Exploring the Potential of Immunotherapy for Movement Disorders

Howard Gendelman, MD

When caring for people with movement disorders, neurologists have long relied on treatment options that target the symptoms of the disease. In Parkinson disease (PD), for example, current therapies address motor symptoms and nonmotor symptoms such as psychosis or cognitive decline.¹ While such therapeutic options have steadily improved in terms of availability and efficacy, a void remains in the treatment of movement disorders that only disease-modifying therapies can fill.²

“So far, we only have symptomatic therapies available: These are dopamine replacement thera- pies, which can be quite effective, especially in the early stage of Parkinson disease. However, after a while, these therapies tend to lose their effectiveness and health problems get worse for patients,” said Lars Tönges, MD, head of the Movement Disorders Unit in the Department of Neurology, Ruhr University, Bochum, Germany. Indeed, symptomatic treatments do not target the root cause of a disease and may even lead to undesirable adverse effects for patients.³

Addressing the longstanding need for a novel curative treatment for movement disorders, immunotherapy has emerged as a promising area of development.

Tönges, who is involved in multiple studies exploring possible strategies to cure movement disorders, said interest in immunotherapy to treat PD is very high “because it is an entirely novel approach to treat PD. So far, we have no therapy to tackle the pathogenic origins of the disease. However, immunotherapies will not only improve symptoms; they may also stop or at least slow down the disease itself.”

Recent studies in neurology and immunology show that the immune response may be significantly involved in countering the progression of movement disorders. In particular, researchers are increasingly exploring the role that the pathology of α-synuclein may play in treating movement disorders.²

While much of this research is still in the development phase, Howard Gendelman, MD, the Margaret R. Larson Professor of Internal Medicine and Infectious Diseases and chairman of the Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center in Omaha, said he believes that “immunotherapy for movement disorders has a bright future.” Indeed, clinical development of immunotherapies for move- ment disorders is progressing rapidly, with many studies shifting from animal trials to human clinical trials.^4,5

Novel Strategies in Immunotherapy

Recent studies exploring immunotherapy for movement disorders revolve around 2 main strategies: the use of antibodies to target the α-synuclein pathology and harnessing the neuroprotective properties of regulatory cells.

The role of antibodies in α-synuclein pathology

Α-synuclein performs various functions, including communication among neurons.⁶ In PD, α-synuclein can become a pathological agent that leads to toxic effects on neurons and drives neuroinflammation.⁷

“Due to α-synuclein and its aggregation in the brain and the central nervous system (CNS), there are many resulting disturbances in cell function. Protein ubiquitination systems are affected, the synaptic vesicle release is disturbed, and new inflammatory

a-Synuclein Immunotherapy processes are fostered,” Tönges said. Subsequently, a common goal in developing immunotherapy for PD is to reduce the α-synuclein burden in the CNS.⁸ “Our primary goal is to find a cure for Parkinson disease. This means targeting the α-synuclein pathology, which is undoubtedly the primary pathology,” he said.

The use of immunologic, antibody-based technologies is a novel approach to reduce the burden α-synuclein has on the CNS.⁹ “Antibodies can directly counteract α-synuclein pathology in the brain,” Tönges said. “Those antibodies that have the goal of binding pathogenic α-synuclein aggregates are seen as an effective means to eliminate α-synuclein pathology to a certain extent, and thereby reduce its pathogenic alterations.” The results of research underway by Tönges and his colleagues have shown reductions in pathogenic alterations when α-synuclein antibodies are given as immunotherapy. However, Tönges did note that studies in this area are still only in phase 2: “Currently, the antibody approach represents a new and very important therapeutic approach, but we cannot say yet if it will be effective. Two big clinical trials are still ongoing: the PASADENA study and the SPARK study.”

The PASADENA study is a randomized, double-blind, phase 2 clinical trial of prasinezumab (RO7046015/ PRX002), an investigational monoclonal antibody directed against α-synuclein aggregates.⁴ The antibody is intravenously introduced into patients diagnosed with mild or moderate idiopathic PD. Roche and the biotechnology company Prothena began the study in April 2017 and have completed the recruitment stage. The study is set for primary completion before the end of 2019, with full completion expected in 2021 (FIGURE).

The SPARK study aims to evaluate the safety, pharmacokinetics, and pharmacodynamics of the humanized monoclonal antibody BIIB054 in patients with early-stage PD.⁵ Preclinical data have shown that BIIB054 contributes to a reduction in the spread of α-synuclein and limits its impact on neuron damage.¹⁰ Biogen began the study in January 2018; its initial completion is set for May 2020, with full completion scheduled for June 2021.

“Both the PASADENA and SPARK studies apply α-synuclein anti-bodies intravenously," Tonges said. "Primarily, the aim of these 2 big trials is to see whether these Parkinson disease treatments are safe and well tolerated in patients. The changes in motor and nonmotor symptoms are secondary endpoints. If these phase 2 endpoints are fulfilled, only then will we have larger phase 3 trials and only then can we evaluate whether these antibody therapies are effective in the Parkinson disease patient population."

The role of regulatory cell activites in neuroprotection

According to Gendelman, "What is known to date is that the healthy immune system can temper brain inflammation as it occurs in stroke and in autoimmune and neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, and Parkinson disease.” To leverage the ability of a healthy immune system to mitigate inflammation, researchers are exploring the use of T cells and B cells, as well as mononuclear phagocytes, as a novel strategy to potentially treat movement disorders. T cells and B cells play a role in maintaining peripheral immune tolerance and help to regulate immune response in the body.¹¹ Mononuclear phagocytes such as microglia, macrophages, and dendritic cells also help regulate tissue damage and repair neuroinflammation.¹²

“Recent work by several laboratories in vitro, ex vivo and in vivo have shown how regulatory cells can be harnessed as cell-based therapies for neurological disorders,” Gendelman said. ”Regulatory T cells, B cells, and mononuclear phagocytes are cells mediating brain homeostasis. Regulatory immune cell therapies can attenuate inflammation-associated brain injury and thus affect brain repair.”

Gendelman and colleagues are working on the use of “smart” drugs that are packaged into immunocytes as a “Trojan horse” cell-based mechanism to bypass the blood—brain barrier and enter diseased brain areas. “We are working on long-acting forms of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) that may be packaged into nano formulations,” Gendelman said. “GM-CSF can modulate microglial-associated neurotoxicity and is effective in traumatic brain injury, stroke, amyotrophic lateral sclerosis, Alzheimer disease, and Parkinson disease. However, these solutions remain in development.”

Research on the neuroprotective responses of GM-CSF has moved on from a spectrum of animal models toward human trials. For instance, a phase 1 study conducted by Gendelman and colleagues on the safety and immunomodulatory effects

of sargramostim in PD has since been translated into human trials.¹³ These trials were based on animal investigations span- ning more than 10 years, which demonstrated the neuroprotection features of regulatory T cells in the dopaminergic pathway, revealing a potential for immune transformation in PD.

“Through our prior published works, we have demonstrated that sargramostim treatment modulates the microglial activation and the consequent secretion of proinflammatory factors that ultimately damage neurons,” Gendelman said.

He further explained that such neurons are in the pars compacta, which is part of the brain’s substantia nigra located in the midbrain and formed by dopaminergic neurons that may be damaged in PD. “We have shown that the modulation by GM-CSF treatment can occur through induction of regulatory T cells that can migrate from the periphery across the blood—brain barrier and, as such, lead to neuroprotective activities during Parkinson disease,” he said.

In their early clinical trials, Gendelman and colleagues have shown that the effects of modulation by sargramostim treatment is linked to improved motor functions in patients with PD. Furthermore, patients administered sargramostim showed modest improvements according to the Unified Parkinson’s Disease Rating Scale. Patients also showed improved motor activities and regulatory T cell numbers and function, demonstrating the potential for using GM-CSF to modulate immune response and thus provide thera- peutic gain for patients with PD.¹³

In another ongoing study, yet to be published, Gendelman demonstrates how restoration of the balance in regulatory cells can improve disease conditions. Specifically, he is looking at how a transforma- tion from effector cells to regulatory cells can lead to neuroprotection in a broad range of neurodegenerative conditions.

Beyond Parkinson Disease: Immunotherapy for Other Movement Disorders

Studies on the potential therapeutic gain of harnessing antibodies and regulatory cells in the immune system are mostly geared toward developing treatments for PD. “In my opinion, there has been a very strong development in immunotherapy and Parkinson disease because we now know the disease not only on a pathological level but also on a neuromolecular level. We now know that multiple immune processes are associated with neurodegeneration,” Tönges said. He pointed out that, fortunately, “There are new technologies, where we can find immunotherapeutic targets in Parkinson disease that we can also use as therapeutics for other diseases.”

Specifically, the research so far on antibodies against α-synuclein might also apply in other etiologies and forms of parkinsonism as well as in other movement disorders with α-synuclein co-pathology.

Multiple system atrophy

Multiple system atrophy (MSA) is a severe neurodegenerative condition characterized by symptoms similar to those in PD. One study found that antibody levels that are significantly low in PD were almost absent in MSA. This indicates that patients with MSA have impairments in the processes that block the toxic effect of α-synuclein aggregation and that modulate the progression of inflammatory symptoms.¹⁴

The pathogenesis of MSA remains unknown because of a lack of understanding of the causative mechanisms underlying the condition.¹⁵ However, MSA is another disease with a strong α-synuclein pathology, involving the aggregation of the protein. “Antibodies are a potential treatment in MSA and should be studied soon,” Tönges said.

Huntington disease

Huntington disease (HD) is an inherited neurodegenerative disorder that involves uncontrolled tremors, cognitive impairment, and psychiatric issues for which no disease-modifying treat- ments exist.¹⁶ However, understanding of the pathogenesis of HD has been increasing, allowing the identification of potential therapeutic targets and research into disease-modification approaches. While not all clinical trials regarding HD disease modification have produced favorable results, immunotherapies are still believed to hold promise in modulating neuroinflammation.⁹ For instance, the SIGNAL trial, a randomized, double-blind phase 2 study, is investigating the effect of mAb 67-2 (a monoclonal antibody) on semaphorin 4AD, a protein that modulates neuroinflammation pathways in the nervous system.¹⁷

The modulation of α-synuclein also has application in efforts to develop a treatment for HD. “We know that α-synuclein pathology spreads out in the brain and that, of course, antibodies offer a very clear first approach to directly target this pathology,” Tönges said. “Other therapies could also be directed toward lowering α-synuclein levels, such as antisense oligonucleotides. These have been successfully implemented in HD to downregulate the protein huntingtin.” Indeed, pharmaceutical companies are harnessing antisense oligo- nucleotides, which can interfere or silence the gene that promotes HD, to develop treatment for the condition.¹⁶

Paraneoplastic movement disorders

Paraneoplastic movement disorders (PMDs) are neurological conditions characterized by either hyperkinetic or hypokinetic movements. A recent review showed that identifying the right antibody could be essential for applying immunotherapy to the treatment of PMDs.¹⁸

Specifically, PMDs are immune-mediated, as demonstrated by the presence and rapid onset of antineuronal antibodies in biological samples of patients during diagnosis. Two classes of antineural antibodies exist: those against intracellular neuronal antigens and those against surface antigens (NSAs). The former are considered markers of the so-called “classical PMDs,” but they do not have a direct pathogenic role in movement disorders. Measuring the antibodies against these antigens, therefore, does not provide a full picture of the potential of immunotherapy for treating PMDs.

NSAs were found to respond more frequently to immunotherapy than intracellular neuronal anti- gens, demonstrating that the antibodies reacting against NSAs have a direct pathogenic role in PMDs.18 “When the antibody has a direct pathogenic role, it is easier to target it with immunotherapy compared with intracellular neuronal antigens,” said Carlo Colosimo, MD, chairman of the Department of Neurology at Santa Maria University Hospital in Terni, Italy.

In terms of the future of immunotherapy for PMDs, Colosimo has high hopes: “We see great potential, particularly in increasing the knowledge and diagnosis of PMDs. The earlier these patients are diagnosed, the better their outcome will be in terms of survival, considering that PMDs may manifest up to 6 years before full onset. More patients will also be enrolled in future clinical trials and new disease-modifying treatment options will be available.”

Clinical Relevance

Recent studies on the potential therapeutic uses of antibodies and regulatory cells augment clinicians’ current clinical understanding of movement disorders and their common disease pathways. “We now have a very good molecular understanding, with new insights into the pathology of movement disorders,” Tönges said.

Neurologists should pay attention to developments in immunotherapies for movement disorders, as they could lead to improved clinical benefit for patients. Moreover, neurologists may be able to apply existing immunotherapies for movement disorder treatment, thus helping to optimize the use of currently available immunotherapies. “In movement disorders, we use exactly the same therapies that are used in other fields, and the main progress in immunotherapies has already been done for autoimmune diseases as well as for oncological disorders,” Colosimo said.

Clinical benefit has yet to be clearly demonstrated, but Tönges is optimistic: “We see that these antibodies really meet their goal of precise molecular targeting.” In addition to precision targeting, advancements in immunotherapy for movement disorders could ultimately lead to the development of treatments that target the cause of the disease in the near future.

REFERENCES

1. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. doi: 10.1038/nrdp.2017.13.

2. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson Disease. Neurol Ther. 2019;8(1):29-44. doi: 10.1007/s40120-018-0122-z.

3. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80- 89. doi: 10.1002/mds.26125.

4. A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s disease (PASADENA). clinicaltrials.gov/ct2/show/NCT03100149. Updated April 26, 2019. Accessed October 3, 2019.

5. Evaluating the safety, pharmacokinetics, and pharmacodynamics of BIIB054 in participants with Parkinson’s disease (SPARK). clinicaltrials.gov/ct2/show/NCT03318523. Updated September 6, 2019. Accessed October 3, 2019

6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi: 10.1016/j.neuron.2013.09.004.

7. Sulzer D, Edwards RH. The physiological role of α-synuclein and its relationship to Parkinson’s disease. J Neurochem. 2019;150(5):475-486. doi: 10.1111/jnc.14810.

8. Zella MAS, Metzdorf J, Ostendorf F, et al. Novel immunotherapeutic approaches to target alpha-synuclein and related neuroinflammation in Parkinson’s disease. Cells. 2019;8(2):E105. doi: 10.3390/cells8020105.

9. Bashir H. Emerging therapies in Huntington’s disease. Expert Rev Neurother. 2019;19(10):983-995. doi:10.1080/14737175.2019.1631161.

10. 10. Weihofen A, Liu Y, Arndt JW, et al. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson’s disease models. Neurobiol Dis. 2019;124:276-288. doi: 10.1016/j.nbd.2018.10.016.

11. Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. 2019;10:43. doi: 10.3389/fimmu.2019.00043.

12. Locatelli G, Theodorou D, Kendirli A, et al. Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat Neurosci. 2018;21(9):1196-1208. doi: 10.1038/s41593-018-0212-3.

13. Gendelman HE, Zhang Y, Santamaria P, et al. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis. 2017;3:10. doi:10.10.1038/s41531-017-0013-5.

14. Folke J, Rydbirk R, Løkkegaard A, et al. Distinct autoimmune anti-α-synuclein antibody patterns in multiple system atrophy and Parkinson’s disease. Front Immunol. 2019;10:2253. doi: 10.3389/fimmu.2019.02253.

15. Monzio Compagnoni G, Di Fonzo A. Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives. Acta Neuropathol Commun. 2019;7(1):113. doi: 10.1186/s40478-019-0730-6.

16. Malcolm E. Antisense oligonucleotides. Huntington’s Disease News website. huntingtonsdiseasenews.com/antisense-oligonucleotides/. Accessed October 3, 2019.

17. SIGNAL: a new investigational approach to early treatment of Huntington’s disease. Huntington Study Group website. huntingtonstudygroup.org/current-clinical-trials/signal-trial/. Accessed October 3, 2019.

18. Chirra M, Marsili L, Gallerini S, Keeling EG, Marconi R, Colosimo C. Paraneoplastic movement disorders: phenomenology, diagnosis, and treatment. Eur J Intern Med. 2019;67:14-23. doi: 10.1016/j. ejim.2019.05.023.