Simon Frantz

Associate Editor (News), Nature Reviews Drug Discovery
 

Earlier this year, Elan Pharmaceuticals and Wyeth-Ayerst were forced to halt Phase II studies of their vaccine for Alzheimer's disease after the discovery that 15 patients had developed severe brain inflammation. The vaccine — a fragment of amyloid precursor protein (APP) known as A₄₂, which stimulates a response to the -amyloid plaques that are a hallmark of the disease — had shown highly promising results in preclinical models and Phase I trials.

Two studies in Nature Medicine now indicate that there could still be hope for this strategy after all. Nitsch and colleagues detected a positive antibody response in a subset of patients who took part in the ill-fated trial, and McLaurin and colleagues show that refining the epitope might eliminate the side effects.

Nitsch and colleagues found that serum antibodies from most patients treated with the vaccine plus booster recognized -amyloid plaques, diffuse A deposits and vascular -amyloid in the brain blood vessels of transgenic mice bred to develop marked Alzheimer's-like -amyloid deposits. Importantly, the antibodies did not cross-react with APP, which is found in the nerve cells of both healthy subjects and patients with Alzheimer's disease. In other words, the vaccine selectively induced the desired immune response against disease-associated forms of A — whether it can prevent cognitive decline will be the focus of future studies.

The study by McLaurin and colleagues assessed whether the beneficial effects of the vaccine could be separated from the inflammatory side effects. Mass spectrometry showed that therapeutic antibodies raised against A₄₂ recognized an epitope defined by residues 4 to 10 (termed A_4–10). Incubating serum that contains antibodies raised against A₄₂ with cells was used to show that these antibodies can inhibit both the generation of fibrils (the long thread-like aggregates of misfolded proteins that are associated with the formation of amyloid plaques) and cytotoxicity. When the immune response that is induced by A_4–10 was assessed in mice, the researchers found that A_4–10 stimulates a T helper 2 (T_H2) response and the production of anti-A_4–10 antibodies. But, T_H1 responses, which many speculate were the cause of the adverse side effects in the clincial trial, were not detected.

These results indicate that a more refined vaccine, based on A_4–10, might be effective and safe in humans. And, intriguingly, a clearer understanding of the antibody–antigen interactions might lead also to the generation of small-molecule drugs that mimic the effects of the vaccine.

References and links

	ORIGINAL RESEARCH PAPERS Hock, C. et al. Generation of antibodies specific for -amyloid by vaccination of patients with Alzheimer disease. Nature Med. Oct 15 2002 (DOI 10.1038/nm783) | PubMed |
	McLaurin, J. et al. Therapeutically effective antibodies against amyloid- peptide target amyloid- residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nature Med. Oct 15 2002 (DOI 10.1038/nm790) | PubMed |
	FURTHER READING Schenk, D. Amyloid- immunotherapy for Alzheimer's disease: the end of the beginning. Nature Rev. Neurosci. 3, 824-828 (2002) | Article  | PubMed |

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