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The FASEB Journal, Vol 9, 73-80, Copyright © 1995 by The Federation of American Societies for Experimental Biology
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R Raag and M Whitlow
Department of Chemistry, University of California at Berkeley 94720.
Single-chain Fvs (sFvs) are recombinant antibody fragments consisting of only the variable light chain (VL) and variable heavy chain (VH) domains covalently connected to one another by a polypeptide linker. Due to their small size, sFvs have rapid pharmacokinetics and tumor penetration in vivo. Single-chain Fvs also show a concentration- dependent tendency to oligomerize. Bivalent sFvs are formed when the variable domains of a sFv disassociate from one another and reassociate with the variable domains of a second sFv. Similar rearrangement and reassociation of variable domains from different sFvs can result in the formation of trimers or higher multimeric oligomers. Each Fv in a bivalent or multivalent Fv is composed of the VL domain from one sFv and the VH domain from a second sFv. Modifying linker length or the inclusion of antigen may stabilize the VL/VH interface against rearrangement such that specific multimeric or monomeric forms of sFvs may be isolated. Nuclear magnetic resonance studies have shown that McPC603-derived Fv and sFvs have similar structures, and that the sFv linker is a rapidly moving, highly flexible peptide with a random coil- like structure. In X-ray crystallographic investigations of three different sFvs, linkers have also been found to be disordered. Indirect evidence suggests that a monomeric sFv has been crystallized in one case, and dimeric sFvs in the other two.
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