Abstract
Antibody-drug conjugates (ADCs) are promising state-of-the-art biopharmaceutical drugs for selective drug-delivery applications and the treatment of diseases such as cancer. The idea behind the ADC technology is remarkable as it combines the highly selective targeting capacity of monoclonal antibodies with the cancer-killing ability of potent cytotoxic agents. The continuous development of improved ADCs requires systematic studies on the nature and effects of warhead modification. Recently, we focused on the hydrophilic modification of monomethyl auristatin E (MMAE), the most widely used cytotoxic agent in current clinical trial ADCs. Herein, we report on the use of micellar electrokinetic chromatography (MEKC) for studying the hydrophobic character of modified MMAE derivatives. Our data reveal a connection between the hydrophobicity of the modified warheads as free molecules and their cytotoxic activity. In addition, MMAE-trastuzumab ADCs were constructed and evaluated in preliminary cytotoxic assays.
Highlights
Natural science has witnessed many breakthroughs during the past decades
The technique is excellent for the separation of charged and neutral compounds, and for assessing the hydrophobicity of analytes
Liposomes and micelles are accepted models for interpreting the interactions between molecules and lipid bilayers, and studying the interaction of the payload molecules in this system creates a simplified model for studying the interactions of the liberated drugs with cellular membranes
Summary
Natural science has witnessed many breakthroughs during the past decades. The new biological insights gained, the improved biochemical protocols and analytical tools developed, and the constant advances in chemical reaction technologies have paved the way for exciting and multidisciplinary research fields such as the field of antibody-drug conjugates (ADCs). Separations 2018, 5, x FOR PEER REVIEW The. The development development of of modern modern ADCs. ADCs requires requires systematic systematic research research on on antibodies, antibodies, bioconjugation bioconjugation technologies, as well as information on the properties of the payload molecules the characteristics characteristics technologies, as well as information on the properties of the payload molecules and and the of Recently, hydrophilic of the the end end products. Hydrophilic derivatization derivatization of of payload payload molecules molecules was was reported reported to to have have beneficial effects on the overall properties of the ADCs, for example, on the therapeutic index and beneficial effects on the overall properties of the ADCs, for example, on the therapeutic index and the the pharmacokinetics current research research trends, pharmacokinetics [7,8]
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