On the heels of this clinical anti-protofibril antibody comes a different, preclinical one that supposedly also recognizes Aβ “aggregates” much more strongly than monomers, though no structural information about the particular antigen is available. At AD/PD, Christoph Hock of Neurimmune, a biotech company based in Schlieren, Switzerland, introduced BIIB037, a monoclonal antibody that Neurimmune’s larger U.S. partner Biogen Idec of Cambridge, Massachusetts, will push into human trials this year, according to Hock. This antibody is unusual in that it is not a humanized form of a mouse antibody but was isolated directly from humans in what Hock called “reverse translational medicine.” This means that the Swiss scientists started with living older people who appear resistant to AD, and tried to exploit their immune response. “We speculate that natural generation of antibodies protects some people,” Hock said.
How would this work? Using a donor cohort of 265 research volunteers in their seventies, the scientists screened the B cells of those people who were cognitively stable over a period of three years, recovered from mild cognitive impairment, or whose AD barely progressed. The scientists generated recombinant versions of naturally occurring antibodies from sequence information, and selected for development an IgG1 that binds to aggregated Aβ with an affinity below one nanomolar. With repeated intraperitoneal injection into Tg2576 mice, the antibody crossed the blood-brain barrier, accumulated on amyloid plaques, and persisted in brain over the measurement period of 2 weeks, Hock said. Repeated injection to mimic chronic treatment of chimeric versions of the human-derived antibody dose-dependently reduced soluble and insoluble Aβ40 and 42, as well as plaque load in hippocampus and cortex. “This human antibody dramatically lowered all Aβ species where deposits can be measured by biochemistry and immunohistochemistry,” Hock said.
At the same doses (3 to 30 mg/kg), microglial activation went up around plaques; amyloid angiopathy or frequency of microhemorrhages stayed unchanged, Hock added. He presented data suggesting that the antibody appears to protect the shape and survival of adult-born neurons in APP/PS1 transgenic mice as well as dendritic spines in cultured neurons (Biscaro et al., 2009). Fielding a question about memory tests in those mice, Hock noted that the antibody improves their performance in contextual fear conditioning and other tests. In response to a second question about exactly what BIIB037 binds to, Hock demurred, divulging only that binding to monomer is many fold weaker than to aggregates. “We are not disclosing the epitope,” Hock said.
As the field at large develops the basic science and translational knowledge base for further anti-oligomer or anti-protofibril approaches, investigators would be well advised to become much more precise in how they prepare, study, and name those potential targets, Dominic Walsh of Brigham and Women’s Hospital in Boston told the audience in Barcelona. “I don’t like the term ‘oligomers’ because it is nebulous. The chemical definition of oligomer as a ‘low-N mer’ tells us nothing about structure,” Walsh said. There are studies about Aβ56*, about ADDLs, about dimers extracted from human brain, the globulomer, protofibrils, and various other synthetic species. “We cannot all dump them into the same category, call them ‘oligomers’ and essentially consider them the same. We need to be much more specific,” Walsh said.
“I do think the protofibrils are one of the mediators of toxicity. The stable dimer boosts protofibril formation and may be the fundamental building block of synaptotoxic protofibrils. Going forward, I prefer that we talk about biophysically defined species,” Walsh went on. Indeed, a strongly worded editorial published in the current Nature Neuroscience makes the same point. Charging that a multitude of different methods and vague language “muddle the field,” the journal calls for scientists to state exactly where the particular form of Aβ used in their experiment comes from, to characterize its aggregation state rigorously, and to discuss its physiological relevance.
Notwithstanding the precise antigen, a slew of vaccine-based approaches are wending their way through trials. Relkin surveyed these studies, in particular noting three passive vaccines that are now in Phase 3: Eli Lilly and Company, Indianapolis, has solanezumab in trials (EXPEDITION and EXPEDITION2); Janssen Alzheimer Immunotherapy, South San Francisco, California, has bapineuzumab in trials (ApoE4 Carrier and ApoE4 Non-Carrier); and Baxter Healthcare Corporation, Deerfield, Illinois, has intravenous immunoglobulin in trials. Results from these studies should come out in 2012 and 2013, Relkin said, at which point the field can reassess what works and what does not. In addition, Merck, Genentech/Roche, Novartis, Affiris, and other companies have antibodies in Phases 2 and 1, and many labs are working on yet more preclinical ones.
With all these immunotherapies, does the field really need another? Indeed it does, Agadjanyan told Alzforum. First, multiple approved vaccines will be needed, because some people will respond to one vaccine but not another. Secondly, the field of AD immunotherapy is so young—and in Agadjanyan’s view, still a bit thinly staffed with card-carrying immunologists—that many of the vaccines that are currently in development have not been deliberately optimized for an elderly population. Vaccines for older people should be specifically designed to tap and reactivate the patient’s pre-existing memory T helper cells. That’s because in older people, those constitute by far the larger pool of T helper cells than naïve ones, which predominate in younger people. In other words, an AD vaccine could rouse an older patient’s memory T helper cells if it contained as its carrier protein a foreign T helper epitope from a conventional public health vaccine against which large numbers of older people had already mounted a T cell response earlier in life. Those could be epitopes that proved their mettle in childhood vaccines, such as from the diphtheria or tetanus toxins, or in influenza vaccines widely used in the elderly. When coupled with multiple copies of the right self-epitope from Aβ’s N-terminus, such heterologous vaccines would rally memory T helper cells to ignite a robust immune response, whereas the actual antibodies the AD patient’s B cells churn out would target Aβ. “If these vaccines prove safe, they may help especially older people overcome immune senescence,” Agadjanyan told the audience.
His group experiments with various peptide-based epitope vaccines along these lines. In Barcelona, he told the audience that some of these generate a strong response in mouse models and rabbits, whereby the T helper cell reaction was specific to the vaccine’s T cell epitope and the humoral response to Aβ. One vaccine is ready for tests in rhesus monkeys; another one, which boosts pre-existing memory T helper cells specific to the tetanus toxin epitope P30, reduced cored and diffuse amyloid plaques in Tg2576 mice. Another category of vaccine use DNA, not peptides. For those, the challenge lies in strengthening the body’s immune response, which tends to be feeble. Commercial vaccine research is developing ways to do that, for example, adjuvant patches that stimulate Langerhans cells in the skin or hand-held electroporation devices, Agadjanyan said. In addition, his group is working out prime-boost regimens that enhance both humoral and T helper cell responses with successive injections of DNA and protein (Davtyan et al., 2010).—Madolyn Bowman Rogers and Gabrielle Strobel.
This is Part 1 of a two-part summary of experimental therapies. For a discussion of small-molecule, metal-targeting, and other AD therapeutic approaches, see Part 2.
[No authors listed]. State of aggregation. Nat Neurosci. 2011 Apr;14(4):399. Abstract