Protein misfolding and/or aggregation is a common characteristic underlying many neurodegenerative diseases. One approach for treating these diseases is with therapeutics that target the disease protein in question, either by interfering with production or propagation of its disease specific isoform/conformation, or by promoting its clearance. Antibodies have found particular utility as therapeutic agents in this regard, most notably in AD and prion disease. At the same time, it is widely appreciated that not all antibodies to a particular target have equivalent activities. Recently, investigators have begun turning to x-ray crystallography to provide greater insight at the atomic level into features that distinguish antibodies with differing in-vitro or in-vivo activities, to guide approaches for improved therapeutics, and ultimately, to gain insights into structural features of the disease protein which contribute to its pathologic form. This study by Antonyuk et al. provides a very nice illustration of how structural analysis benefits these objectives.

The investigators...  Read more

Protein misfolding and/or aggregation is a common characteristic underlying many neurodegenerative diseases. One approach for treating these diseases is with therapeutics that target the disease protein in question, either by interfering with production or propagation of its disease specific isoform/conformation, or by promoting its clearance. Antibodies have found particular utility as therapeutic agents in this regard, most notably in AD and prion disease. At the same time, it is widely appreciated that not all antibodies to a particular target have equivalent activities. Recently, investigators have begun turning to x-ray crystallography to provide greater insight at the atomic level into features that distinguish antibodies with differing in-vitro or in-vivo activities, to guide approaches for improved therapeutics, and ultimately, to gain insights into structural features of the disease protein which contribute to its pathologic form. This study by Antonyuk et al. provides a very nice illustration of how structural analysis benefits these objectives.

The investigators provide evidence that antibody potency (defined as neutralizing activity in cell models of antibodies recognizing two in-vitro generated conformations of PrPc, termed αPrP and βPrP), correlates with their binding affinities for PrPc, particulary for cell surface exposed epitopes of PrPc. Antonyuk et al. investigated the structural basis underlying the bioactivity of one of their more in-vitro and in-vivo potent antibodies, ICSM 18, using x-ray crystallography of a truncated PrPc fragment (residues 119-231), in complex with a Fab fragment of the antibody. The x-ray structure revealed two key details: a) numerous contact points between the antibody and a helical segment, termed H1 (residues 143-156), of the PrPc fragment; and b) a series of 4 anti-parallel β-sheets that mediate interactions between neighboring PrPc molecules. The helical segment has been implicated in the β-sheet transformation that distinguishes PrPSc from PrPc, and tight binding of this domain in PrPc by ICSM 18, via the multiple contacts, is consistent with the bioactivity of ICSM 18, i.e., it stabilizes PrPc. Independently, the anti-parallel β-sheets have also been observed between neighboring PrP molecules in the crystal structure of sheep PrP, and the authors speculate that a critical residue at position 129 in this region may explain genetic susceptibility and prion strain selection in humans by contributing to PrPSc formation, and prion propagation. Hence, the study of Antonyuk et al. highlights a preferred epitope on PrPc for therapeutic mAbs, and suggests how the structural features elucidated provide a basis for prion disease. The implication of their finding regarding the epitope bound by ICSM 18 would benefit from comparative x-ray crystallography of PrPc complexed with an antibody that has equal binding affinity as ICSM 18, but lower potency for inhibiting prion propagation in cells of, e.g., ICSM antibodies 17, or 19.

View all comments by Guriqbal S Basi