectin. The P-selectin antibodies prevent P-selectin from binding to its cognate receptor. The P-selectin antibodies can be used to treat inflammatory and thrombotic conditions, e.g., sickle cell disease, pain crisis associated with sickle cell disease, deep vein thrombosis, asthma, rheumatoid arthritis, psoriasis, and ischemia reperfusion injury in a patient in need thereof.
1. A method of treating sickle cell disease in a subject, the method comprising
administering a therapeutically effective dose of a humanized antibody or binding fragment thereof to the subject, the humanized antibody or binding fragment thereof comprising a light chain variable region comprising, in sequential order, a first light chain complementary determining region (CDR) having the sequence KASQSVDYDGHSYMN (SEQ ID NO: 1), a second light chain CDR having the sequence AASNLES (SEQ ID NO: 2), and a third light chain CDR having the sequence QQSDENPLT (SEQ ID NO: 3); and
a heavy chain variable region comprising, in sequential order, a first heavy chain CDR having the sequence SYDIN (SEQ ID NO: 4), a second heavy chain CDR having the sequence WIYPGDGSIKYNEKFKG (SEQ ID NO: 5), and a third heavy chain CDR having the sequence RGEYGNYEGAMDY (SEQ ID NO: 6); and
wherein the first, second, and third light chain CDRs are within a framework region of a humanized light chain variable region and wherein the first, second, and third heavy chain CDRs are within a framework region of a humanized heavy chain variable region;
wherein the humanized antibody or binding fragment binds P-selectin with a dissociation constant between 10 −7 M and 10 −13 M, and
wherein the effective dose of the humanized antibody or binding fragment treats the sickle cell disease.
2. The method of claim 1 , wherein said humanized antibody is recombinant.
3. The method of claim 1 , wherein said humanized antibody is an immunoglobulin G.
4. The method of claim 1 , wherein the humanized antibody has binding specificity for P-selectin.
5. The method of claim 1 , wherein the humanized antibody or binding fragment is administered by subcutaneous injection, intramuscular injection, or intravenous injection.
6. The method of claim 1 , wherein the humanized antibody or binding fragment is administered in an aqueous formulation.
7. The method of claim 6 , wherein the humanized antibody or binding fragment is administered in an aqueous carrier.
8. The method of claim 7 , wherein the humanized antibody or binding fragment is administered in a formulation comprising a concentration of at least about 1.0% antibody.
9. The method of claim 1 , wherein the humanized antibody or binding fragment is administered in a dose from about 0.5 mg/kg of body weight to about 5 mg/kg of body weight.
10. The method of claim 1 , wherein the therapeutically effective dose of the humanized antibody or binding fragment is administered as multiple administrations to the subject.