Structure-function relationships of the variable domains of monoclonal antibodies approved for cancer treatment.
Due to their exquisite specificity for a given epitope on the target antigen, recombinant monoclonal antibodies (rmAb) can deliver "targeted therapy" in oncology. This review focuses on the structural bases of "antigen specificity" to aid clinical researchers and pharmacologists in managing these new drugs. The fine structure of the Fv (Fragment variable) module (combination of VH and VL domains) from the five unconjugated antibodies currently approved for cancer treatment, namely rituximab, cetuximab, alemtuzumab, trastuzumab and bevacizumab, is presented and analysed. Co-crystal and functional studies are reviewed to define rmAb residues contributing to antigen binding site (paratope)-epitope interfaces. The genetic origin of these recombinant monoclonal antibodies, determined through the IMGT/3Dstructure-DB database and IMGT/V-QUEST (http://imgt.cines.fr), is presented, allowing the evaluation of homologies between antibodies and their closest germline human counterparts and hence their possible immunogenicity. Overall, the IMGT standards appear as a first and crucial step in the evaluation of recombinant antibodies.
Magdelaine-Beuzelin
Charlotte
C
Université François Rabelais de Tours, EA 3853 Immuno-Pharmaco-Génétique des Anticorps thérapeutiques, France.
Kaas
Quentin
Q
Wehbi
Vanessa
V
Ohresser
Marc
M
Jefferis
Roy
R
Lefranc
Marie-Paule
MP
Watier
Hervé
H
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D001666:Binding Sites, Antibody; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D007167:Immunotherapy; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000628:therapy*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins