PLATFORM TECHNOLOGY - Morphomer(TM) & SupraAntigen(TM) Platforms: Targeting Misfolded Proteins in Neurodegenerative Disorders

INTRODUCTION

Neurodegenerative diseases are an ongoing public health crisis, with the two most common, Alzheimer’s disease and Parkinson’s disease, affecting more than 55 million patients worldwide.^1-3 Marketed therapies for these debilitating disorders provide only temporary relief from symptoms leaving patients and their caregivers to cope with disease progression and society bearing the tremendous socioeconomic costs associated with medical care and lost productivity.^4,5 Advanced forms of neurodegenerative diseases are particularly challenging to treat; indeed, using current diagnostic technologies, it may already be too late to intervene at the time of diagnosis.⁶ Thus, an urgent need exists for new technologies that can detect pre-symptomatic neurodegenerative disease, as well as novel disease-modifying treatments that can halt or reverse disease progression.

Protein misfolding and aggregation within and around neurons is a major hallmark of neurodegenerative diseases.⁷ Proteins that normally carry out essential functions in the healthy brain undergo changes in their three-dimensional structures resulting in abnormal conformations that can alter or completely disrupt protein functions. For example, changes in three-dimensional protein structure may lead to rearrangement of hydrogen bonding sites and an increased tendency for misfolded proteins to aggregate into specific oligomers, forming β-sheets. Pathological changes to three-dimensional protein structure, proteinopathies, in the brain can be caused by various events, such as genetic mutations and oxidative stress, but in most cases, the specific mechanisms underlying changes in protein structure remain poorly understood.

Each neurodegenerative disease has a specific hallmark protein (or set of proteins) that undergoes structural changes and assembles into insoluble aggregates. In Alzheimer’s disease, amyloid-beta and the protein Tau form amyloid plaques and neurofibrillary tangles, respectively; whereas, in Parkinson’s disease, alpha-synuclein accumulates and generates cellular inclusions known as Lewy bodies. Depending on the protein, these toxic aggregates can accumulate inside neurons or in the extracellular space and ultimately cause irreversible damage to neurons.

Misfolded proteins in the extracellular space may also drive the progression of neurodegenerative disease through the induction of seeding, a process by which misfolded proteins drive the spread of protein aggregates throughout the brain by inducing the misfolding of protein molecules still in their naïve state. Further, interactions between different protein species can lead to cross-seeding events and the existence of co-pathologies. For example, people with advanced stages of Alzheimer’s exhibit aggregation of not only Tau and amyloid-beta, but are also more likely to harbor misfolded variants of other proteins, such as alpha-synuclein or TAR DNA-binding protein 43 (TDP-43).^8,9

The complex aggregation and interactions of the many protein species involved in neurodegenerative diseases have motivated the pursuit of precision and combination medicine approaches to target the right protein at the right time. To drive the development of such therapies, therapeutic and diagnostic tools targeting a broad array of proteins are needed. Moreover, tools should specifically target aggregated forms of the relevant proteins or their pathological precursors, as less-specific targeting of all forms, including the “normal” form, of a protein may disrupt critical biological functions. The development of these tools may enable the detection of misfolded proteins before clinical symptoms are evident and the prevention of the neurodegeneration that leads to cognitive or motor impairment.

As well as the usual challenges of drug development, there are challenges specific to the development of agents designed to target proteins of the central nervous system (CNS). CNS-targeting therapies and diagnostics must distinguish between normal and toxic forms of the same proteins that differ only by their spatial conformation, a substantial challenge that the body’s natural innate immune system cannot meet. Further, such targeting agents must have an ability to cross the highly impermeable blood-brain-barrier, while, at the same time, maintaining a favorable safety and tolerability profile.

Here, we detail the efforts of AC Immune, a Swiss-based, clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, to develop the therapeutic and diagnostic tools necessary to enable precision medicine approaches targeting the right protein, at the right time, in the right patient. AC Immune’s industry-leading pipeline includes a broad array of conformation-specific antibodies, vaccines, and small molecules directed against misfolded and pathological forms of both well established (eg, Tau and amyloid-beta) and novel (eg, TDP-43) targets in neurodegenerative diseases.

The pipeline is powered by the company’s two proprietary drug development platforms, SupraAntigen^TM and Morphomer^TM. Together, these platforms accelerate the design, development, and validation of highly selective small molecules, antibodies, and vaccines for therapeutic and diagnostic applications. These platforms are complementary and have been optimized specifically to overcome the challenges of developing therapeutic or diagnostic candidates for CNS proteinopathies.

THE MORPHOMER^TM PLATFORM

Morphomer is a platform designed to enable the development of small molecules (Morphomers) able to bind/interact with β-sheet containing fibrillary aggregates from candidate selection through preclinical proof-of-concept. Morphomers (Figure 1) can target pathological protein aggregates in any brain compartment and are equally well suited for therapeutic and diagnostic applications.

The first key component of the Morphomer platform is its library of rationally designed, CNS-optimized non-dye compounds. AC Immune’s extensive know-how has enabled the identification of CNS compounds that penetrate the brain and demonstrate selectivity for the target. This knowledge has been used to focus the Morphomer library to approximatively 10,000 compounds that display these favorable characteristics, making this library an ideal starting point when developing molecules to target human proteinopathies of the CNS. Thus, rather than using the non-directed trial-and-error strategy of the typical drug development process, the Morphomer platform utilizes its bias for successful CNS candidates to improve efficiency and accelerate the early stages of the drug development process.

Following the identification of initial hits from the Morphomer library, promising compounds undergo several rounds of iterative medicinal chemistry hit-to-lead optimization. A thorough testing process highlighted by AC Immune’s proprietary suite of quantitative and qualitative selection assays provides the required feedback for continued compound optimization. These assays are designed to identify the hits showing in vitro activity against selected targets. The different assays are designed to provide detailed insights into one specific component of the molecule’s target mechanism of action and allows the ranking of compounds according to their performance. Such ranking is useful both for the identification of potential lead compounds, and to further refine the original CNS-biased compound library for future applications. Compared to typical drug development assays, AC Immune’s assays expedite the lead selection process by reducing false positives, and ultimately more accurately identify compounds likely to specifically bind selected targets in vivo.

Once identified as a lead compound, the candidate then moves into the next phase of proof-of-concept testing. While no animal model can fully reflect the complexity of a human neurodegenerative disease, AC Immune has developed or gained access to a large collection of rigorously validated, relevant translational animal models to systematically evaluate a candidate’s effect on the individual processes of human disease. Understanding how a small molecule targets pathological protein aggregates, if it prevents seeding rather than spreading: each feature can be determined through the application of a specific state-of-the-art assay to AC Immune’s highly translational animal models.

The Morphomer platform has grown into an invaluable asset that has contributed to the development of AC Immune’s industry-leading clinical pipeline for neurodegenerative diseases. Today, it stores years of research resulting in a detailed mechanistic understanding of the interactions of small molecules with an ever-increasing number of hallmark proteins implicated in neurodegenerative diseases. It provides a painstakingly optimized array of assays and compounds to further expand this expertise and accelerate the progression of small molecules through the drug development process. The platform has generated PI-2620, a Tau-positron emission tomography (PET)-tracer in Phase 2 development in partnership with Life Molecular Imaging, and ACI-3024, a small molecule Tau inhibitor in Phase 1 testing under a partnership with Eli Lilly and Company. Most importantly, it offers a strong foundation to continue to create the next generation of small molecules addressing novel targets with increasing efficiency.

THE SUPRAANTIGEN^TM PLATFORM

SupraAntigen is a liposome-based technology platform developed to generate biologicals for immunotherapy. It was first developed by AC Immune’s scientific co-founders for applications in oncology to overcome a challenge common to both cancer and neurodegenerative diseases: the lack of immunogenicity of disease-causing self-proteins. The SupraAntigen platform uses liposomes (small spherical vesicles formed by a lipid bilayer, as shown in Figure 2), to present specific antigens designed to evoke an immune response and generate antigen-targeting antibodies. SupraAntigen is used to generate conformation-specific antibodies for immunotherapy in neurodegenerative diseases.¹⁰ The overarching idea behind the platform is that antibodies, which are large in size, are well-suited to target extracellular proteins, interrupt spreading of pathological proteins, and break up and clear aggregates of misfolded proteins through phagocytosis.

AC Immune is the first and only company that has acquired advanced mastery of the design and manipulation of liposomes to develop either passive or active immunization techniques to generate antibodies targeting neurodegenerative diseases. When pursuing active immunization approaches, AC Immune uses liposomes carrying a specific antigen as a vaccine. After vaccination with a liposome, antigen and confirmation-specific antibodies are produced naturally by the host with very high affinity without further optimization. This immune response can be long-lasting and may be ideal to prevent the onset of a disease, as the immune system is now primed to rapidly identify disease-causing misfolded proteins.

To develop passive immunization strategies, AC Immune relies on the generation of antibodies, for example by injecting liposome constructs in mice, adapting them to the human immune system, and finally administering them to the patient to promote clearance of misfolded proteins. While passive immunization relies on frequent administration of exogenous antibodies, the “external” generation offers the opportunity to optimize antibodies for specific properties, which can prove critical when the patient’s immune system is not capable of producing the desired antibodies on its own.

AC Immune is pioneering the liposome approach in CNS-targeted immunotherapy and has gained unique experience when it comes to engineering peptides, adjuvants, and liposomes. Such experience has facilitated the development of an approach that is superior to standard liposome-based techniques. While early liposome work suggested a length limitation of 15-50 amino acids for single peptides attached on a liposome, AC Immune’s liposome technologies can incorporate several short peptides or whole proteins, enabling larger yield of antibodies and antibodies targeting a broad range of epitopes and epitopes with post-translational modification.

A critical aspect of AC Immune’s liposome-based technology is its ability to generate antibodies that are specific for precise protein conformations, as the misfolded proteins that are the hallmark of neurodegenerative disease differ from self-proteins only by their conformational state. This tour de force is achieved by precisely controlling and stabilizing the spatial arrangement of the peptides on the surface of the liposome, allowing peptides to be presented to the immune system in a conformation-specific configuration. Arranging peptides in repetitive arrays can simulate aggregates and generate antibodies that recognize pathologic self-proteins as foreign. Excitingly, it is now possible to specifically induce a β-sheet conformation of peptides on the surface of the liposome.¹¹

As AC Immune’s liposome approach creates a range of antibodies against a specified target, it allows for the selection of those antibodies with the highest affinity and selectivity. When pursuing passive immunization techniques, AC Immune aims to select an antibody candidate that combines high affinity and high specificity for the target, as this enables a favorable safety and tolerability profile. Compared to typically employed antibody selection approaches, AC Immune employs an accelerated process by utilizing an extensive collection of specific proprietary assays. These assays are comparable to the proprietary assay suite used in the Morphomer platform, and have been designed and implemented by AC Immune to expedite the drug development process in a similar manner.

SupraAntigen has generated numerous anti-Tau and anti-Abeta antibodies such as crenezumab, currently in Phase 2 testing in partnership with Genentech, a member of the Roche group. ACI-35.030, an anti-phosphoTau vaccine in Phase 1b/2a development and partnered with Janssen Pharmaceuticals, was also developed using the platform.

Similar to Morphomers, the development of potential lead antibodies is accelerated by access to AC Immune’s previously described bank of human brain tissue from patients with neurodegenerative diseases. Once in vitro activity target engagement with human tissue has been established, an antibody candidate is further validated in AC Immune’s collection of relevant translational animal models. As with Morphomer, the SupraAntigen platform is much more than a technique by which to generate candidate vaccines and antibodies, as it accelerates the drug development process from its initial stages through preclinical proof-of-concept and validation in human tissue.

CLINICAL & EXTERNAL VALIDATION

The AC Immune platforms are the foundation of a pipeline that includes nine therapeutic and three diagnostic candidates, with six being actively studied in clinical trials. Candidates target a broad array of pathological proteins, including classical hallmarks of Alzheimer’s disease, such as amyloid-beta and Tau, as well as novel targets, such as alpha-synuclein and TDP-43.

The power of the Morphomer and SupraAntigen platforms can also be seen when focusing on a single target, such as Tau. AC Immune has advanced four Tautargeting assets into the clinic, including the anti-phosphoTau vaccine ACI-35.030, Morphomer Tau small molecule aggregation inhibitor ACI-3024, anti-Tau monoclonal antibody semorinemab, and Tau-PET-tracer PI-2620. Further highlighting the truly comprehensive approach the company is taking against this high-value target, several of these assets are first-in-class with all having best-in-class potential in a highly competitive race to bring Tau-targeting therapeutics and diagnostics to patients.

The immense value of the Morphomer and SupraAntigen platforms is validated not only by the exciting preclinical and clinical data generated to date, but also by AC Immune’s partnerships with leading global pharmaceutical companies, including Genentech, Janssen, and Lilly, all of whom have maintained long-standing dominant positions in development and sales of CNS therapeutics. These partnerships have already generated significant revenue for AC Immune, more than the company has raised from investors, without including potential milestones and royalties. In summary, these platforms are remarkable from both the scientific and business perspective, and their productivity will only increase as AC Immune continues to accumulate knowledge and adapt to the discovery of novel targets in proteinopathies, paving the way for precision medicine in neurodegeneration.

REFERENCES

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Prof. Andrea Pfeifer co-founded AC Immune in 2003, where she holds since foundation the position of CEO. Prior to AC Immune, she was head of Nestlé’s Global Research in Lausanne, Switzerland, and managed a group of more than 600 people. While at Nestlé, she led the scientific development of the first Functional Food, LC1, and one of the first Cosmoceutical products in a joint venture with L’Oreal, Innéov Fermeté. She also cofounded the Nestlé Venture Capital Fund, a €100Mio. Life Sciences corporate venture fund. She serves as chairwoman of the Biotechmedinvest AG Investment Fund, Basel, and AB2Bio, Lausanne, and is member of the Supervisory Board of Symrise AG, Holzminden. Prof. Pfeifer is a member of the the CEOi Initiative on Alzheimer’s disease. She was recognized in 2009 as Technology Pioneer by the WEF and Swiss Entrepreneur of the Year by Ernst&Young. Additional recognitions include the BioAlps prize 2013, the election as one of the top 10 women in biotech from Fierce Biotech, and one of the 300 most influential personalities in Switzerland. Prof. Pfeifer earned her PhD in Toxicology, Cancer Research from the University of Würzburg, Germany and continued with post-doctoral work in Molecular Carcinogenesis at the National Institutes of Health, Human Carcinogenesis Branch, in Bethesda, USA. She is a registered Toxicologist and Pharmacist, received her habilitation from the University of Lausanne, Switzerland, and is an honorary professor at the Ecole Polytechnique Fédérale de Lausanne, Switzerland. She has published more than 200 papers and abstracts in leading scientific journals.