Ever since the phase two clinical trial of Elan's Aβ peptide vaccine was halted (see live discussion), the community has pondered if a vaccine against this disease will ever reach the clinic. Many questions surround both the rationale of this approach, the reasons behind the inflammation seen in some of the trial participants, and the direction to take in the future. Two advanced online publications in yesterday's Nature Medicine attempt to answer at least some of these questions.
Researchers in Roger Nitsch's lab at the University of Zurich, Switzerland, report on the properties of antisera collected from a cohort of 30 patients who participated in the trial of Elan's AN1792 vaccine. The sera were found to recognize β-amyloid plaques in transgenic mice carrying human AβPP and in post-mortem sections from patients who had had Alzheimer's with cerebral amyloid angiopathy. In contrast, pre-immune sera, and sera pre-absorbed with Aβ42, failed to pinpoint plaques.
An important characteristic of the immune sera appears to be selectivity for Aβ aggregates. First authors Christopher Hock and Uwe Konietzko et al. used immunostaining and Western blot experiments to demonstrate that the patient's antisera did not cross-react with AβPP, C-terminal fragments of AβPP, or soluble Aβ. In addition, cerebrospinal fluid from four of six patients tested did contain antibodies against Aβ42, but the one CSF sample tested for antibodies to AβPP or its soluble derivatives did not appear to contain those.
The latter finding suggests that the meningoencephalitis suffered by some of the trial participants is unlikely to stem from an antibody-mediated response against cellular precursor protein, the authors write. This conclusion is supported by the observation that the one patient in this cohort who developed inflammation recovered after treatment, even while the CSF titer of the antibody did not change.
This study does not answer the question what, then, caused the inflammation in this patient? As the humoral arm of the immune system appears to have been exonerated for now, it is likely that the cellular arm was activated, the authors write.
A collaborative research effort between Peter St. George-Hyslop's lab at the University of Toronto, Canada, and Michael Przybylski, University of Konstanz, Germany, sheds more light on the inflammation problem. These authors report that in mice, antibodies directed against residues 4-10 of Aβ42 can elicit beneficial effects without activating pro-inflammatory responses.
First author JoAnne McLaurin et al. used aggregated Aβ42 to immunize transgenic mice expressing human AβPP. Epitopes recognized by the resulting antisera were then determined by proteolytically digesting immobilized immune complexes and testing them with a sophisticated mass spectrometer. The dominant epitope found comprised residues 4-10 of the fragment. Antibodies generated by the mice against this epitope were predominantly of the immunoglobulin G2b type, known to be a poor activator of the immune complement system. Not surprisingly, these mice showed no signs of inflammation after immunization.
The suggestion here is that antibodies against residues 4-10 may prove to be efficacious and safe in humans. The authors show that these antibodies inhibit fibrillogenesis in vitro and can break up Aβ fibers. The test, again, will lie in clinical trials.
"Yes, animals immunized with these fragments have no inflammation," commented Blas Frangione, New York University School of Medicine, "but animals immunized with previous preparations have had no inflammation either. The data is still unrelated to humans, so it doesn't really help" See also commentaries below.—Tom Fagan
- McLaurin J, Cecal R, Kierstead ME, Tian X, Phinney AL, Manea M, French JE, Lambermon MH, Darabie AA, Brown ME, Janus C, Chishti MA, Horne P, Westaway D, Fraser PE, Mount HT, Przybylski M, St George-Hyslop P. Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nat Med. 2002 Nov;8(11):1263-9. PubMed.
- Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 2002 Nov;8(11):1270-5. PubMed.