SIM0708, an antibody-drug conjugate (ADC) with half-life extended anti-IL-4 receptor a (IL-4Ra) antibody and glucocorticoid receptor modulator exhibits superior efficacy treating inflammatory diseases 4657

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Abstract Description Background IL-4Ra plays an important role in the pathogenesis of inflammatory diseases including atopic dermatitis, asthma, COPD, etc. Glucocorticoids (GCs) are efficacious drugs commonly used for treating inflammatory diseases, but their doses and treatment duration are limited because of GCs’ side effects. We therefore sought to identify an ADC approach to deliver GCs selectively to inflamed tissues, aiming to effectively inhibit the pro-inflammatory pathways. Methods A novel and potent anti-IL-4Ra antibody was developed and conjugated with Simcere’s proprietary glucocorticoid payload and hydrophilic linker. Mutations were introduced to the Fc region of the antibody to achieve half-life extension. Results SIM0708 exhibited potent GR activation and B cell suppression. Low-dose ADC led to rapid on-set and superior efficacy in mice dermatitis model, whereas anti-IL-4Ra antibody partially reduced the disease severity. Enhanced therapeutic window was also observed comparing to oral prednisolone, and no obvious systemic glucocorticoid-related safety risks existed. SIM0708 was highly stable in plasma. Limited exposure of free payload and half-life extension were determined in pharmacokinetics studies. In addition, favorable developability supports subcutaneous formulation of this ADC. Conclusion These results suggest that SIM0708 may provide the rapid and improved efficacy beyond anti-IL-4Ra antibody alone in inflammatory diseases while minimizing the systemic side effects. Topic Categories Therapeutic Approaches to Autoimmunity (THER)

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