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Humanization of rodent monoclonal antibodies by CDR grafting

Humanization of rodent monoclonal antibodies by CDR grafting

Methods 8(2): 83-93

Many rodent antibodies with possible therapeutic applications in humans have been isolated and characterized. Clinical results with rodent antibodies, however, have been disappointing primarily because rodent antibodies are highly Immunogenic in humans. To help overcome this problem, rodent antibodies have been partially and fully humanized. Partial humanization consists of joining the rodent variable regions to human constant regions to create a chimeric antibody. Full humanization means taking only the portions of the rodent variable regions that are directly involved In antigen-binding, the complementarity determining regions (CDRs), and grafting these regions into human variable regions. The "reshaped human" variable regions are then joined to human constant regions to create a fully humanized, CDR-grafted antibody. Full humanization by CDR grafting is a more complex type of protein engineering than partial humanization by chimerization. Reliable methods for humanization by CDR grafting, however, have been developed. This article describes the methods developed and used at the MRC Collaborative Centre. The methods rely on selecting human variable regions with a high degree of similarity to the rodent variable regions and constructing a molecular model of the rodent variable regions. The model Is used to help identify amino acid residues that participate either directly or indirectly in antigen binding and then to decide what amino acid substitutions might be necessary In the human variable regions in order to achieve good binding to antigen. The methods are described In general and then Illustrated for humanizing a mouse anti-human IgE antibody. The article also lists 80 examples of rodent antibodies humanized by CDR grafting.

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