ANG1005 is a conjugate of Angiopep-2 (An2) with three paclitaxel molecules that
enters the brain via LRP-1 receptor-mediated transcytosis. As native paclitaxel
is a P-glycoprotein substrate that does not cross the BBB, An2 conjugation not
only confers increased brain uptake, but also evades efflux from BBB endothelial
cells and other cell types. Reduction of intracranial tumor size has been
demonstrated in patients treated with ANG1005 in Phase I and Phase II clinical
For biologics, access to brain parenchyma is an even greater challenge. ANG403
is a conjugate of An2 and a mAb directed at the HER2 receptor. While the native
mAb does not achieve therapeutic concentrations in brain, ANG4043 crosses the
BBB, targets HER2-positive tumors, reduces tumor size and increases survival in
mice that have been intracranially implanted with HER2-expressing tumor cells.
Successful generation of these brain-penetrant conjugates with high therapeutic
potential demonstrates that An2 conjugation can be applied to drugs and
biologics to circumvent the obstacle of the BBB.