1st-in-human CAR T targets MUC1 transmembrane cleavage product

Abstract

Background & Aim We developed a CAR T that recognizes the growth factor receptor form, MUC1*, does not bind full-length MUC1, hits a wide range of cancers and shows to little or no binding to normal tissues. No therapeutic has ever been tested in humans that targets the MUC1 transmembrane cleavage product – MUC1*. A 1st-in-human clinical trial of huMNC2-CAR44, NCT04020575, for metastatic breast cancers is underway at the Fred Hutchinson Cancer Research Center. We expect to have patient data by conference time. Methods, Results & Conclusion MUC1* is a Class I growth factor receptor that is activated when onco-embryonic growth factor NME7AB dimerizes its truncated extra cellular domain. The binding site for NME7AB is ectopic and is only unmasked after the tandem repeat domain of MUC1 is cleaved and shed from the cell surface. Unlike full-length MUC1, MUC1* has no sites for O-linked glycosylation, so antibodies such as 5E5 that bind to aberrant, trapped glycans cannot bind to the MUC1*. Anti-MUC1* antibody huMNC2 binds to the conformational epitope that is unmasked when MUC1 is cleaved to MUC1* by MMP9. MMP9 has now been linked to poor prognosis and metastasis. huMNC2 competes with onco-embryonic growth factor NME7AB for this same conformational epitope on MUC1*. Neither huMNC2 nor NME7AB binds to full-length MUC1. IHC studies of thousands of human tissues – both normal and cancerous – show that the tumor associated antigen is MUC1* and not full-length MUC1. Patient-match primary and metastases show that as cancer stage progresses the amount of MUC1* increases. huMNC2-scFv bound robustly to 95% of the breast cancers, 83% ovarian, 78% pancreatic and 71% of lung cancer tissues (specimens n>2,800). There was little to no staining of normal tissues. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n>400). If safety is demonstrated, we will file for INDs for next-gen CARs, including logic-gated CARs with increased in vivo persistence. Conclusions MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that target a conformational epitope in the membrane-proximal MUC1* extra cellular domain are tumor selective. CAR T cells targeting MUC1* extra cellular domain are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal to no staining of normal tissues predicts large therapeutic window for huMNC2-CAR44 T cell dosing.