Pilot Study Shows Promise of Passive Immunotherapy

April 14, 2005. A new approach to immunotherapy for Alzheimer disease (AD) took center stage Tuesday afternoon at the American Academy of Neurology meeting in Miami. Norman Relkin of Weill Cornell Medical College presented results of a pilot study showing that mental function improved in six of seven AD patients treated with an intravenous immunoglobulin (IVIG) antibody preparation.

IVIG, an FDA-approved purified immunoglobulin fraction from normal human donor blood, has a 30-year track record of safe use for the treatment of immune and inflammatory diseases. Relkin’s results, while preliminary, indicate that the preparation, which contains natural antibodies to amyloid-β (Aβ), warrants further study as a potential way to deliver a controlled immune attack on the peptide while potentially avoiding the immune toxicities that doomed clinical trials of Elan’s Aβ vaccine (see ARF related news story on the various forms of immunotherapy currently being developed for AD).

Relkin and his colleagues first considered the idea of passive immunization after they discovered that AD patients had lower levels of Aβ antibodies than do normal people of the same age. When they determined that the commercial IVIG preparation contained antibodies to amyloid-β, including the forms most toxic to brain cells, they decided to try the IVIG as a kind of antibody replacement therapy. In the phase I study, seven participants averaging 74 years old with mild to moderate AD received one to four IVIG infusions each month for 6 months. Follow-up included measurements of blood and CSF Aβ levels and cognitive testing. The researchers showed that blood levels of anti-Aβ antibodies increased after the infusion. More importantly, Relkin and colleagues measured a significant increase in plasma levels of Aβ, indicating that the peptide was being mobilized by the antibody treatment—the ability of peripheral antibodies to draw Aβ out of the brain was previously documented (see ARF related news story on the “peripheral sink” effect). No significant side effects were reported. These results echo a report last year from German researchers (Doda et al., 2004) who treated five patients with IVIG and saw a drop in Aβ in the CSF and an increase of the protein in the blood of those patients. In contrast to Relkin’s results, Doda and colleagues reported stabilization of cognitive decline, but no improvement in their patients.

In a press release, Relkin and senior investigator Marc Weksler called the results preliminary but “promising,” and said they provide a clear rationale for further development of IVIG for AD. Preparations for a phase II controlled trial in more patients are underway, according to the press release.—Pat McCaffrey.

Comments

  1. Dr. Norman Relkin and colleagues presented data at this year’s American Academy of Neurology meeting on the use of intravenous immunoglobulin (IVIG) in patients with Alzheimer disease. IVIG is utilized to treat several neurological disorders that have an immune-mediated basis such as acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome). The reason that IVIG is effective in these disorders is unknown. It has been shown that most humans have some immunoglobulins in their plasma that are directed against Aβ. It was rationalized that, given IVIG is pooled from many individuals, it would contain anti-Aβ antibodies and that its administration might mimic the effects of passive immunization with anti-Aβ antibodies.

    Seven patients diagnosed with mild to moderate AD were given IVIG over 6 months. There was no decline and was an actual improvement on some neuropsychological test scores in these patients over this time. There was also an increase in plasma Aβ in patients given IVIG. The reason for the increase in detectable plasma Aβ still needs to be worked out. This was a small, open-label study in which all patients received IVIG. From a clinical perspective, the small study is interesting and will need follow-up with a randomized trial to understand whether this treatment has the potential to be beneficial. The amount of anti-Aβ antibodies and their titer in IVIG is likely much lower than what has been given to animal models of AD or what was generated in many humans who were actively immunized with Aβ42. It will be important to further characterize the anti-Aβ antibodies that are present in IVIG preparations, as well as their effect on plasma and CSF Aβ. If in the long run, it turns out that there is an effect of IVIG on cognition in AD, it may or may not have to do with its effects on Aβ. It is interesting that despite the fact that IVIG is effective for certain inflammatory neurological diseases, we still do not completely understand its mechanism of action.

    View all comments by David Holtzman
    • User Profile Image Leon Thal
      Former professor at UCSD
    • Posted:

    The work by Norman Relkin is an intriguing approach to passive immunotherapy. IVIG has been safely administered to thousands of patients and has a good safety record. It is readily available and FDA-approved for other indications. The study presented is open-label and quite preliminary. The conclusion must be that in a small number of patients with AD, IVIG could be administered safely. There are many developmental issues that need to be explored, including dose, frequency, and antibody content of the preparation, before definitive phase 2-3 trials can be undertaken.

    View all comments by Leon Thal

  3. Dr. Norman Relkin and colleagues reported about the use of intravenous immunoglobulin (IVIG) in patients with AD. Unfortunately, the amount of anti-Aβ antibodies in the IVIG is difficult to measure and it should be very low. At the same time it is important to mention that the level of mouse anti-Aβ antibodies, required to provide therapeutic benefits, has not been clearly defined in the majority of active and passive immunizations studies. Determining the minimal therapeutic concentrations of anti-Aβ antibodies in mouse model of AD may help to design new passive immunizations clinical trials and better understand the mechanisms of clearance of Aβ from the brain. Thus, it likely will be very important to further characterize the specificity and determine the exact concentrations of anti-Aβ antibodies that are present in IVIG preparations in future pre-clinical and clinical trials.

    View all comments by Michael G. Agadjanyan

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References

News Citations

  1. Sorrento: Immunotherapy Update Hot Off Lectern of AD/PD Conference
  2. Two Ways to Attack Amyloid: Metal Chelator and Antibody

Paper Citations

  1. Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4. PubMed.

External Citations

  1. press release

Further Reading

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