A recent paper published in Frontiers in Drug Discovery examines the potential of bispecific and trispecific biologics (multi-specific biologics), a new class of therapies in development for atopic dermatitis (AD).
AD, a chronic condition characterized by inflammation, itching, and skin barrier dysfunction, affects approximately 16.5 million adults in the U.S. and 10-20% of children worldwide. Exacerbated by pollution, climate, and exposure to irritants, AD affects individuals of all races, ethnicities, and skin types, causing discomfort, pain, lifestyle limitations, and even mental health challenges.
Providing Broader Relief
Designed to target multiple immune and inflammatory pathways, bispecific and trispecific biologics aim to address several drivers of AD simultaneously, rather than blocking one specific molecule or pathway. These therapies are engineered to inhibit multiple immune signals at once, including IL-13, a cytokine that drives inflammation and skin barrier dysfunction, and OX40L, a molecule involved in T-cell activation and chronic inflammation. By targeting both IL-13 and OX40L, these agents may reduce inflammation while promoting regulatory T-cell activity to help rebalance the immune response.
Because AD arises from a complex interaction of immune cells, cytokines (chemical messengers), and barrier dysfunction, current monospecific biologics — such as dupilumab — may not be effective for all patients or disease subtypes. While dupilumab has transformed the management of moderate-to-severe AD, offering meaningful improvements in skin clearance, itch, and quality-of-life, gaps in disease control remain.
Multi-specific biologics may offer broader and more consistent efficacy by addressing multiple aspects of the disease, including inflammation, itch, and skin barrier repair.
Notably, some patients treated with existing biologics develop unusual skin conditions, such as head and neck dermatitis with psoriasis-like features, which may be linked to IL-22 — another cytokine involved in skin inflammation.
Closing the Gap
While multi-specific biologics represent a promising advancement, the complexity of AD pathophysiology presents ongoing challenges. The disease involves multiple immune pathways— including Th2, Th22, and Th17 — and it remains unclear which ones are most critical for long-term disease control.
The new biologics face another hurdle in the path to real-world adoption: “therapeutic inertia.” Many doctors hesitate to switch treatments, even when current therapies aren’t working well, and this reticence to change course could limit the use of multi-specific biologics.
The development of bispecific and trispecific biologics marks the next phase in therapeutic innovation, aiming to bridge the efficacy gap between JAK inhibitors and monospecific biologics. By expanding cytokine coverage while preserving biologic specificity — and incorporating extended half-life engineering strategies — these therapies may offer efficacy comparable to JAK inhibitors, while providing less frequent dosing — an appealing option for patients.
Future Directions
Clinical trials for multi-specific biologics are ongoing, and their results will help determine ways to deliver durable relief to patients with AD. Key questions remain, including which immune pathways should be targeted and whether these new drugs can provide better outcomes than existing treatments like JAK inhibitors and single-target biologics.
Challenges remain, but the strategy of targeting multiple immune pathways at once using multi-specific biologics represents a promising new approach to treating AD and providing better, longer-lasting results for patients who don’t respond well to current treatments.
Key Takeaway
Bispecific and trispecific biologics represent a promising new approach to atopic dermatitis, with the potential to deliver broader, more durable disease control by addressing multiple underlying immune pathways.
