Beyond one pathway: tackling heterogeneity in respiratory and immune-mediated diseases

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Significant advances have helped to transform the treatment of respiratory and immune-mediated diseases, yet many people living with these diseases still do not achieve the control that both they and their clinicians seek. Together, these chronic conditions affect hundreds of millions of people worldwide and place a substantial burden on patients, health systems and society, with respiratory diseases alone responsible for approximately four million premature deaths each year.^1,2,3

One reason progress has stalled is because the drivers of disease often differ between patients. These differences are known as biological heterogeneity, where multiple pathways drive disease simultaneously or are important at different stages of disease progression. We have learned that single-target therapies are not enough for some patients to achieve disease control. For example, monoclonal antibodies (mAb) that target a single pathway, such as TNF-α in rheumatoid arthritis (RA), have delivered efficacy approaching 50% in terms of clinical remission in certain clinical trials;^4,5 single-target therapies preventing IL-4Rα signalling in chronic obstructive pulmonary disease (COPD) have delivered efficacy up to 34% in terms of reducing exacerbations.⁶ As there is no dominant disease-driving cytokine across all patients and stages of a disease, a single targeted mAb may not achieve maximal efficacy in everyone.

How the complexity of disease leaves patients uncontrolled

For decades, respiratory diseases such as COPD, idiopathic pulmonary fibrosis (IPF) and immune-mediated diseases such as systemic lupus erythematosus (SLE) and RA were often treated as though each disease was driven by a singular inflammatory mechanism. Today, advances in human genetics, multi-omics technologies and tissue analysis have revealed a far more complex reality.

In COPD and asthma, airway dysfunction, inflammation and tissue remodelling can coexist and interact, contributing to persistent symptoms and exacerbations despite treatment. As a result, around 50% of patients remain uncontrolled (difficulty breathing/exacerbations).^7,8 In lupus, multiple immune pathways may contribute to disease activity, organ damage and treatment resistance with approximately 33–50% of SLE patients developing irreversible organ damage within five years of diagnosis.^9,10 Similarly, fibrotic lung diseases involve interconnected inflammatory, metabolic and fibrotic pathways which may help to explain why current therapies only slow progression rather than halt it.¹¹

Adding another layer of complexity, patients with the same diagnosis can have strikingly different underlying biology. Multiple immune, inflammatory and fibrotic pathways can contribute to disease simultaneously or at different stages of disease. This may help explain why more than two-thirds of people with certain forms of inflammatory bowel disease do not currently achieve long-term remission.¹² It may also reveal why treatment switching remains common, and why durable responses can be difficult to maintain.¹³

As our molecular understanding of these diseases deepens, a critical question is emerging: if several biological pathways are driving a disease, how can we design medicines that address more than one disease mechanism at once, without over burdening the patient or losing scientific precision?

Why multispecific antibodies matter

At AstraZeneca, we are exploring multiple approaches designed to address several disease mechanisms at once. These include combination therapies, dual-target small molecules and advanced multispecific antibodies.

Among these options, multispecific antibodies are particularly compelling. Advances in antibody engineering mean they can be designed to bind to two or more different targets in distinct disease-driving pathways, combining multiple biologic actions with a single engineered molecule.

The potential advantage is straightforward. If disease is being driven by several pathways at once, a medicine capable of addressing multiple pathways simultaneously may have the potential to deliver deeper and more durable responses than targeting a single mechanism alone.

Importantly though, multispecifics alone, as a platform, are not a guaranteed answer. Their promise depends on identifying the right target combinations that are biologically connected, clinically relevant and feasible to engineer. Selecting two targets because each looks important in isolation is unlikely to be enough; the science must show why addressing them together could change disease outcomes. That is where advances in understanding disease pathogenesis are critically important.

Following the science to identify the right combinations

The ability to design multispecific medicines has advanced rapidly. The limiting factor is no longer whether we can engineer these molecules, but how we identify the optimal biological targets. At AstraZeneca, this effort begins with understanding disease in greater biological detail and connecting that insight to translational and clinical decision-making.

Our capabilities are strengthened with extensive clinical and biological datasets. Through large-scale genomics, multi-omics, advanced tissue profiling, we are building sophisticated, multi-dimensional maps of respiratory and immune-mediated diseases. We are also expanding these capabilities through partnerships with Helix, a leader in genomics research. This partnership broadens our access to large-scale clinico-genomic datasets that include diverse populations, supporting the discovery of novel targets linked to therapy resistance or disease progression. This allows us to prioritise therapeutic combinations with stronger translational rationale and improved probability of success.

Our breadth, knowledge and expertise across therapeutic areas is also key – diseases rarely exist in isolation. Patients frequently experience cardiovascular complications, infections, fibrosis and other comorbidities that influence disease outcomes. By bringing together expertise from respiratory, immunology, cardiovascular, oncology and infectious disease research, we can apply insights across disciplines and investigate disease through a broader biological lens.

This is where AstraZeneca brings a different perspective: deep respiratory and immunology expertise, human genetics and multi-omics capabilities, biologics engineering, and cross-discipline execution. The aim is not simply to make multispecific molecules, but to know which multispecifics are worth making.

Turning insight into innovation

The next step is translating scientific understanding into medicines designed around specific disease mechanisms. That means using disease biology to guide both the targets we pursue and the therapeutic modality best suited to address them.

In RA, this approach points to an upstream autoimmune process that current therapies may not fully address. In many patients, RA is driven by autoantibodies against citrullinated proteins known as anti-citrullinated protein antibodies (ACPA).^14,15 Two enzymes, PAD2 and PAD4, are involved in generating citrullinated proteins, creating targets that the immune system can attack.^12,13 Many current therapies focus on single targets and aim to suppress the downstream inflammation associated with this process, rather than addressing the continued production of autoantigens.^17,18 Removing the production of autoantigen may require blocking both PAD2 and PAD4, as they are co-released from activated neutrophils and both contribute to the generation of citrullinated proteins.^14,19 Bispecific approaches inhibiting both enzymes simultaneously aim to elicit a more complete blockade of autoantigen production driving the early disease course.

The same principles can also guide the design of small molecules. In COPD, airflow obstruction and chronic airway inflammation are two key features of disease that contribute to symptom burden and disease progression, but they reflect different aspects of the underlying biology.^20,21 PDE3 is prominently expressed in airway smooth muscle and is associated with airway constriction, while PDE4 is heavily involved in mediating the inflammatory response.^18,19

Targeting either pathway alone only addresses part of the disease. PDE3 inhibition could improve lung function through bronchodilation, but may have limited impact on inflammatory cell populations where PDE4 is more prominent.¹⁹ PDE4 inhibition can reduce inflammation and exacerbations but may have limited bronchodilatory effect.^22,23 Bringing both mechanisms together in a single inhaled treatment offers the potential to combine bronchodilatory and anti-inflammatory activity directly in the lung. Dual PDE3/PDE4 inhibition could have the potential to deliver both effects in a single molecule.

What this could mean for the future of respiratory and immunology care

Disease heterogeneity is one of the greatest challenges in respiratory and immunology research. Yet it may represent one of the greatest opportunities if we can translate biological complexity into better-designed medicines.

As our understanding of disease biology continues to improve, we are moving beyond viewing diseases as singular entities and towards understanding the diverse molecular mechanisms that underpin them. That shift is helping redefine how new medicines are discovered and developed.

Multispecific antibodies are one promising approach. Combined with advances in human biology, genomics, data science and biologics engineering, they offer the potential to better align therapeutic design with the complexity of disease itself.

At AstraZeneca, we believe the future of respiratory and immunology innovation lies in following the biology wherever it leads. By combining deep scientific understanding with advanced therapeutic engineering, we aim to develop the next generation of medicines capable of overcoming the challenges of disease heterogeneity and bringing better outcomes within reach for more patients.

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