You could say the concept that endogenous proteins in the body can misfold, aggregate, and spread disease from cell to cell has created infectious enthusiasm for drug development across the field of neurodegeneration and beyond. After all, a pathogenic protein that leaves one cell and passes through intercellular space before slipping into another ought to be a ready target for antibodies to intercept it. If having the “pathogen” spend time outside of neurons does not exactly make it a sitting duck for drugs seeking it out, it does render it more reachable than if it were operating solely from inside neurons. Scientists quickly caught on, and several groups presented new results on this front at the 11th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2013), held 6-10 March in Florence, Italy.
In a session jointly sponsored by the Swiss biotech company Neurimmune in Schlieren and its larger U.S. partner Biogen Idec in Weston, Massachusetts, researchers showed new preclinical data on antibodies that go after the ALS protein SOD1 and the diabetes protein IAPP (see below). Human antibodies against tau, α-synuclein, and TDP-43 exist but have not been publicly presented yet. In Florence, scientists also presented additional preclinical data on an antibody against the Alzheimer’s protein Aβ and the first clinical results. Taking that story further, scientists from an imaging CRO disclosed first results of how a prodromal AD trial of this antibody is using amyloid PET to test new diagnostic criteria in the imperfect world of multicenter studies (see Part 2 of this series).
Led by Roger Nitsch and Christoph Hock, the Neurimmune scientists have corralled more than 1,000 aged donors, who are either healthy or whose disease is not progressing, into giving blood for analysis of their memory B cells. The idea is that the donors have withstood disease because over their lifetimes, their immune systems have generated and matured effective auto-antibodies against abnormal endogenous proteins. These auto-antibodies may not show up as a straight-up titer in an aged person. Yet they persist in the form of memory B cells and can be amplified by screening these cells against pathogenic protein aggregates in a process the company calls Reverse Translational Medicine. This generated a set of therapeutic human monoclonal antibodies. “We are interested in those that do not bind to physiologic proteins but selectively target the pathologic conformation,” said Nitsch. Jeff Sevigny of Biogen Idec, which licensed several of these antibodies, noted that this makes the antibodies attractive from a safety standpoint. “We think the human immune system is better at engineering antibodies than are people,” said Sevigny.
In Florence, Jan Grimm of Neurimmune added new data to a previously introduced class of antibodies against the enzyme superoxide dismutase 1 (SOD1) as a potential therapy for amyotrophic lateral sclerosis (ALS). While SOD1 mutations account for only a fifth of familial ALS, the protein aggregates in sporadic ALS as well (e.g., Graffmo et al., 2013; Bosco et al., 2010;Forsberg et al., 2010). An ongoing analysis of sporadic ALS tissue samples gathered in Switzerland and Sweden has detected misfolded SOD1 in motor neurons of every one of 20 cases analyzed so far, Grimm said. This was done with Neurimmune’s new SOD1 antibodies. While this is an obvious study to do, it was not possible in the past because antibodies that are highly sensitive for misfolded SOD1 have only recently become available, Grimm said.
This finding makes SOD1 a target for the entire population of some 75,000 patients in Europe, the U.S., and Japan combined, Grimm claimed. It also means that SOD1 remains a drug target, even as newly discovered molecular players have opened up ALS research and researchers are increasingly dividing the disease into different subtypes. “FUS, C9ORF72, and TDP-43 mutation cases have misfolded SOD1, too. It may be a common final pathologic pathway,” Grimm said. SOD1 aggregates can spread from cell to cell (Chia et al., 2010), and adjoining motor neurons degenerate sequentially in ALS (Ravits and Spada, 2009).
In binding studies, one SOD1 antibody specifically targets pathological, misfolded SOD1 with low picomolar affinity but does not bind to misfolded tau or other proteins, Grimm said. The scientists infused 0.1 mg/kg/day of the antibody into the brain in the widely used SOD G93A mouse model starting at 60 days of age, before the mice start having motor symptoms. The chronic treatment almost doubled the number of surviving motor neurons. As the mice got sick, the treated ones retained more weight and a stronger grip, and preserved their gait in a high-speed film assay presented by Tobias Welt at the University of Zurich. The treatment reduced SOD1 aggregate pathology and added 10 days to the mice’s lifespan. This is a significant response in an aggressive model known for its 20-fold SOD1 overexpression. “It is rather difficult to see therapeutic effects in this model,” Grimm said.
The antibody showed a more profound effect in a different model. The G37R line (Wong et al., 1995) overexpresses SOD1 fivefold and develops a slower form of ALS. Weekly injections of 10 mg/kg into the bellies of these mice delayed the onset of symptoms by 49 days, slowed muscle atrophy, and pushed out death by 59 days. “This is the most dramatic effect ever seen in this model,” Grimm told Alzforum, adding that it is also the first reported therapeutic effect with a peripherally delivered antibody in ALS. “These are wonderful data,” said John Trojanowski at the University of Pennsylvania, Philadelphia.
ALS is increasingly understood to also affect cognition. At AD/PD, Fabian Wirth and other researchers in Welt’s laboratory and at Neurimmune reported that they detected SOD1 aggregates in the hippocampus, along with a subtle deficit in object recognition memory—a hippocampal-dependent task. This happened before motor symptoms set in, and antibody treatment reportedly restored this type of memory as well. This experiment was done in the SOD1 G93A model. None of the mouse studies brought up safety concerns, Grimm said.
Therapeutic effects in mice have raised hope before, only to disappoint in subsequent clinical studies (see ARF Webinar; see Shineman et al., 2011). Why would this be different? The new research avoids many of the shortcomings of early preclinical studies that have since been identified, Grimm told Alzforum. It used large groups of up to 24 mice in each experiment, was blinded, and saw the same effect by way of different routes of administration in different mouse strains, whose transgene copy number was confirmed for each study.
Grimm’s antibody is not the only one in play. The Canadian biotech company Amorfix is working with Biogen Idec on antibodies for ALS, and other groups are evaluating antibodies and active vaccines (see ARF related news story).
One Person’s Auto-Antibody, Another’s Diabetes Treatment?
From their healthy donors, Neurimmune scientists also derived antibodies against what they consider to be pathologic conformations of fibrillar aggregates of islet amyloid polypeptide (IAPP). This is a peptide hormone implicated in type 2 diabetes. The antibodies do not recognize native IAPP, Nitsch said. Β cells in the pancreas secrete IAPP along with insulin, and IAPP gene expression is co-regulated with expression of insulin in response to glucose. A sugary diet and subsequent insulin resistance hence drive up IAPP production, and when its concentration rises, it forms aggregates that are toxic to pancreatic islet cells. Like Aβ, IAPP is cleaved by neprilysin and IDE.
In a transgenic mouse model that develops IAPP protofibrils and diabetes, 18 weeks of treatment with these antibodies reduced this pancreatic islet amyloidosis. The treatment also improved B cell function. It brought down fasting glucose levels and insulin resistance, and restored the mice’s response to glucose challenge, Nitsch said.—Gabrielle Strobel.
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