Comparison of surface accessible residues in human and murine immunoglobulin Fv domains. Implication for humanization of murine antibodies.

Statistical analysis of a database of unique human and murine immunoglobulin heavy chain and light chain variable regions reveals that the precise patterns of exposed residues are different in human and murine antibodies, while most individual surface positions have strong preferences for a small number of residue types. Consideration of these surface patterns alone generates almost identical family groupings for light and heavy chain variable domain sequences to those produced by methods such as those of Kabat et al., where N-terminal framework sequences only are compared, or Tomlinson et al., in which entire variable region nucleotide sequences are used. This unexpected result suggests that the surfaces of V-regions are at least as well conserved as the core framework sequences. Furthermore, using these patterns of human and murine surface residues a novel method for the "humanization" of murine antibodies has been developed and tested.