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Humanized Antibodies
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans (for example, antibodies developed as anti-cancer drugs). Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system (such as that in mice). The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients What are humanized antibodies ?Humanisation (also called Reshaping or CDR-grafting) is now a well-established technique for reducing the immunogenicity of monoclonal antibodies (mAbs) from xenogeneic sources (commonly rodent) and for improving their activation of the human immune system; in fact there are many humanised mAbs in clinical trials and a few have been given approval to be used as drugs. Although the mechanics of producing the engineered mAb using the techniques of molecular biology are relatively straightforward, simple grafting of the rodent complementarity-determining regions (CDRs) into human frameworks does not always reconstitute the binding affinity and specificity of the original mAb.List of Humanized antibodies Production of humanized antibodiesIn order to humanize an antibody, the design of the humanized antibody is now the critical step in reproducing the function of the original molecule. This design includes various choices: the extents of the CDRs, the human frameworks to use and the substitution of residues from the rodent mAb into the human framework regions (backmutations). The positions of these backmutations have been identified principally by sequence/structural analysis or by analysis of an homology model of the variable regions' 3D structure. Recently, phage libraries have been used to vary the amino acids at chosen positions. Similarly, many approaches have been used to choose the most appropriate human frameworks in which to graft the rodent CDRs. Early experiments used a limited subset of well-characterised human mAbs (often where the structure was available), irrespective of the sequence identity to the rodent mAb (the so-called fixed frameworks approach). Some groups use variable regions with high amino acid sequence identity to the rodent variable regions (homology matching or best-fit); others use consensus or germline sequences while still others select fragments of the framework sequences within each light or heavy chain variable region from several different human mAbs. There are also approaches to humanisation developed which replace the surface rodent residues with the most common residues found in human mAbs ("resurfacing" or "veneering") and those which use differing definitions of the extents of the CDRs.Humanized antibody method by Cambridge University Uses of humanized antibodiesIt includes: |