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Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues.

Humanization of murine monoclonal antibodies for human therapy has commonly been achieved by complementarity-determining region (CDR) grafting, in which murine CDR loops are grafted onto human framework regions. Difficulties with that method have revealed the importance of certain framework residues in determining both the 3-D structure of CDR loops and the overall affinity of the molecule for its specific ligand. In the general model of structure-function relationships presented here, each amino acid position in the variable region is classified according to the benefit of achieving a more human-like antibody versus the risk of decreasing or abolishing specific binding affinity. Substitutions of human residues at low-risk positions (exposed to solvent but not contributing to antigen binding or antibody structure) are likely to decrease immunogenicity with little or no effect on binding affinity. Changes at high-risk positions (directly involved in antigen binding, CDR stabilization or internal packing) are avoided to preserve the biological activity of the antibody. Moderate-risk changes are made with caution. This model has been tested experimentally using H65, an anti-CD5 murine monoclonal antibody, whose binding activity had been greatly reduced by two previous attempts at humanization by conventional CDR grafting. The new 'human-engineered' H65 antibody containing 20 low-risk human consensus substitutions (expressed as either IgG or Fab) retains the full binding avidity of parental murine and chimeric H65 antibodies. A human-engineered antibody with an additional 14 moderate-risk substitutions has unexpectedly enhanced avidity (3- to 7-fold). This method is generally applicable to the design of other human-engineered antibodies with therapeutic potential.