Abstract Introduction Depemokimab (GSK3511294) is an ultra-long-acting anti-IL-5 monoclonal antibody (mAb) engineered with enhanced IL-5 binding affinity, high potency, and an extended half-life via YTE modification to the heavy chain Fc regions enabling twice-yearly dosing for patients and enabling sustained suppression of type 2 inflammation. Mepolizumab (Nucala) is a first-in-class humanized IgG1 anti-IL-5 mAb. It is approved for monthly dosed add-on treatment for inflammatory conditions with an eosinophilic phenotype including severe asthma. Here, we aimed to quantitatively evaluate the impact of the YTE modification on tissue biodistribution by comparing depemokimab to mepolizumab in cynomolgus monkeys in-vivo by Positron Emission Tomography and Computed Tomography (PET/CT) imaging. Method 89Zr (half-life ∼3.3-days) based PET/CT imaging of depemokimab and mepolizumab was performed in three cynomolgus female monkeys per group up to 14-days post intravenous administration of 10mg/kg total dose, including 1mg 89Zr-labelled-mAb. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics1. Results The quantitative PET data showed a trend of higher group mean 89Zr-depemokimab uptake in blood on day 1 that achieved statistical significance (p 0.01) on day 3. There was a trend of higher group mean 89Zr-depemokimab uptake in the upper respiratory tract compared to 89Zr-mepolizumab uptake that achieved statistical significance (p 0.05) on day 14 in the pulmonary bronchi. There was a trend of lower group mean 89Zr-depemokimab uptake in the liver compared to 89Zr-mepolizumab uptake beginning on day 3. The tissue-to-blood ratio in liver were significantly lower for 89Zr-depemokimab than 89Zr-mepolizumab beginning on day 3 (p 0.05). There were no noteworthy differences between 89Zr-depemokimab and 89Zr-mepolizumab tissue-to-blood ratios in other tissues examined, including pulmonary bronchi. The calculated simian terminal half-life are 28.5 and 9.3 days for depemokimab and mepolizumab, respectively. Additionally, the PBPK model (figure) predicted that the antibody biodistribution coefficient (ABC) % for every tissue was similar for both depemokimab and mepolizumab. Conclusions This in-vivo biodistribution study in healthy monkeys showed that 89Zr-demepokimab had higher uptake in blood and pulmonary bronchi, and lower uptake in liver, compared to 89Zr-mepolizumab. 89Zr-depemokimab tissue to blood ratio was lower in liver compared to 89Zr-mepolizumab, this observation is consistent with the lower clearance and longer half-life of depemokimab compared to mepolizumab. PBPK modeling demonstrated that the YTE substitution had not impacted the relative antibody biodistribution to tissues when comparing non-residualized depemokimab and mepolizumab. Reference 1Aweda et al, EJNMMI 50(3),667-678. This abstract is funded by: GSK
Alsaid et al. (Fri,) studied this question.