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Terminus-specific antibody development and bioanalytical assay validation to quantify active DR10624 in
Zhenxing Zhou1, Kexin Cao1, Gaofeng Yao1
1Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd., Hangzhou, China.
Introduction:
Multi-specific drugs play important roles in addressing multi-factorial disease conditions. DR10624 is a first-in-class long acting Fc fusion triple agonist targeting FGF21R, GLP-1R, and GCGR, which has shown promising efficacy in reducing liver fat and triglycerides. Accurate quantification of the intact, pharmacologically active form of DR10624 in serum is essential for reliable pharmacokinetic (PK) characterization.
Methods:
Rabbit monoclonal antibodies that specifically recognize the N- and C-termini regions of DR10624 were developed and strategically paired for precise quantification. An electrochemiluminescence (ECL) based immunoassay was established and rigorously validated in accordance with regulatory guidelines. Additionally, a preclinical pharmacokinetic study in cynomolgus monkeys was performed to compare drug exposure using different assay formats.
Results:
Antibody screening successfully identified highly specific rabbit monoclonal antibodies, notably clones 4G7 and 1A12, which selectively bound to the intact N- and C-termini of DR10624 and effectively neutralized its GLP-1/GCG and FGF21 activities, respectively. Furthermore, the preclinical pharmacokinetic study in cynomolgus monkeys revealed a marked discrepancy between total and intact DR10624 exposure, indicating in vivo instability and underscoring the need to quantify active drug concentrations. The ECL-based immunoassay was successfully validated across a wide concentration range of 5.00-1,250 ng/mL in serum, confirming its accuracy, precision, selectivity, linearity, absence of hook effect, and stability.
Discussion:
The validated dual-monoclonal ECL method provides a robust and specific approach for quantifying intact, bioactive DR10624 in human serum. This assay supports reliable PK assessment in ongoing and future clinical trials, facilitating the continued development of DR10624 for the treatment of MASLD/MASH, severe hypertriglyceridemia (SHTG), and related metabolic diseases.
