Rademikibart Differentiates From Dupilumab With Optimized IL-4Rα Inhibition and Enhanced Binding Stability

“When we apply the molecular dynamics analysis to rademikibart, and IL-4 receptor alpha [IL-4Rα], we see strong stability of this antibody antigen complex, suggesting that rademikibart truly is a next-generation optimized IL-4Rα inhibitor, and this explains why it has twice the binding affinity to IL-4Rα as dupilumab,” said Christopher Bunick, MD, PhD, in an interview with Dermatology Times at Fall Clinical 2024 in Las Vegas, Nevada.

Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut, Dermatology Times’ 2024 Winter Editor in Chief, and study author, presented a poster detailing an in-depth analysis comparing first-generation and second-generation IL-4 receptor alpha (IL-4Rα) inhibitors, focusing on dupilumab (Dupixent; Sanofi and Regeneron) and rademikibart (Connect Biopharma).

Rademikibart is an optimized next-generation human monoclonal antibody targeting IL-4Rα. Recent phase 3 trials have shown that approximately 63% of patients with atopic dermatitis who were treated with rademikibart achieved EASI 75 at week 16 compared to approximately 48% of patients treated with dupilumab.^1,2

“The 63% EASI 75 response rate suggests that rademikibart demonstrates a very good initial efficacy; additionally, with 4-week dosing, an unprecedented 91% of patients maintained at least 75% skin clearance through to week 52. These data will push clinicians to demand medications with higher efficacy and a demonstrated safety profile,” said Raúl Collazo, PhD, study author and Vice President of Global Medical Affairs at Connect Biopharma, in a statement to Dermatology Times.

In their research, Bunick et al examined the x-ray crystal structure of rademikibart’s fragment antigen-binding (Fab) bound to IL-4Rα and compared it to the complex of dupilumab Fab and IL-4Rα.

“Our data provides a molecular and structural rationale for the enhanced IL-4Rα inhibition by rademikibart over dupilumab which corresponds to rademikibart’s optimized epitope on IL-4Rα that overlaps more closely with the natural IL-4 epitope,” wrote Bunick et al.

Dupilumab, a first-generation inhibitor, binds to IL-4Rα at a key site where IL-4 and IL-13 interact. Molecular dynamics modeling showed a moderate stability of the dupilumab- IL-4Rα.

Rademikibart, as a second-generation IL-4Rα inhibitor, showed notable advancements. Using X-ray crystallography, Bunick’s team observed a 60-degree rotational shift in rademikibart’s binding to IL-4Rα, enabling it to engage fully with IL-4 and IL-13 interaction domains, including domain 1, domain 2, and a small hinge region. Molecular dynamics further confirmed rademikibart’s superior binding stability compared to dupilumab, highlighting its optimized epitope design.

“Rademikibart binds to unique epitopes when compared to dupilumab. The unique binding demonstrated in this molecular structure study may explain differences seen in asthma studies where eosinophils are decreased with rademikibart rather than increased, as seen with dupilumab, where hypereosinophilia has been reported,” said Collazo.

According to Bunick, the structural optimization of rademikibart translates into twice the binding affinity of rademikibart to IL-4Rα, supporting its potential as an advanced therapeutic option. Early studies in atopic dermatitis and asthma have shown promising results, with rademikibart showing enhanced efficacy and a favorable safety profile, particularly in asthma, positioning it as a next-generation treatment in inflammatory conditions.

“These data provide a molecular and structural rationale for the enhanced IL-4Rα inhibition by rademikibart over dupilumab, confirming rademikibart as an optimized second-generation IL-4Rα inhibitor. This enhanced inhibition may lead to better efficacy in many atopic disorders related to Type 2 inflammation like atopic dermatitis and eosinophilic driven asthma or COPD,” concluded Collazo.

Reference

1. Shi Y, Ho M, Li H, Collazo R, Bunick CG. Optimized second-generation IL-4Rα inhibition: structural and molecular dynamics properties of rademikibart Fab-IL-4Rα complex. Poster presented at: Fall Clinical Dermatology Conference; October 24-27; Las Vegas, Nevada.
2. Rademikibart (CBP-201). Connect Biopharma. Accesed November 1, 2024. https://www.connectbiopharm.com/rademikibart/