CB17-SCID-Ces1c-KO Mouse

Ces1c, the mouse carboxylesterase 1C (Carboxylesterase 1C) gene, encodes an enzyme highly expressed in rodent plasma, responsible for hydrolyzing various ester- or amide-containing drugs, particularly cleavable linkers (Linker) in antibody-drug conjugates (ADCs) such as Val-Cit (VC) linkers ^[1-2]. Mouse Ces1c causes non-specific hydrolysis of ADCs in plasma, accelerating drug clearance and severely deviating pharmacokinetic (PK) profiles from human reality ^[3-4]. In humans, CES1 and CES2 are mainly distributed in the liver and intestine, with negligible activity in plasma, whereas mouse Ces1c, lacking an endoplasmic reticulum retention signal, is secreted in large amounts into plasma ^[3-4]. Besides its role in drug metabolism, Ces1c is also involved in physiological processes such as lipid metabolism. Studies show that, in evaluating VC-based ADCs, Ces1c in mouse plasma miscleaves the VC-PABC structure, causing premature release of toxic payloads, resulting in systemic toxicity and underestimation of antitumor activity ^[5-9].

In preclinical evaluation of ADCs, differences in immunodeficient strain backgrounds affect the biodistribution, clearance rates, and reliability of PK/PD results for humanized antibodies ^[10-15]. For example, highly immunodeficient NOD-SCID and its derivative strains, due to enhanced Fc-FcγR interactions, lead to shortened serum half-life of ADCs and increased off-target organ trapping, thereby underestimating antitumor activity ^[10-15]. In contrast, the CB17-SCID background exhibits superior characteristics in maintaining antibody half-life and optimizing biodistribution, providing more reliable efficacy data ^[13-15].

The CB17-SCID-Ces1c-KO mouse is a gene knockout (KO) model, generated on the CB17-SCID immunodeficient background with excellent PK/PD properties, using gene editing technology to knock out the Ces1c gene in mice. This model can be used for ADC drug development, particularly for evaluating VC linker drugs, and to avoid non-specific interference in mouse plasma, provides more clinically predictive efficacy data.