Details

Autor(en) / Beteiligte

• Adem, Yilma T
• Schwarz, Kelly A
• Duenas, Eileen
• Patapoff, Thomas W
• Galush, William J
• Esue, Osigwe

Titel

Auristatin Antibody Drug Conjugate Physical Instability and the Role of Drug Payload

Ist Teil von

• Bioconjugate chemistry, 2014-04, Vol.25 (4), p.656-664

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• The conjugation of hydrophobic cytotoxic agents such as monomethyl auristatin E (MMAE) to the interchain sulfhydryl groups of monoclonal antibodies (Mabs) through a protease-labile linker generates a heterogeneous drug load distribution. The conjugation process can generate high-drug-load species that can affect the physical stability of antibody–drug conjugates (ADCs). In this study, the mechanism of physical instability of ADCs was investigated by formulating the ADC pool as well as isolated drug load species in high and low ionic strength buffers to understand the effect of ionic strength on the stability of drug-conjugated Mabs. The results showed that the presence of high ionic strength buffer led to time-dependent aggregate and fragment formation of ADCs, predominantly ADCs with high-drug-load species under stress conditions. In addition, differential scanning calorimetry (DSC) results confirmed that there is a direct correlation between thermal unfolding and drug payload and that specific changes in the DSC thermogram profiles can be assigned to modifications by MMAE.