Over the last decade, the potential of antibodies as therapeutic strategies to treat Alzheimer s disease (AD) has been growing, based on successful experimental and clinical trials in transgenic mice. Despite, undesirable side effects in humans using an active immunization approach, immunotherapy still remains one of the most promising treatments for AD. In this study, we analyzed the V genes of twelve independently isolated monoclonal antibodies raised against the N-terminal immunodominant epitope of the amyloid beta peptide (Abeta or A beta). Surprisingly, we found a high and unusual level of restriction in the VH/VL pairing of these antibodies. Moreover, these antibodies mostly differ in their heavy chain complementary determining region 3 (HCDR3) and the residues in the antibodies which contact Abeta are already present in the germline V-genes. Based on these observations and or co-crystal structures of antibodies with Abeta, the aim of the current study was to better understand the role of antibody V-domains, HCDR3 regions, key contact residue (H58) and germline encoded residues in Abeta recognition. For that purpose, we designed and produced a range of recombinant Fab constructs. All the Fabs were tested and compared by surface plasmon resonance on Abeta(1-16), Abeta(1-42) high molecular weight and Abeta(1-42) low molecular weight soluble oligomers. Although all the Fabs recognized the Abeta(1-16) peptide and the Abeta(1-42) high molecular weight soluble oligomers, they did not bind the Abeta(1-42) low molecular weight soluble oligomers. Furthermore, we demonstrated that: (1) an aromatic residue at position H58 in the antibody is essential in the recognition of Abeta and (2) Fabs based on germline V-genes bind to Abeta monomers with a low affinity. These findings may have important implications in designing more effective therapeutic antibodies against Abeta.
Robert, R., Lefranc, M-P., Ghochikyan, A., Agadjanyan, M. G., Cribbs, D. H., Van Nostrand, W. E., Wark, K. L., & Dolezal, O. (2010). Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid beta peptide. Molecular Immunology, 48(1-3), 59 - 72. https://doi.org/10.1016/j.molimm.2010.09.012