Refining Intravenous IgG Pools for AD Immunotherapy

Intravenously delivered immunoglobulin G (IVIgG) is a mixture of antibodies extracted from human blood which has demonstrated promising preliminary results in clearing the beta-amyloid (Abeta) deposits that drive the pathogenesis of Alzheimer's disease. A recent study compares multiple commercial sources of IVIgG and finds significant differences in their Abeta-binding activity, suggesting that results from impending clinical trials are likely to be highly dependent on the specific "brand" of IVIgG in use.

Elan/Wyeth’s bapineuzumab has advanced further down the clinical pipeline than any other immunotherapy targeting removal of Abeta from the AD brain. While its lead status has brought much attention to this damage-repair approach, its prominence has at the same time had the unfortunate side-effect of eclipsing numerous alternative Abeta immunotherapies that span the range of earlier stages of development. Amongst the most advanced of these are Eli Lilly’s LY2062430/solanezumab and Novartis’ CAD106.

The most perverse of these effects has occurred following the ambiguous  results of the bapineuzumab Phase II trial, which gave given rise to an artificial mood of pessimism in the minds of some commentators regarding the entire therapeutic strategy — a pesssimism which takes little note of the independent lines of evidence supporting these alternative candidates, each with evidence of distinct mechanisms and therapeutic and safety profiles in earlier-phase research.

One of the least-publicized of the Abeta immunotherapies is the use of intravenous polyclonal human IgG (IVIgG) derived from detergent-purified, pooled plasma human plasma, which has shown a great deal of promise in small, early-phase clinical trials of IVIgG for Alzheimer’s disease.

Several IVIgG preparations are already available for other indications, including Baxter’s Gammagard (Kiovig  in the EU) and Octagam from Switzerland’s Octapharma AG. While existence of several competing, non-patentable IVIgG products may create some difficulty in acquiring and maintaining financing for clinical trials, Baxter has announced that they will cosponsor Phase III trials of Gammagard for Alzheimer’s in conjunction with the NIH, and Octapharma is now recruiting subjects for a Phase II trial of Octagam.

One might reasonably expect, however, that different IVIgG preparations — derived using different protocols and even from different donor populations — might vary in their therapeutic profile. Preliminary research designed to test this possibility has just recently been published:

… we compared different brands of IVIG for [antibodies against amyloid-beta (nAbs-Abeta)] and have found differences in the specificity of the nAbs-Abeta towards Abeta_{1-40} and Abeta_{1-42}. We analyzed the influence of a pH-shift over the course of antibody storage … [on] antibody dimerization  … [and] differences in the IgG subclass distributions among the IVIG … Furthermore, we investigated the epitope region of purified nAbs-Abeta. The differences found in Abeta specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer’s disease.(1)

Of course, such mechanistic studies can only be taken as suggestive of the relative merits of any given approach, but if used in proper feedback with results emerging from clinical trials might well help to progressively optimize the ultimate therapeutic products, through improved protocols for derivation and storage, identifying the most important IgG clones, and clarifying the mechanism of clearance to allow for rational design of monoclonal Abeta-targeting Abs. The ability to enrich and ultimately perhaps generate the most active species could then lead to their production through recombinant DNA — a critical step for the widespread deployment of a product for the clinic, due to the inherent limits of supply imposed by sourcing IVIgG from pooled human plasma.

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