A recent study showed improvements in animals with mutant huntingtin protein treated with AFFiRiS AG’s investigational monoclonal antibody.
AFFiRiS AG has announced in vivo data of its monoclonal antibody C6-17 that targets mutant huntingtin protein (mtHTT), showing that the agent reduced mtHTT levels in the central nervous system (CNS) and periphery. These data were presented at the 16th Annual Huntington's Disease Therapeutics Conference, April 27-29, 2021.1
“Interference with the extracellular mtHTT by a specific antibody could reduce and block intercellular mtHTT transmission and spread of HD pathology. This is expected to modify disease progression in the brain and periphery,” Günther Staffler, PhD, chief technology Officer, AFFiRiS AG, said in a statement. “Our previous findings supported [monoclonal antibody] C6-17 as a potential passive immunotherapy to treat features of Huntington disease (HD). These new in vivo data are further evidence of the potential of this monoclonal antibody in fighting this disease.”
The targeted mtHTT is ubiquitously expressed in individuals with HD and propagates from cell to cell to disseminate the pathology. Targeting mtHTT may be a way to neutralize the defective protein in the extracellular space and modify disease progression. C6-17 is a monoclonal antibody targeting a particularly exposed region of the HTT protein.
In vitro testing previously showed that C6-17 is able to significantly inhibit mtHTT uptake in cultured cells.2 Investigator Amber Southwell, PhD, assistant professor, Burnett School of Biomedical Sciences, Division of Neuroscience, University of Central Florida, and colleagues used cell-based assays to demonstrate that C6-17 almost entirely blocked extracellular secretion of mtHTT into cell culture media and its subsequent uptake in recipient HeLa cells. They confirmed that C6-17 is specific to mtHTT aggregates by immunohistochemical staining of post-mortem HD brain tissue. Their findings demonstrate that C6-17 successfully targets mutHTT and inhibits cell uptake. These results led to the presented study that showed that this antibody could interfere with the pathological processes of mtHTT spreading in vivo.
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The study presented at the conference showed that C6-17 quickly distributes in the body into peripheral organs and the central nervous system (CNS). Data suggest that C6-17-treated animals exhibited significantly reduced mtHTT levels in peripheral organs and the CNS and had improved motor performance.
“RNA/DNA targeted approaches focusing on the CNS may not be sufficient to treat a full body disease like Huntington disease, as they could leave a quantity of mtHTT still capable of inducing pathology in the periphery and also the CNS,” Southwell, principal investigator of the presentation, added to the statement.
“Our findings demonstrate that mAB C6-17 treatment may slow progression of motor deficits by inducing degradation of extracellular mtHTT protein. Immunotherapies such as C6-17 could therefore be a useful approach in combination with other HTT-lowering interventions to obtain a more complete depletion of mtHTT and to achieve a more comprehensive benefit in the treatment of HD,” she continued.
While still in its early phases of testing, this announcement of potential in HD is a positive sign after a slew of harsh news in March 2021 for the HD community. Over the course of a few short weeks, Roche discontinued the clinical development of its HD agent based on the investigational therapy’s potential benefit/risk profile for study participants, and shortly thereafter, Wave Life Sciences called off its trials of its investigational agents targeting the single nucleotide polymorphisms (SNPs) SNP1 and SNP2.
NeurologyLive recently spoke with Daniel Claassen, MD, MS, director, Huntington’s Disease Clinic, and division chief, Behavioral and Cognitive Neurology, Vanderbilt University Medical Center, about the current HD pipeline amid this news. He discussed Roche’s termination of the phase 3 GENERATION HD1 study of tominersin and Wave Life Sciences’s termination of the phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating WVE-120102 and WVE-120101, respectively, and the impact the news had on the community.3,4 Episode 34 of our Mind Moments podcast "Hope and the Huntington Disease Pipeline” featuring this conversation with Claassen is available below.