With growing interest in tau immunotherapy, researchers are exploring new antibodies that may have therapeutic potential for Alzheimer’s disease. In particular, recent findings suggest that antibodies against tau’s mid-region are the most effective at stopping the cell-to-cell propagation of aggregates (Apr 2018 conference news). In the December 4 issue of Structure, researchers led by Ian Wilson at The Scripps Research Institute in La Jolla, California, in collaboration with scientists at Janssen Pharmaceuticals, describe one such antibody that was isolated from human blood.
- New tau antibody binds to the protein’s mid-region.
- In vitro, it recognizes unphosphorylated and recombinant tau.
- In AD brain sections, it appears specific for tau aggregates.
The antibody, CBTAU-24.1, bound to both monomeric and aggregated tau in vitro, and had only slightly higher affinity for phosphorylated than unphosphorylated tau. However, on AD brain sections, it recognized only aggregates. The reason for this remains unclear.
“This is an elegant and comprehensive structural study, which will help guide future studies,” noted Rakez Kayed at the University of Texas Medical Branch in Galveston in an email to Alzforum. However, he pointed out that the study did not examine any control brains, or tauopathies other than AD. “The biochemical and immunohistochemical data fall short of demonstrating the antibody’s specificity for pathological tau,” Kayed added.
Caught Midstream. Tau antibody CBTAU-24.1 binds to proline-rich region P2, just before the four repeat domains. [Courtesy of Zhang et al., Structure.]
Janssen researchers previously exposed pooled memory B cells taken from healthy donors to phosphorylated tau, and recovered 52 different tau-binding antibodies (Pascual et al., 2017). CBTAU-24.1 was one of them. In vitro binding studies determined that it recognized residues in the second proline-rich region of tau, just before the first repeat domain (see image above). The antibody bound recombinant tau, as well as paired helical filaments of tau isolated from AD brain.
To pin down the binding site, first author Heng Zhang at the Beijing Synchrotron Radiation Facility in China crystallized CBTAU-24.1 in complex with a tau fragment, then measured the electron density to 2.6 angstrom resolution. This showed the antibody interacted with residues 235–243 via a combination of hydrogen bonds, hydrophobic interactions, and van der Waals electrostatic forces (see image below). Phosphorylation of Ser237 disrupted these interactions and prevented antibody binding. However, a phosphate group on Ser238 pointed away from the antibody and had no effect on binding. Because phosphorylation at these residues occurs late in AD, it may have a minimal effect on the antibody’s ability to recognize hyperphosphorylated tau (Hanger et al., 2007).
Phosphorylated? No Problem. Mid-section tau fragment (yellow) binds specific residues (green, blue) on CBTAU-24.1, while a phospho group (orange) on S238 points away from the binding pocket. [Courtesy of Zhang et al., Structure.]
In sections from AD brain, Janssen researchers found that CBTAU-24.1 decorated neurofibrillary tangles and neuritic plaques, although it bound more weakly to them than did the phospho-tau-specific antibody AT8. Janssen has applied for a patent on CBTAU-24.1.
Einar Sigurdsson at New York University School of Medicine wondered if this antibody was the same as Janssen’s mid-tau antibody JNJ-63733657, now in clinical trials for AD. “It would also be interesting to find out how the Janssen antibody(ies) against this region differ from the UCB tau antibody in clinical trials,” Sigurdsson added. UCB0107 recognizes residues 235-246, almost the same region as CBTAU-24.1 does. The authors could not be reached for comment.—Madolyn Bowman Rogers
- Pascual G, Wadia JS, Zhu X, Keogh E, Kükrer B, van Ameijde J, Inganäs H, Siregar B, Perdok G, Diefenbach O, Nahar T, Sprengers I, Koldijk MH, der Linden EC, Peferoen LA, Zhang H, Yu W, Li X, Wagner M, Moreno V, Kim J, Costa M, West K, Fulton Z, Chammas L, Luckashenak N, Fletcher L, Holland T, Arnold C, Anthony Williamson R, Hoozemans JJ, Apetri A, Bard F, Wilson IA, Koudstaal W, Goudsmit J. Immunological memory to hyperphosphorylated tau in asymptomatic individuals. Acta Neuropathol. 2017 May;133(5):767-783. Epub 2017 Mar 24 PubMed.
- Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH, Ward MA, Anderton BH. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem. 2007 Aug 10;282(32):23645-54. PubMed.
- Zhang H, Zhu X, Pascual G, Wadia JS, Keogh E, Hoozemans JJ, Siregar B, Inganäs H, Stoop EJ, Goudsmit J, Apetri A, Koudstaal W, Wilson IA. Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody. Structure. 2018 Sep 12; PubMed.