A Bispecific Antibody Targeting the alpha v and alpha 5 beta 1 Integrins Induces Integrin Degradation in Prostate Cancer Cells and Is Superior to Monospecific Antibodies

摘要

Fibronectin-binding integrins alpha 5 beta 1 and alpha v collaborate in prostate cancer-bone stromal interactions relevant to the colonization of the bone marrow microenvironment. Combinatorial inactivation of these integrins on prostate cancer cells was assessed. Monospecific antibodies to alpha 5 beta 1 and alpha v integrins alone (MAb) and in combination (cMAb), and a bispecific antibody that simultaneously targets alpha 5 beta 1 and alpha v integrins (BsAb alpha 5 beta 1/alpha v) were compared in assays of chemotaxis, clonogenic survival, and induction of endothelial migration. Cellular expression of integrins, their transcription, translation, and degradation fate was compared. The BsAb alpha 5 beta 1/alpha v was superior to MAbs and cMAbs in abrogating adhesion, migration, clonogenic survival, and induction of endothelial migration responses by prostate cancer cells. Integrin upregulation observed with MAbs or cMAbs was abrogated with the BsAb alpha 5 beta 1/alpha v. Loss of integrin expression was uniquely induced by the BsAb alpha 5 beta 1/alpha v and blocked by lysosomal inhibition.