. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8. PubMed.


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  1. The immunological concept in the treatment of conformational diseases, such as Alzheimer’s, is based on antibody-antigen interactions involving conformational changes in both antibody and antigen. Appropriate mAbs interact at strategic sites where protein aggregation is initiated, stabilize the protein and prevent further aggregation. For such an active role, the mAbs require a high binding constant to the "strategic" positions on the antigen molecule (Solomon, 2002). The existence of strategic positions where conformational changes are initiated has been shown in model systems (Silen et al., 1989; Solomon et al., 1995), recently in Alzheimer’s Aβ peptide (Frenkel et al., 1998; Frenkel et al., 1999) and prion-related diseases (Peretz et al., 2001; Hanan et al., 2001). The many authors of the Bard et al. paper show in a most convincing way that antibodies against the N-terminus of Aβ are effective in clearing amyloid plaques (Hanan et al., 1996; Solomon et al., 1997), thus partially avoiding the drawbacks related to immunization with whole Aβ1-42. At the same time, the study lacks the rationale regarding the minimal epitope of anti-aggregating antibodies.

    Using a phage-peptide library composed of filamentous phage displaying three million random combinatorial peptides, we defined the EFRH residues located at positions 3-6 of the N-terminal Aβ as the epitope of anti-aggregating antibodies within Aβ (Frenkel et al., 1998; Frenkel et al., 1999). The EFRH is not only the epitope of anti-aggregating antibodies but acts as a regulatory site controlling both the formation and disaggregation process of the amyloid fibrils. Locking of this epitope by highly specific antibodies affects the dynamics of the entire Aβ molecule, preventing self-aggregation as well as enabling resolubilization of already formed aggregates. This conclusion was reached from experimental data with different lengths of Aβ peptides or similar peptides with one or two mutations in EFRH region (Frenkel et al., 1998; Frenkel et al., 1999).

    Antibodies resulting from EFRH immunization are similar in their anti-aggregating properties to antibodies raised by direct injection with whole Aβ and/or mAbs directed to this region (Frenkel et al., 2000). Such antibodies at low titer (1-100—1-1000) are enough to reduce the amyloid plaques to the same extent as passive immunization with larger amounts of antibodies directed to EFRH (Frenkel et al., 2003). Antibodies that bind to the epitope containing only a few amino acids from EFRH, such as mAb 3D6 (Bacskai et al., 2002), are less effective compared to mAb 10D5, which binds to the whole sequence.

    However, not all the antibodies that bind to EFRH exhibit anti-aggregating properties. Mab 2H3, whose epitope is located between amino acids 1-7, binds with a higher binding constant (10-9M) to the whole epitope, but only with (10-4M) to EFRH and did not have anti-aggregating properties, highlighting the importance of the high affinity of the antibodies to this specific sequence on the behavior of whole Aβ (Frenkel et al., 1999).

    Unfortunately, immunization could have contradictory effects; besides disaggregating amyloid plaques it could trigger also microglial overactivation, which might lead to neuroinflammation. Mabs that bind to available epitopes of Aβ in brain (passive or active immunization) activate the Fc receptors which may initiate the inflammatory response. Modulation of FcR activation, using antibodies devoid of the Fc region, or partial FcR blockage, may be efficient practical therapeutic approaches for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD (Solomon, 2002).

    View all comments by Beka Solomon
  2. This is a study on a quite impressive scale that compares different isotypes of anti-Abeta antibodies with respect to efficacy in attenuating amyloid loads in PDAPP mice. The conclusion is anti-Abeta IgG with high affinity for Fc receptors are more effective then those with lower affinity for FcR. This supports this group's hypothesis that microglial uptake of anti-Abeta:Abeta complexes is important in Abeta immunotherapy.
    Our group is currently preparing a manuscript that is not easily reconcilable with these findings. Our data has also been presented at recent meetings. We find that Abeta immunotherapy is equally effective in Tg2576 mice crossed into an FcR gamma knockout background mice as it is in wt Tg2576 mice. Our studies would seem to preclude FcR mediated uptake of anti-Abeta:Abeta complexes as a factor in determing efficacy of immunization.

    Although there was no good correlation between efficacy in the bard study and binding affinites of the antibodies to soluble or aggregated Abeta, perhaps there is some other property of the anibodies that is more closely associated with efficacy? For example binding to oligomers, ability to cross the blood brain barrier, etc....