AFFiRiS announces preclinical results of monoclonal antibody mAB C6-17 in Huntington's

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."

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Targeting regulatory T cells could boost the effects of cancer immunotherapy

A Ludwig Cancer Research study has identified a mechanism by which regulatory T cells, which suppress immune responses, adapt their metabolism to thrive in the harsh microenvironment of the tumor. This mechanism, the study finds, is exclusively engaged by regulatory T cells (T_regs) that reside in tumors and could be disrupted to selectively target such T_regs and boost the effects of cancer immunotherapy.

"It has long been known that the T_regs found in tumors protect cancer cells from immune attack, so countering T_regs would be an important strategy for cancer immunotherapy," says Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led the study. "But a major hurdle to such interventions is that the systemic suppression of T_reg activity can cause severe autoimmune reactions. We have discovered a potential approach to overcoming that problem, one that selectively targets T_regs in tumors and could therefore prevent such adverse effects."

T_regs play a critical role in healthy tissues, where they prevent autoimmune disease and aid wound-healing. But, when recruited into tumors, T_regs also thwart anti-cancer immune responses-;and immunotherapy. The current study, published in Nature Immunology, identifies a protein that drives the metabolic adaptations of intratumoral T_regs. The researchers show in a mouse model of melanoma that targeting that protein with an antibody significantly boosts the efficacy of immunotherapy without causing autoimmune side effects.

The cores of tumors are often acidic and starved of oxygen and vital nutrients, which forces resident cells to adapt their metabolism to survive. Ho and graduate student Haiping Wang suspected those adaptations might also reveal vulnerabilities unique to intratumoral T_regs. To find those vulnerabilities, they analyzed a dataset of T_reg gene expression in breast tumors and blood compiled a few years ago by the laboratory of Ludwig MSK Director Alexander Rudensky.

They found that those and other intratumoral T_regs expressed high levels of genes involved in lipid uptake and metabolism- particularly CD36, a receptor involved in lipid import. An analysis of T_regs from human melanoma patients conducted by Ludwig Memorial Sloan Kettering (MSK) researchers Taha Merghoub and Jedd Wolchok yielded similar results.

To explore the role of CD36 in intratumoral T_regs, the researchers generated mice that lacked the CD36 gene only in their T_reg cells and engrafted them with melanoma. "We found that the tumor burden was reduced in CD36-deficient mice," says Wang, "and the number and functionality of T_regs declined only within tumors, not in the other, healthy tissues of the mice."

CD36 deficiency induced in intratumoral T_regs a form of cell suicide known as apoptosis that was driven by a decline in the health and number of mitochondria-;the power generators of cells. Further study revealed that CD36 fuels the activity of PPARβ, a protein essential to the genesis and function of mitochondria.

Treating mice bearing melanoma tumors with an antibody to CD36 resulted in a decline of intratumoral T_regs that was not seen in genetically identical control mice. When this antibody was combined with an immunotherapy known as PD-1 blockade, which stimulates a T cell attack on cancer cells, tumor growth slowed significantly, prolonging the survival of the mice.

By targeting CD36 with an antibody, we don't just create trouble for intratumoral T_regs, we also createtrouble for the tumor's ability to maintain an immunosuppressive microenvironment and hamper immunotherapy."Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research

Ho's lab is now working to translate these findings into a potential cancer therapy while exploring how CD36-targeting might be combined with other interventions to more extensively disable T_regs selectively within tumors. They are also exploring which other types of solid tumors harbor T_regs that are dependent on CD36 for survival.
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New method found to inhibit Parkinson’s disease

Contrary to earlier discovery that a chemical found in a synthetic opioid, MPTP, induced a form of Parkinson's disease, a new study has found that it is an enzyme in the body that can metabolise compounds formed in the brain from alkaloids causing a neurodegenerative condition in mice.

The study  suggested that the enzyme, mitochondrial CYP2D6, presents a potentially powerful new target for Parkinson's treatment. "Over the past two or three decades, researchers have tried inhibiting the process by they believed MPTP was metabolised, with mixed success," he said.

"We believe that mitochondrial CYP2D6 is the more direct drug target, which might prove better in treating idiopathic Parkinson's disease," added one of the researchers. The study investigated the mechanism of Parkinson's disease when a specific cause cannot be pinpointed.

Previous studies have shown that MPTP and similar toxic compounds induce Parkinson's disease in rodents and primates. The mechanism of action, as scientists understood it, involved the compounds being oxidised to form MPP+, a toxic metabolite.

The enzyme that was believed to be responsible is called monoamine oxidase B (MAO-B), present in the nervous system's glial cells. In that conception of the mechanism, MPP+ was thought to then be transferred to dopamine neurons by dopamine transporter proteins, and, indeed, Parkinson's is characterised by unusually low dopamine levels in the brain.

Researchers have tried to stem the effects of Parkinson's by targeting two players in this presumed pathway, both MAO-B and the dopamine transporter protein, with only mixed success. In earlier work, Avadhani and colleagues had shown that the enzyme CYP2D6, localised to the body's energy factories, the mitochondria, could play a role in metabolising MPTP to MPP+.

In the new investigation, they took a closer look at beta-carbolines and isoquinolines, toxins that resemble MPTP which the body produces from substances found in tobacco smoke, alcohol, and some foods.

They found that, instead of MAO-B, it was mitochondrial CYP2D6 that activate the beta-carbolines and isoquinolines inside the dopamine-producing neurons, rather than the glial cells. This route of activation, in a mouse model, results in neuronal damage and oxidative stress, symptoms akin to Parkinson's. "CYP2D6 is known to play a role in influencing the activity of a number of drugs," said a researcher.

In an attempt to target this pathway, the researchers showed that mice lacking CYP2D6 did not exhibit severe symptoms than mice with the protein did. In addition, an inhibitor of CYP2D6 prevented neuronal damage in the mice.

"The CYP2D6 inhibitor ajmalicine is a member of the reserpine family of alkaloids, found in the plant Rauwolfia serpentine and was long used in India for treating mental illness, such as paranoia and schizophrenia," he said. "Mitochondrial targeting of such compounds is likely to be effective in treating Parkinson's patients, and pursuing that is our future strategy," said the researcher.

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