title: ANG4043, a novel brain-penetrant peptide-mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice.
abstract: Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2-mAb conjugate penetrates the BBB with a rate of brain entry (Kin) of 1.6 × 10(-3) mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2-drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications.
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Regina
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Demeule
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Lord-Dufour
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Currie
authors.affiliation: Département de Chimie, Université du Québec à Montréal, Montréal, Québec, Canada.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Iddir
authors.affiliation: Département de Chimie, Université du Québec à Montréal, Montréal, Québec, Canada.
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Castaigne
authors.affiliation: Angiochem Inc., Montréal, Québec, Canada. jlachowicz@angiochem.com.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Lachowicz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; C000601491:ANG4043; C531860:Angiopep-2