14 October 2011. Another antibody joins the ranks of those reported to clear Aβ from the brains of patients with mild to moderate Alzheimer's disease. Gantenerumab, a human monoclonal antibody, clears plaques in a matter of months, report scientists at F. Hoffmann-La Roche Ltd., Basel, Switzerland, in a study published online in the October 10 Archives of Neurology. Senior author Luca Santarelli and colleagues used positron emission tomography (PET) scans of carbon 11-labeled Pittsburgh Compound B (11C-PIB) to compare plaque levels in brain before and after intravenous antibody treatments, and saw dose-dependent decreases. It is still too early to compare the performance of this new antibody with others currently in Phase 3 trials. The study did not evaluate cognition, but trials are underway to address that. "The encouraging result is that they demonstrated some lowering of amyloid retention in PIB scans in a relatively short period of time with a small sample," said Stephen Salloway of Butler Hospital, Providence, Rhode Island, one of the clinical investigators involved in trials of another Aβ antibody, bapineuzumab.
There are about a dozen anti-Aβ antibodies in preclinical and clinical testing, including solanezumab, developed by Eli Lilly and Company, Indianapolis, Indiana, which, along with bapineuzumab, is furthest along in clinical development. An earlier small study of the Elan Pharmaceuticals/Wyeth antibody bapineuzumab (now developed by Janssen Alzheimer Immunotherapy, Dublin, Ireland) also used PIB-PET scans to compare plaque levels in brain before and after intravenous antibody treatment. This antibody lowered brain amyloid levels in Alzheimer's patients by an average of 8.5 percent over 18 months, compared with a 16.9 percent increase in untreated patients (see ARF related news story on Rinne et al., 2010). This small trial did not have the statistical power to assess the clinical outcomes of the plaque reduction; that will be addressed in Phase 3 clinical trials, the results of which are expected next year. Phase 3 trials are also underway for solanezumab.
In the current study, 18 patients, aged 50-90, who had mild to moderate AD, received either placebo or gantenerumab (60 mg or 200 mg) in up to seven monthly intravenous infusions. At the end of the study, PIB-PET scans indicated that the six patients in the low-dose group lost 15.9 percent of their plaques, while the six in the high-dose group dispatched 35.7 percent. If this holds up, it would indicate faster amyloid removal than reported for bapineuzumab.
To figure out how the antibody worked, first author Susanne Ostrowitzki and colleagues incubated human brain tissue slices from AD patients with the antibody and microglial cells, which are proposed to mediate clearance of Aβ. Live cell imaging showed that the more antibody was applied, the more amyloid the microglia took up.
"We think the drug works by engaging [microglial] cells to eat up the toxic amyloid from the brain," said Santarelli.
A separate paper in the September 28 Journal of Alzheimer's Disease by Roche scientists, including senior author Hansruedi Loetschera, details the method by which the team created the antibody. They selected it from a human phage display library based on its strong, specific binding to Aβ plaques. The paper reports that gantenerumab recognizes both the N-terminal and central portions of Aβ, which the authors claim is unique, and that in double-transgenic (APP751SwexPS2N141I) mice, it both clears plaques and prevents their accumulation by recruiting microglia. Bapineuzumab and solanezumab bind the N-terminal and central region of Aβ, respectively.
One issue that dogs the use of antibodies for treating AD is amyloid-related imaging abnormalities (ARIAs), which include microhemorrhages and vasogenic edema (see Sperling et al., 2011). This is a frequent problem, particularly with antibodies that engage Fc receptors on microglia, and more often experienced by ApoE4 carriers. In the current human trials, two patients in the high-dose group, both of whom were homozygous for the ApoE4 allele, showed evidence of ARIAs in the areas of highest plaque removal. As with bapineuzumab, ARIAs occurred more frequently in people carrying ApoE4 as well as those on the higher dose. These abnormalities resolved after the researchers stopped treatment. Most researchers interviewed thought that despite the risk for ARIAs with these antibodies, the effects are manageable and transient. Patients can resume treatment, often on a lower dose, after their MRI scans return to normal. Some hypothesize that anti-Aβ antibodies cause blood vessels to become leaky due to the movement of amyloid-β from brain plaques across blood vessel walls, which might explain why ARIAs occur in areas of highest plaque removal (see ARF related news story).
Does Aβ Removal Rescue Memories?
As with the other anti-Aβ antibodies currently in Phase 2 and 3 clinical trials, it is unclear whether Aβ clearance by gantenerumab prevents or slows cognitive decline. The field anticipates results of Phase 3 trials of solanezumab and bapineuzumab next year, which will reveal whether clearance of Aβ provided any cognitive benefit in mild to moderate AD. Elan's original trial of the AN-1792 antibody, which was halted in Phase 2a because some patients developed meningoencephalitis (see ARF related news story), showed plaque removal but only hints on cognition, with no overall benefit but positive signals in certain memory assessments (Gilman et al., 2005). Some think that may be because the study participants were too far along in the disease progression. "There's a growing consensus that these agents are likely to have their biggest impact when administered earlier in the disease course—in the preclinical or early symptomatic phases," Salloway old ARF.
If none of these antibodies improve cognition, will that be the final nail in the coffin for the amyloid hypothesis? Absolutely not, said Eric Siemers of Lilly. "A number of us are a little concerned that if there's not an early success, then people will prematurely give up on the amyloid hypothesis," he said. If early trials of these antibodies do not show cognitive improvement, it may be that other species of Aβ should be targeted or patients need to be treated earlier on in the disease process. "We don't want to give up too early," Siemers emphasized.
The ongoing Phase2b trial aims to test gantenerumab on patients with what researchers call prodromal AD. Researchers are recruiting patients who meet set criteria for cerebrospinal fluid Aβ and cognitive impairment, but whose impairment falls short of a dementia diagnosis. During the two-year treatment, Santarelli and colleagues will administer the antibody subcutaneously, rather than intravenously, and look for cognitive effects primarily using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB), a global measure of cognition and functional ability.
To the casual observer, gantenerumab may seem to be just another antibody that aims to clear Aβ. In truth, not all of these antibodies are created equal, Siemers said. Each one targets a different form of amyloid in the brain: Solanezumab targets the mid-region of soluble Aβ monomers; bapineuzumab gloms onto the N-terminus of Aβ and is presumed to bind monomer, oligomer, and plaque Aβ; and gantenerumab grabs both central and N-terminal portions of Aβ. "What's not known at this point is which species of Aβ treatment should target," Siemers said. That's because the actual culprit of toxicity still is not clear. Researchers predicted that if one of these antibodies successfully removes a form of Aβ and improves clinical symptoms, it might illuminate which Aβ species causes neuron death.—Gwyneth Dickey Zakaib.
Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu Z, Loetscher H, Santarelli L. Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab. Arch Neurol. 2011 Oct 10. Abstract
Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H. Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β. J Alzheimers Dis, 2011 Sep 28. Abstract