Microtubules (MTs)/tubulins are the largest filamentous components of the eukaryotic cytoskeleton and are essential for every cell as they control cell shape, division, motility and differentiation[2]. MMAD (Monomethyl Dolastatin 10), a potent tubulin inhibitor, is a toxin payload in antibody-drug conjugates (ADCs) which comprise antibodies covalently attached to highly potent drugs using a variety of conjugation technologies. These conjugates were found to have good biophysical properties and a drug-to-antibody ratio (DAR) of ~1.9[3]. The two conjugates (C16-HC-AcLys-vc-MMAD and C16-LC-AcLys-vc-MMAD) showed similar cell killing in vitro with IC50 values of 0.053 and 0.054 nM, respectively, in BxPC3 pancreatic cancer cell line (M1S1 +++) and 0.058 and 0.075 nM in the A431 epidermoid carcinoma cell line (M1S1 +++). In vivo, single doses of either C16-HC-AcLys-vcMMAD (DAR 1.9) or C16-LC-AcLys-vcMMAD (DAR 1.8) at 3 mg/kg were able to induce similar tumor shrinkage percentages on week 1 and week 2 [4]. What’s more, the resulting ADCs demonstrate complete tumour regression in rodents, which also have an improved toxicology profile in rats[3].
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