Abstract 2657: Utilization of the Angiopep platform to enable brain penetration of therapeutic mAbs or Antibody-Drug Conjugates for treatment of brain tumors
Authors: Demeule Michel , Lachowicz Jean E. , Tripathy Sasmita , Yang Giogang , Das Sanjoy , Che Christian , Currie Jean-Christophe , Lord-Dufour Simon , Regina Anthony , Castaigne Jean-Paul 
Published: May 2015

Abstract
Monoclonal antibodies directed against receptor tyrosine kinases such as HER2 have been demonstrated to reduce tumor size and increase survival. However, these agents achieve little to no brain penetration, making them ineffective against metastatic brain tumors. The blood-brain barrier (BBB), efficient at restricting entry of proteins such as mAbs into the brain, is comprised of capillary endothelial cells with tight junctions and efflux pumps. Entry of nutrients, hormones, and other required molecules is accomplished by processes such as receptor-mediated transcytosis. As low-density lipoprotein receptor-related protein 1 (LRP1) is known to perform this function in BBB endothelial cells, we have created a family of peptides (Angiopeps) designed for LRP1 recognition. Conjugation of the Angiopep-2 (An2) to confer brain permeability has been validated for small molecules (ANG 1005, Phase II), peptides and proteins. For example, therapeutic concentrations of an anti-HER2 mAb have been achieved with An2 conjugation. This Angiopep-Antibody Conjugate, ANG4043, displays HER2 binding affinity and in vitro cytotoxic potency similar to that of native anti-HER2. ANG4043 demonstrates a high rate of entry into the brain, consistent with achieving therapeutic concentrations. Mice intracranially implanted with BT-474 human breast cancer cells showed reduced brain tumor size when dosed with ANG4043 compared to controls and increased mice survival. Here, we also describe the chemical conjugation between a brain penetrant Angiopep, a cytotoxic agent and a mAb directed against HER2. This new peptide-antibody-drug-conjugate shows a much higher in vitro anti-proliferative potency against HER2+ BT-474 cells than the native antibody. Furthermore, this new peptide-drug-antibody-conjugate demonstrates a high rate of entry into the brain when compared to the unconjugated antibody. Overall, these data demonstrate that the addition of an Angiopep to therapeutic mAbs or Antibody Drug Conjugates (ADCs) can improve their brain penetration. These results extend the validation of Angiopep conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs or ADCs for development of new brain-penetrant antitumor therapeutics.
Citation Format: Michel Demeule, Jean E. Lachowicz, Sasmita Tripathy, Giogang Yang, Sanjoy Das, Christian Che, Jean-Christophe Currie, Simon Lord-Dufour, Anthony Regina, Jean-Paul Castaigne. Utilization of the Angiopep platform to enable brain penetration of therapeutic mAbs or Antibody-Drug Conjugates for treatment of brain tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2657. doi:10.1158/1538-7445.AM2014-2657