Humanized immunoglobulins and their production and use

A method of producing a humanized immunoglobulin having a human acceptor framework region and Kabat complementarity determining regions (CDRs) from a donor immunoglobulin, which humanized immunoglobulin binds to an antigen, said method comprising substituting at least three non-CDR amino acids of the acceptor heavy chain framework with corresponding amino acids from the donor immunoglobulin, at positions where the amino acid in the acceptor framework is rare for said position and the corresponding amino acid in the donor framework is common for said position in human immunoglobulin sequences; or the amino acid is adjacent to one of the CDRs; or the amino acid is predicted to have a side chain atom capable of interacting with the CDRs of the humanized immunoglobulin.