Norman Relkin, at Weill Medical College of Cornell University in New York, presented the latest data on his efforts to test intravenous immunoglobulin (IVIg), a somewhat mysterious mixture of purified human polyclonal antibodies originating from the plasma of blood donors. It has been used safely, with the FDA’s blessing, for immune deficiency and inflammatory conditions for 25 years. Researchers do not know precisely which component of this preparation does what with regard to Alzheimer disease pathogenesis, but what they do know indicates that some of the antibodies in the mix dissociate Aβ fibrils and enhance Aβ clearance (see Istrin et al., 2006). IVIg contains so-called natural antibodies that always course through people’s bodies rather than being made specifically in response to a given infection. The numbers of natural antibodies appear to decline in people with AD.

Relkin first mentioned a 6-month phase 1a study in which eight AD patients received monthly infusions of IVIg. They either stayed stable or improved by an average of 2.75 points on the MMSE. After 6 months, their CSF Aβ had decreased. When the researchers washed the drug out, the patients declined rapidly, reverting to their previous cognitive state after 3 months. In a second, 9-month, phase 1b trial in the same people, the investigators re-infused the preparation every other week, and tested the patients’ cognitive status at weeks 9, 12, 15, and 18. During the second treatment phase, the patients’ symptoms remained stable and some trended upward, Relkin reported.

The trial was an open-label, add-on study of IVIg. This means its inclusion criteria require that the patients be on cholinesterase inhibitors and/or memantine prior to IVIg and declined despite these conventional treatments. All patients took at least one of these drugs when they began IVIg treatment and kept doing so throughout the entire 18 months.

The trial included five spinal taps on each patient, three in the first 6 months, one after 9 months, and one after 18 months. Plasma Aβ increased after IVIg infusions, whereas CSF Aβ42 and 40 declined from baseline (compare to other AD immunotherapies). After several months of IVIg infusion, plasma Aβ levels, too, began to decline in half the patients. Relkin noted that he believes a peripheral sink effect is at work in his patients in that the presence of the IVIg antibodies slowly drives Aβ towards peripheral clearance. This is not mutually exclusive with central mechanisms, as the investigators also noted a dose-dependent increase of CSF immunoglobulin levels. Relkin cautioned that more work is needed to sort out the complicated relationship between the different forms of Aβ in plasma and CSF. To address this issue, Relkin collaborated with Gerald Boehm, who founded ACGT ProGenomics, a German biotech company that claims to have developed the first test to detect Aβ oligomers in physiological fluids. This test indicated a decrease in the level of detectable oligomers after IVIg treatment, suggesting the preparation might act against oligomers, Relkin said.

At present, a 24-subject, double-blind, placebo-controlled phase 2 trial with additional outcome measures is in progress, with results expected early next year. A phase 3 trial through the Alzheimer Disease Cooperative Study is being planned for 2007, Relkin noted. The product, by Baxter Bioscience, is expensive and in limited supply. This might raise thorny questions about who will get access to IVIg should larger trials confirm its promise.

A Better Clioquinol to Enter Phase 2
Clioquinol is a former antibiotic with a storied history. It has served to prove the point that a drug that dampens the metal-mediated redox activity of Aβ, and also revs up its clearance, has potential as an Alzheimer drug (White et al., 2006; Ritchie et al., 2004). Clioquinol fell short as a candidate for a new AD medicine due to manufacturing difficulties (see ARF related news story), but Prana Biotechnology, the Australian company behind it, has a new horse running.

A principal academic proponent of this approach has been Ashley Bush of the Mental Health Research Institute, Victoria, Australia. In Madrid, Bush reported that PBT2, Prana’s second-generation compound, is an 8-hydoxyquinoline that outdoes clioquinol on a range of preclinical parameters in vitro and in transgenic mouse models for AD. Importantly, PBT2 enters the brain at a more rapid clip and shows better pharmacokinetics, such that it can probably be given once a day. Two phase 1 trials of PBT2, a single-dose trial in healthy men and a multi-dose series in healthy, elderly men and women, showed no significant side effects. Prana is currently gearing up for a multi-site phase 2a trial of PBT2 in people with early AD, to be conducted in Sweden starting late this year. Also at ICAD in Madrid, Prana’s co-founder Colin Masters, University of Melbourne, Australia, received a Lifetime Achievement Award in Alzheimer Disease Research.—Gabrielle Strobel.

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  1. IVIg is also used to treat hyper-IgM syndrome. Grewal and colleagues (1) report that protein glycosylation by alpha2,6-sialyltransferase (ST6Gal-I) restricts access of antigen receptors and Shp-1 to CD22 and operates by a CD22-dependent mechanism that decreases the basal rate of IgM antigen receptor endocytosis. Kitazume and colleagues (2) report that BACE1 transgenic mice have increased levels of ST6Gal I in plasma. Has anyone looked at IgM receptor endocytosis in AD?

    It's interesting that PIR-B recruits Shp-1 and provides an alternative inhibitory pathway for B calls which is complementary to CD22 (3). Would you expect increased recruitment of Shp-1 by PIR-B in BACE1 transgenics? Does BACE1 restrict synaptic plasticity as is reported for PIR-B in the news comment by Pat McCaffrey (4)?

    See also:

    Immune Receptor Controls Synaptic Plasticity; LTP Makes Memories

    References:

    . ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling. Mol Cell Biol. 2006 Jul;26(13):4970-81. PubMed.

    . In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase. J Biol Chem. 2005 Mar 4;280(9):8589-95. PubMed.

    . The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2446-51. PubMed.

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References

News Citations

  1. Madrid: News from the Vaccine Front—Phase 1 Hopefuls
  2. Side-Reactions Sideswipe Clioquinol—Prevent Clinical Trial
  3. Madrid: Clinical Trials Update—Where Do Things Stand?
  4. Madrid: Highs and Lows of The Insulin Connection

Paper Citations

  1. . Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res. 2006 Aug 1;84(2):434-43. PubMed.
  2. . Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem. 2006 Jun 30;281(26):17670-80. PubMed.
  3. . Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec;60(12):1685-91. PubMed.

Further Reading

Papers

  1. . Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J Cell Biol. 2001 Feb 19;152(4):785-94. PubMed.

News

  1. Madrid: Clinical Trials Update—Where Do Things Stand?