AFFiRiS, a clinical-stage biotechnology company developing novel disease-modifying specific active immunotherapies (SAITs), today announced that detailed preclinical results with its monoclonal antibody mAB C6-17 to treat Huntington's Disease (HD) were published in the peer-reviewed journal Neurobiology of Disease.
Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by changes in personality, impairments in cognition and loss of motor function, leading to death over a period of 10 to 30 years. The disease is caused by a highly polymorphic CAG trinucleotide expansion in the gene encoding for the huntingtin protein (HTT). The resulting mutant huntingtin protein (mutHTT) is ubiquitously expressed but also exhibits the ability to propagate from cell-to-cell to disseminate pathology; a property, which may serve as a new therapeutic focus and suggest that immunotherapy may provide a viable approach to neutralize mutHTT in the extracellular space.
Accordingly, AFFiRiS set out to develop a monoclonal antibody (mAB) targeting a particularly exposed region of the HTT protein. The results published in Neurobiology of Disease show that this monoclonal antibody, designated C6-17 effectively binds mutHTT and is able to deplete the protein from cell culture supernatants. Using cell-based assays, AFFiRiS demonstrated that extracellular secretion of mutHTT into cell culture media and its subsequent uptake in recipient HeLa cells can be almost entirely blocked by mAB C6-17. Immunohistochemical stainings of post-mortem HD brain tissue confirmed the specificity of mAB C6-17 to human mutHTT aggregates.
New therapies for Huntington's disease are urgently needed to address the root cause of this debilitating disease. Our findings demonstrate that mAB C6-17 not only successfully engages with its target, mutHTT, but also inhibits cell uptake. This suggests that the antibody could interfere with the pathological processes of mutHTT spreading in vivo. These results validate our HTT/mutHTT targeting monoclonal antibody that could ultimately be used as passive immunotherapy to treat features of Huntington's disease."
Günther Staffler, PhD, Chief Technology Officer of AFFiRiS AG
The majority of current preclinical and clinical mutHTT lowering strategies are based on gene silencing such as micro ribonucleic acids (miRNA) and anti-sense oligonucleotides (ASOs). These strategies are geared towards targeting mutHTT expression in the brain to interfere with the abnormal protein directly within neurons. However, mutHTT is ubiquitously expressed and antibodies would allow targeting of extracellular mutHTT throughout the body (brain and peripheral organs, tissues and plasma). This would be one of the most attractive features of this therapeutic approach.
Previous reports indicate that the ability of peripheral antibodies to enter the brain is limited. However, considering that the peripheral nervous system can impact the central nervous system, our antibody may have the capacity to exert some beneficial effect on the brain as well, by influencing mutHTT levels in the periphery. Additionally, combining our antibodies with intracellularly acting ASO or miRNA could provide us with a two-pronged therapy that can simultaneously tackle both intra and extracellular mutHTT. Antibody-based interventions have been demonstrated to be safe and straightforward in application and handling. As such we foresee that antibodies, such as our lead antibody C6-17, could pioneer a new therapeutic strategy for reducing extracellular mutHTT, giving hope to patients suffering from this extremely serious and difficult to treat disease."
Noel Barrett, Ph.D., CEO of AFFiRiS AG
Bartl, S., et al. (2020) Inhibiting cellular uptake of mutant huntingtin using a monoclonal antibody: Implications for the treatment of Huntington's disease. Neurobiology of Disease. doi.org/10.1016/j.nbd.2020.104943.