Investigation of Hydrophilic Auristatin Derivatives for Use in Antibody Drug Conjugates

Antibody
drug conjugates offer a targeted cancer treatment for
the delivery of potent cytotoxic drugs. Derivatives of the natural
product dolastatin 10 containing pyridines and other basic amines
were examined with the objective of determining if a more hydrophilic
auristatin derivative would be potent enough for use as part of an
ADC. This may be advantageous if a less hydrophobic drug makes a better
ADC. A pyridine derivative, monomethyl auristatin PYE, showed the
greatest potency when tested in vivo. While only a modest tumor growth
inhibition was observed when the HCC1954 human breast cancer xenografts
were treated with“non-cleavable” linker ADCs, tumor
regression was seen when treated with an enzymatically degradable
“cleavable” linker ADC when conjugated to trastuzumab.
Based on these studies, monomethyl auristatin PYE shows promise for
use as an ADC payload.