Tim D. Bovee

TL;DR: The in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylaurists E (MMAE), linked to the chimeric mAbs cBR96 and cAC10, illustrate the importance of linker technology, drug potency and conjugation methodology in developing safe and efficacious mAb-drug conjugs for cancer therapy.

TL;DR: Several new linkers were generated in which various components within the L1 linker were either altered or deleted to optimize the ADC, and one of the most promising linkers contained a noncleavable maleimidocaproyl (L4) spacer between the drug and the mAb.

TL;DR: In vivo studies demonstrate that the increased stability characteristics of the drug-linker can lead to improved ADC antitumor activity and reduced neutropenia.

TL;DR: This work shows that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design, and exemplifies this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.

TL;DR: Results demonstrate that manipulation of the C-terminal peptide sequence used to attach auristatins to the mAb carrier can lead to highly potent and specific conjugates with greatly improved therapeutic windows.