Constructing antibody derivatives

The antibody fragments obtained from phage display libraries are monovalent, whereas in many in vitro and in vivo applications, multivalency is a desirable property. In addition, linking two or more binding sites efficiently increases the functional avidity of antibody molecules. Multivalent (and multispecific) scFv and Fab fragments have been successfully produced by association of antibody fragments through flexible linker polypeptides, chemical cross-linking and fusion to transcription factor-derived multimer-ization domains. For instance, scFv antibody frag-

rnents can be converted to dimers by genetic fusion of the scFv moiety to peptides derived from Fos and Jun or to tetramers by fusion to GCN4 protein interaction domains. Thus modified scFv fragments spontaneously multimerize to bivalent (scFv)2 or tetra-valent (scFv)4 fragments in the bacterial periplasm. ScFv antibodies from phage display libraries have also been converted to complete immunoglobulin molecules by insertion of the variable region genes in eukaryotic expression constructs containing the constant region genes encoding each human immunoglobulin isotype. These 'natural' monoclonal antibodies can be produced in eukaryotic cells, retain the specificity of the original scFv and perform effector functions associated with the immunoglobulin Fc portion.

ScFv fragments may be incorporated into liposomes to create immunoliposomes with specific cellular or tissue-targeting properties. Addition of the £. coli lipoprotein signal sequence to scFv fragments results in the in vivo biosynthetic lipid modification of scFv, efficiently anchoring the scFv fragments to membrane encapsulated vesicles while retaining their specificity.

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