Progress in programming antibody fragments to crystallize

Completion of the X-ray analysis of the human B7-15A2 Fab opened a new vista (Immunotechnology 3, no. 4). In the crystal lattice, both the lambda-type light chain (C-L domain) and gamma 1-type heavy chain (C(H)1 domain) participated in formation of antiparallel beta-pleated sheets with neighboring molecules related to the reference Fab by 2-fold axes. This observation evoked memories of the first description of this type of packing for human Bence-Jones (lambda chain) dimers 20 years ago (Ely K.R. et al. Biochemistry 1978;17:158-167). Reexamination of packing interactions in selected crystal systems revealed that the C domains of lambda and gamma 1 chains were structurally amenable to the formation of such cross-molecule beta-structures, but kappa chain C-L domains were not. In the latter, a single proline residue disrupted the order of beta-strand 3-3 in the middle of the surface used in lambda and gamma 1 chains for intermolecular interactions with symmetry-related molecules. For the packing of Fv molecules, the V-L domains are structurally well suited for analogous packing interactions through antiparallel 4-1 beta-strands in adjacent molecules. Such interactions have been shown to provide the driving force in the crystal packing of a human (Pot) Fv from an IgM-kappa cryoglobulin. Together, these observations suggest several avenues through which propensity to crystallize can be programmed into the designs of synthetic human Fabs, Fvs and single-chain antibodies. (C) 1998 Elsevier Science B.V.