Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C-Lock linker.

Antibody-drug conjugates (ADCs) belong to a promising class of biopharmaceuticals in which target-killing of tumor cells was achieved by marrying the potency of the cytotoxic payload with the tumor specificity of the antibody. Here we developed a novel ADC (ZV0508) that targets 5T4 oncofetal antigen, which is overexpressed in many carcinomas on both bulk tumor cells and cancer stem cells. A novel cytotoxic payload called Duostatin-5 (Duo-5) which was derived from monomethyl auristatin F (MMAF) was attached to a 5T4 targeting antibody (ZV05) by interchain cysteine cross-linking conjugation via a disubstituted C-Lock linker.

Novel conjugation of tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) with monomethyl auristatin E for efficient antitumor drug delivery.

Monomethyl auristatin E (MMAE) is conjugated with TNF-related apoptosis-inducing ligand (TRAIL) via a linker that is stable in extracellular fluid, while it is cleaved by cathepsin once the conjugate has entered a tumor cell, thus activating the antimitotic mechanism of MMAE. The TRAIL-MMAE conjugate is a conceptually viable therapeutic strategy with improved in vitro antitumor activity, cell circle arrest and specific accumulation in tumor to treat TRAIL-resistant tumors.

[Heterogeneous expression of human CYP and its application in early stage of new drug research and development].

Human cytochrome P450 (CYP) has a pivotal role on metabolism of xenobiotics and endogenous substances in clinical practice. Since the CYP from human tissue is very complex, and the human tissue itself is not easy to obtain, investigators begin to use all kinds of expression system to heterogeneously express the CYP. The single CYP expressed was then used for drug metabolism and drug-drug interaction research, to improve the efficiency of high-throughput drug screening greatly.

[Optimization of tri-expression of human CYP3A4 with POR and cyt b5 in Sf 9 cells].

Objective: To investigate the optimal conditions of tri-expression of CYP3A4, POR and cyt b5 in Sf 9 cells.

Methods: The Sf 9 cells expressing CYP3A4, POR and cyt b5 were cultured in shaker flasks. The optimized conditions, including the temperature and rotation speed, the culture volume, the amount of surfactant and the culture time were studied.