D8-MMAF hydrochloride是MMAF hydrochloride的氘代形式。
D8-MMAF hydrochloride is a deuterated form of MMAF hydrochloride, which is a microtubule disrupting agent.
MMAF shows in vitro cytotoxicity against a panel of cell lines. The IC50 values for Karpas 299, H3396, 786-O and Caki-1 are 119, 105, 257, and 200 nM, respectively. Targeted MMAF is much more potent than the free drug, and that cAC10 conjugates of MMAF display pronounced activities. On a molar basis, the cAC10-L1-MMAF4 is an average of over 2200-fold more potent than free MMAF and is active on all the CD30-positive cell lines tested[1].
The maximum tolerated dose in mice of MMAF (>16 mg/kg) is much higher than MMAE (1 mg/kg). cAC10-L1-MMAF4 has an MTD of 50 mg/kg in mice and 15 mg/kg in rats. The corresponding cAC10-L4-MMAF4 ADC was much less toxic, having MTDs in mice and rats of >150 mg/ kg and 90 mg/kg in rats, respectively[1].
[1]. Doronina SO, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006 Jan-Feb;17(1):114-24.
Cells are treated with serial dilutions of test molecules and incubated 4-6 days depending on cell line. Assessment of cellular growth and data reduction to generate IC50 values is done using Alamar Blue dye reduction assay[1].
Mice: When subcutaneous Karpas 299 tumor size reaches 300 mm3, three animals per group receives one injection of 10 mg antibody component/kg body weight of either cAC10-L1-MMAF4 or cBR96-L1-MMAF4 intravenously. Tumors are then removed and placed in optimal cutting temperature compound, and 5 μm-thin frozen tissue sections are stained using immunohistochemistry evaluation[1].
[1]. Doronina SO, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006 Jan-Feb;17(1):114-24.
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