3 October 2007. In the September 25 PNAS online, researchers led by Chris Dealwis at the University of Tennessee in Knoxville published the first crystal structure of a monoclonal antibody to the amyloid-β (Aβ) peptide. Several antibodies have moved into clinical trials for passive immunotherapy of Alzheimer disease. Yet their proponents readily admit that if any of these succeed, a certain dose of good luck will have had a hand in the success, as well. That’s because scientists remain far from fully understanding the particular characteristics of antibody-Aβ binding that make a therapeutic antibody safe and effective in the AD brain. X-ray crystallography is a step in this direction. It provides not only the basis for examining molecular forces and side chains engaged in antibody-antigen recognition, but also a starting point for structure-based design to refine currently available antibodies.
Electrostatic potential surface of antibody with bound Aβ peptide. Blue: positive charge, red: negative charge, white: apolar surface. Aβ(1-8) is drawn with carbon (yellow), nitrogen (blue), and oxygen (red). The Arg 5 residue sits in a pocket of strong negative charge. Glu 3 has no correspondingly positive region around it, making this position susceptible to substitution and cross-reaction. Image credit: Chris Dealwis|
Anna Gardberg and colleagues generated several new monoclonal IgGs against stabilized protofibrils of Aβ40. They crystallized the antigen-binding fragments (Fabs) of two of them and found one to be complexed with the immunogenic Aβ (1-8) sequence and the other, to their surprise, with a similar sequence found in the human glutamate receptor interacting protein GRIP1 (Guo and Wang, 2007; Kulangara et al., 2007). The scientists characterize the atomic forces and a WWDDD motif with which the antibodies recognize these two similar peptide sequences. The Alzforum caught Chris Dealwis on the eve of a move. Our thanks to him for shooting off some brief last-minute replies from amid the boxes. See Q&A below.—Gabrielle Strobel.
Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C. Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Oct 2 ; 104(40):15659-64. Abstract
Q&A with Chris Dealwis. Questions by Gabrielle Strobel.
Q: Is it possible to do the same research with other Aβ antibodies?
A: Yes, if they have similar binding affinities.
Q: How about the A11?
A: If Charles Glabe's antibody is a monoclonal, then it will be a very interesting mAb to crystallize.
Q: How about the m266?
Q: The 3D6?
Q: Are you already working on any of the better-known antibodies in this
field, or planning to?
Q: Would you expect to see the same or similar WWDDD motif in the binding
region of other antibodies to Aβ? In other words, do you think this is a
common feature of N-terminal Aβ antibodies?
A: Not always.
Q: This is the first public crystal structure of an Aβ-monoclonal antibody complex I am
aware of. Crystallography projects can be famously Herculean efforts. Was
this one especially difficult to do?
Q: Can your structure guide “rational drug designers” on how to improve the
current crop of therapeutic antibodies? What would the structure suggest
they change, for example?
A: Yes, it will improve affinity and specificity.
Q: Can the reactivity to a sequence of the human GRIP1 protein, or to the
Ror2 sequence, be engineered out of the antibody without losing binding to
A: I think so.
Q: GRIP1 is a post-synaptic scaffolding protein thought to play some role in
synaptic activity, possibly through AMPA receptors. Current research also
focuses on Aβ's possible role in AMPA receptor regulation. Pure
A: Interesting, isn't it?