Methods of inhibiting alpha-4-dependent interactions with VCAM-1 with anti-VLA-4 antibodies

A method of inhibiting alpha-4 dependent interaction with VCAM-1 in a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a humanized antibody, wherein the humanized antibody comprises

• (1) a light chain variable region comprising complementarity determining regions CDR1, CDR2, and CDR3 of a mouse 21.6 immunoglobulin light chain variable region (SEQ ID NO:2) in a variable region framework of a human kappa light chain variable region, wherein at least one amino acid position in said variable region framework selected from the group consisting of L45, L49, L58, and L69, designated according to the Kabat numbering convention, is substituted with the amino acid present in the equivalent position of said mouse 21.6 immunoglobulin light chain variable region, and wherein the amino acid at one or more positions selected from the group consisting of L104, L105, and L107, designated according to the Kabat numbering convention, may be substituted with an amino acid present in the corresponding position in a different human immunoglobulin light chain framework;
• and
• (2) a heavy chain variable region comprising complementarity determining regions CDR1, CDR2 AND CDR3 of a mouse 21.6 immunoglobulin heavy chain variable region (SEQ ID NO:4) in a variable region framework of a human heavy chain variable region, wherein at least one framework amino acid position selected from the group consisting of:
• H27, H28, H29, H30, H44 and H71, designated according to the Kabat numbering convention, is substituted with the amino acid from the corresponding position in a mouse 21.6 heavy chain variable region sequence and further wherein positions H36 and H98, designated according to the Kabat numbering convention, may be substituted with a human heavy chain framework residue,
• wherein the humanized antibody blocks alpha-4 dependent interaction and wherein the disease or condition is selected from the group consisting of asthma, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, transplant rejection, graft versus host disease, alpha-4 expressing tumor metastasis, nephritis, atopic dermatitis, psoriasis, myocardial ischemia, adult respiratory disease and acute leukocyte mediated lung injury.