Glioblastoma model mouse rescue from mortality by brain-targeted catalytically-enhanced angiotensin-converting enzyme 2 mutant-antibody fusion protein

We have discovered that an engineered angiotensin-converting enzyme 2 (ACE2)-brain-targeted antibody fusion protein, referred to as ACE2dm-s1, improves survival of CT-2A xenograft glioblastoma (GBM) model mice when administered in combination with a small molecule STING agonist cancer therapeutic. Particularly striking about these survival results is that prior efforts that used losartan, a small molecule angiotensin receptor antagonist that acts on the same Renin-Angiotensin System (RAS) axis that is affected by the action of ACE2dm-s1, showed that this small molecule provided no survival benefit when used as an element of combination therapy in the same CT-2A GBM model used in our experiments. The improved CT-2A mouse survival, which was not observed for ACE2dm-s1 or STING agonist monotherapy, combines with our flow cytometry study results that revealed an ACE2dm-s1-mediated shift of brain immune cell populations toward an anti-tumoral composition to establish ACE2dm-s1's utility as a tumor microenvironment (TME) modulator that could serve as an adjuvant in increasing the efficacy of wide range of cancer treatment modalities including chemotherapeutic agents, immune checkpoint inhibitors, and CAR-T cells.