A new class of drug candidates for neurodegenerative diseases

How does morADC technology combine the properties of small molecules and monoclonal antibodies to enhance antiaggregation activity for CNS applications?

The technology combines two highly selective molecules, each of which has been individually developed to target and destroy pathological forms of proteins (i.e. proteinopathies) such as Abeta, Tau or a-synuclein (a-syn). The morADCs can cross the blood-brain barrier more efficiently and offer higher efficacy than single parent molecules. The new ADC technology was created by merging AC Immune's proprietary discovery platforms for biologics and small molecules (called SupraAntigen® and Morphomer® respectively). The resulting new class of therapeutic candidates exhibits synergistic properties.

Preclinical data have shown that morADC can interact with validated proteinopathies involved in neurodegeneration, including Abeta, Tau, and a-syn. morDAC enables single or dual targeting strategies that deliver combination therapy in a single therapeutic and demonstrate significantly improved antiaggregation effects compared to the parent molecules alone. Conjugation of brain-penetrant proprietary small molecules with a monoclonal antibody can multiply antibody exposure in the brain compared to the parent antibody alone.

These data demonstrating new functionality indicate that morADC has the potential for best-in-class efficacy against multiple therapeutic targets related to neurodegenerative diseases, including Alzheimer's and Parkinson's. We view this as an important advance in our goal of achieving precision prevention for neurodegenerative diseases.

What specific advantages does morADC offer compared to existing treatments in terms of blood-brain barrier penetration and efficacy?

Data from preclinical studies have shown that conjugating the right small molecule – one that both penetrates the brain and is specific to the target – to a monoclonal antibody targeting a specific proteinopathy allows for better penetration of the antibody across the blood-brain barrier and greater efficacy against the target.

Since the blood-brain barrier represents a significant obstacle for many therapeutically active substances, the data certainly indicate a significant advantage of morADC.

How do single-targeting morADCs, which target the same protein using an antibody and a small molecule, compare to dual-targeting morADCs, which target two different targets such as Abeta and Tau?

morADCs have been tested for single targeting, where the antibody and small molecule target the same protein, as well as dual targeting, for example an anti-Abeta monoclonal antibody combined with an anti-tau small morphomer molecule to enable combination therapy in a single therapeutic.

The single-target morADC shows significant synergistic antiaggregation effects compared to the parent molecules, and dual-targeted morADCs targeting, for example, Abeta and Tau were reported at AAIC and show several-fold higher antiaggregation effects. in vitro compared to the parent molecules.

Neurodegenerative diseases generally develop slowly over many years and are difficult to accurately diagnose, especially in the early stages. Therefore, we are still working to fully understand their development, including the precise role played by misformed types of different proteins such as Abeta and Tau over time. Due to this complex nature of neurodegeneration, the possibility of dual targeted therapy in this way could represent a significant treatment advantage.

What are the biggest challenges you expect in developing morADC therapies for neurodegenerative diseases and how do you plan to overcome them?

The development of morADCs is still in its early stages – clinical trials are at least a few years away. These molecules will need to overcome the usual optimization and preclinical toxicity hurdles before being tested in humans. We have learned a lot about these therapeutic targets (Abeta, Tau and a-syn) over the last two decades through our work on developing antibodies, active immunotherapies and small molecules against these targets. Therefore, we are confident that we can manage the complexity of dual-targeting morADCs in this setting and efficiently advance development. Indeed, the data to date is very compelling and the potential is clear.

The bottom line is that morADC has all the hallmarks of potential first and top-line efficacy against multiple high-value therapeutic targets, and we are actively exploring this potential.

Can you give us insights into the future plans for the morADC pipeline?

We have now gained a comprehensive understanding of the development of morADCs and collected proof-of-concept data. in vitro and have quantified the improvements in brain penetration in vivoWe plan to start in vivo We will begin experimenting on models of neurodegenerative diseases in the near future and once we reach that point we will be able to go into more detail about development plans.