MMAE-d8 is a deuterated monomethyl auristatin E (MMAE) that can be used for the detection of MMAE. MMAE is a very effective antimitotic agent that inhibits cell division by blocking the polymerization of tubulin[1].
MMAE is released by cathepsin B cleavage and/or catabolism after Antibody-drug conjugates(ADC) internalization into cells. ADC binds to tumor cells in vitro and releases its payload inside cancer cells after trafficking to appropriate subcellular organelles, such as lysosomes.After treatment of L-82 cells with five ADCs, CD30 (cAC10-vcMMAE, Drug-antibody ratio, DAR of 2, 4, or 8), CD70 (h1F6-vcMMAE, DAR of 4) or CD71 (cOKT9-vcMMAE, DAR of 4) at their respective IC50 concentrations, the intracellular MMAE concentrations were similar, ranging from 98 nmol/L to 150 nmol/L[1-2].
The intratumoral concentration of MMAE determines the in vivo antitumor activity of ADC, and the intratumoral MMAE concentration increases proportionally to the ADC dose. Moreover, the intratumoral MMAE concentrations obtained by cOKT9-vcMMAE and cAC10-vcMMAE treatment are similar at each dose[1].
References:
[1] Li F, Emmerton K K, Jonas M, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models[J]. Cancer research, 2016, 76(9): 2710-2719.
[2] Yip V, Saad O M, Leipold D, et al. Monomethyl Auristatin E (MMAE), a Payload for Multiple Antibody Drug Conjugates (ADCs), Demonstrates Differential Red Blood Cell Partitioning Across Human and Animal Species[J]. Xenobiotica, 2024 (just-accepted): 1-13.
MMAE-d8是一种氘化标记的一甲基澳瑞他汀E（MMAE），可用于MMAE的检测。MMAE是一种非常有效的抗有丝分裂剂，通过阻断微管蛋白的聚合来抑制细胞分裂[1]。
MMAE是由于组织蛋白酶B裂解和/或抗体-药物偶联物（ADC）内化到细胞后分解代谢而解离释放的。ADC在体外与肿瘤细胞结合，并在运输到适当的亚细胞细胞器（例如溶酶体）后在癌细胞内释放有效负载。在使用五种ADC，CD30（cAC10-vcMMAE，药物抗体比，DAR 为 2、4 或 8）、CD70（h1F6-vcMMAE，DAR 为 4）或CD71（cOKT9-vcMMAE，DAR 为 4）以各自的IC50 浓度处理L-82细胞后，细胞内MMAE浓度相似，范围在98 nmol/L至150 nmol/L之间[1-2]。
MMAE的瘤内浓度决定了ADC的体内抗肿瘤活性，瘤内MMAE浓度与ADC剂量成比例增加，并且，cOKT9-vcMMAE和cAC10-vcMMAE治疗获得的瘤内MMAE浓度在每个剂量下相似[1]。