New Drug Modalities in Lung Disease

WRITTEN BY

Maria Belvisi, Vice President and Head, RIA Innovative Medicines

Respiratory science is moving faster and faster. This is thanks to better understanding of the underlying biology driving these often very complex and heterogenous diseases, but also the advancement in new technologies.  New, inhaled drug modalities could help us achieve early intervention, disease modification and ultimately cure of respiratory disease.

In AstraZeneca, our early Respiratory research is focused on four diseases: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis and Chronic Cough. All of these represent diseases where the unmet medical need remains significant and, in some cases, we see an increasing prevalence. To address these unmet needs, transformative therapies are critical aiming to achieve early intervention, disease modification and in the future even cure.  And that in turn means we need to be able to target any novel biology we uncover, and embrace new technologies making this possible. Let me explain why. 

When uncovering new potential drug targets and pathways, these may not be accessible or inappropriate to target with traditional small molecules, monoclonal antibodies or proteins.  However, molecules with different properties could open new routes, and this is where new technology and modalities play an increasing role in our drug modality toolbox. In respiratory, AstraZeneca is exploring a range of these emerging modalities, working in close collaboration with leading biotech companies around the world. I would like to introduce you to some of these modalities.  

Anticalin® Proteins

Anticalin® molecules are artificial proteins that can mimic monoclonal antibodies (mAbs) offering high precision and potency, and suitable for targets that are intractable for traditional small molecules. However, as Anticalin® molecules are much smaller than mAbs, they can be delivered through non-injectable routes. In respiratory, that means they can be inhaled and delivered directly to a target in the lung. AstraZeneca is collaborating with Pieris Pharmaceuticals to develop Anticalin® therapeutics for the treatment of Respiratory diseases, and our first clinical trial started in 2017.  

Immuno-stimulatory oligonucleotides

Oligonucleotides are short strands of DNA or RNA molecules. In Respiratory we have a special interest in so called immuno-stimulatory oligonucleotides. These are structurally similar to naturally occurring DNA but can be produced synthetically and modified to mimic processes in the body, such as the way bacteria and viruses stimulate the immune system. AstraZeneca is working in collaboration with Dynavax Technologies – a company that specialises in immuno-stimulatory oligonucleotides that target so called toll-like receptors (TLRs). These receptors are thought to play a key role in the activation of the immune system, which is often imbalanced in patients with respiratory diseases. Therefore, TLRs are interesting targets for approaches where we aim to modify the underlying drivers of respiratory disease.

Bicyclic peptides    

Bicycles® are synthetic, highly constrained peptides with properties that resembles antibody or small protein in terms of high target specificity and affinity. But, due to their low molecular weight they penetrate deeper into the tissue and allow for inhaled delivery directly to the lung.
Through a collaboration with Cambridge-based Bicycle Therapeutics, we aim to identify and develop Bicycles® to treat respiratory disease and we are currently exploring several interesting opportunities.

mRNA

Messenger RNA (mRNA) has evolved as one of the most intriguing new drug modalities in the pharmaceutical toolbox.  It is a single stranded RNA that conveys genetic information from DNA to the ribosome, where it is translated into protein products. Since mRNA can be used as a blue-print for producing proteins in cells, it can be chemically synthesized as a therapeutic to produce intracellular proteins needed to correct disease. Modifications are made to the mRNA structure to make it more stable and less immunogenic.

Last year, together with MedImmune, we announced a five-year strategic collaboration with Ethris GmbH, a leader in messenger RNA (mRNA)-based therapeutics with the focus on developing new stabilised non-immunogenic mRNA (SNIM®RNA) therapies for respiratory diseases. The collaboration gives us exclusive access to Ethris’ proprietary SNIM®RNA technology and formulations to develop new targets for investigation in the areas of asthma, COPD and IPF.

At AstraZeneca, we aim to transform the treatment of respiratory disease with our portfolio of inhaled and biologics medicines, along with scientific research targeting the underlying causes of the disease. Click here to find out more.