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Publication Detail
Crystal structure of the anti-(carcinoembryonic antigen) single-chain Fv antibody MFE-23 and a model for antigen binding based on intermolecular contacts
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Boehm MK, Corper AL, Wan T, Sohi MK, Sutton BJ, Thornton JD, Keep PA, Chester KA, Begent RHJ, Perkins SJ
  • Publication date:
  • Pagination:
    519, 528
  • Journal:
    Biochemical Journal
  • Volume:
  • Issue:
    Pt 2
  • Print ISSN:
  • Keywords:
    Amino Acid Sequence, Animal, Antibodies, Antibody, Antibody Specificity, Antigen-Antibody Reactions, Biochemistry, Biology, cancer, Carcinoembryonic Antigen, chemistry, colorectal cancer, Epitopes, Immunoglobulins, Fc, immunology, interaction, Mice, model, Molecular Biology, Molecular Sequence Data, N-terminal, Protein Conformation, Structure, Support, Non-U.S.Gov't, 0 (Antibodies), 0 (Carcinoembryonic Antigen), 0 (Epitopes), 0 (Immunoglobulins, Fc), AFFINITIES, affinity, Amino Acid Sequence, antibodies, ANTIGEN, As, BINDING, biology, C terminal, Colorectal, Colorectal Cancer, CRYSTAL, CRYSTAL STRUCTURE, domain, H1, H2, H3, HIGH-AFFINITY, L1, LATTICE, MED, mice, Molecular, MOLECULES, Mutagenesis, Patient, patients, REGION, RESOLUTION, SITE, SURFACE, UK, variable
  • Addresses:
    Department of Biochemistry and Molecular Biology, --- *** Royal Free Campus, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK Univ Coll London, --- *** Royal Free & Univ Coll Med Sch, Dept Biochem & Mol Biol, --- *** Royal Free Campus, Rowland Hill St, London NW3 2PF, England. Univ Coll London, --- *** Royal Free & Univ Coll Med Sch, Dept Biochem & Mol Biol, London NW3 2PF, England. Univ Coll London, --- *** Royal Free & Univ Coll Med Sch, Dept Oncol, London NW3 2PF, England. Univ London Kings Coll, Randall Ctr, London SE1 1UL, England Perkins SJ Univ Coll London, --- *** Royal Free & Univ Coll Med Sch, Dept Biochem & Mol Biol, --- *** Royal Free Campus, Rowland Hill St, London NW3 2PF, England
  • Notes:
MFE-23 is the first single-chain Fv antibody molecule to be used in patients and is used to target colorectal cancer through its high affinity for carcinoembryonic antigen (CEA), a cell-surface member of the immunoglobulin superfamily. MFE-23 contains an N-terminal variable heavy-chain domain joined by a (Gly(4)Ser)(3) linker to a variable light-chain (V(L)) domain (kappa chain) with an 11-residue C-terminal Myc-tag. Its crystal structure was determined at 2.4 A resolution by molecular replacement with an R(cryst) of 19.0%. Five of the six antigen-binding loops, L1, L2, L3, H1 and H2, conformed to known canonical structures. The sixth loop, H3, displayed a unique structure, with a beta-hairpin loop and a bifurcated apex characterized by a buried Thr residue. In the crystal lattice, two MFE-23 molecules were associated back-to-back in a manner not seen before. The antigen-binding site displayed a large acidic region located mainly within the H2 loop and a large hydrophobic region within the H3 loop. Even though this structure is unliganded within the crystal, there is an unusually large region of contact between the H1, H2 and H3 loops and the beta-sheet of the V(L) domain of an adjacent molecule (strands DEBA) as a result of intermolecular packing. These interactions exhibited remarkably high surface and electrostatic complementarity. Of seven MFE-23 residues predicted to make contact with antigen, five participated in these lattice contacts, and this model for antigen binding is consistent with previously reported site-specific mutagenesis of MFE-23 and its effect on CEA binding
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