In a previous update, we reviewed a recent report from a group looking to select the most active beta-amyloid (Abeta)-targeting antibodies from pooled human immunoglobulin for injection (IVIgG). As we noted there, several small, early-phase clinical trials of IVIgG for Alzheimer’s disease have reported promising results. Moreover, the IVIgG preparations used in these trials are already available and approved for other indications. Baxter Pharma has announced that they will cosponsor Phase III trials of their Gammagard IVIgG for Alzheimer’s in conjunction with the NIH, and Octapharma is now recruiting subjects for a Phase II trial of Octagam IVIgG.
There are doubtless only a few antibodies in the mixed IVIgG pool that are responsible for the Abeta-clearing effect. It is reasonable to assume that there will be significant batch-to-batch variability in the concentration of these active antibodies, and that the other antibodies will exert at least some undesirable off-target effects. Thus, the identification of the key species responsible for Abeta removal and clinical benefits would allow for the creation of more effective therapeutics, which could be manufactured in consistent lots through recombinant DNA, improving safety and efficacy and increasing the supply of what is currently an extremely costly therapeutic, due to the inherent limits of imposed by sourcing IVIgG from pooled human plasma.
A recent report further documents the existence and possible physiological significance of these Abs, and may offer significant potential for their identification, isolation, and therapeutic exploitation.
Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD [Alzheimer disease] patients and healthy controls aged 21-89 years.
Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues [soluble Abeta species most implicated in Abeta-related synaptic dysfunction and cognitive deficits -MR], and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity.
Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. [This provides a useful and rapidly-available primate model for the evaluation of any resulting monoclonal Abeta immunotherapy -MR].
Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. (1)
1: Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, LeMieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. Epub 2009 Jul 6. PubMed PMID: 19581601; PubMed Central PMCID: PMC2715538.