Abstract PS11-36: First-in-human chimeric antigen receptor t cells target muc1 transmembrane cleavage product

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-02, Vol.81 (4_Supplement), p.PS11-36-PS11-36
• Main Authors: Bamdad, Cynthia, Stewart, Andrew K, Huang, Pengyu, Smagghe, Benoit J, Moe, Scott T, Swanson, Tyler E, Jeon, Thomas G, Page, Danica M, Grant, Trevor J, Specht, Jennifer M
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.SABCS20-PS11-36

huMNC2-CAR44 is a second generation CAR that recognizes the growth factor receptor form, MUC1*, does not bind to full-length MUC1, hits a wide range of cancers and shows to little or no binding to normal tissues and is the first therapeutic tested in humans targeting the MUC1 transmembrane cleavage product called MUC1*. A 1st-in-human clinical trial of huMNC2-CAR44, NCT04020575, for metastatic breast cancers is underway at the Fred Hutchinson Cancer Research Center. MUC1 biology has historically been poorly understood. Several flawed reports are still widely cited in the literature. We will present data that de-bunks current MUC1 dogma. Namely, we will demonstrate that full-length MUC1 plays no role in tumorigenesis. The cleaved tandem repeat domain does not form a heterodimer with the remaining transmembrane portion. We demonstrate that elimination of full-length MUC1 greatly accelerates tumor growth in vitro and in vivo. MUC1* is a Class I growth factor receptor that is activated by ligand-induced dimerization of its truncated extra cellular domain, which activates the MAP kinase signaling pathway as well as survival pathways. Onco-embryonic growth factor NME7AB binds to an ectopic site on MUC1* that is only unmasked after MUC1 is cleaved and the tandem repeat domain is shed from the cell surface. NME7AB looks like a single chain dimer of pseudo-identical domains that each can bind to a MUC1* extra cellular domain. Because it can dimerize MUC1* as a monomer, it renders the MUC1* growth factor receptor constitutively active. Adult forms of NME7AB limit self-replication by changing multimerization state from the active dimer to the inactive hexamer. Antibodies such as 5E5 and SM3 bind to aberrant, trapped glycans on O-linked glycosylation sites that are only in the tandem repeat domain, which is shed from the tumor after MUC1 cleavage. Unlike full-length MUC1, MUC1* has no sites for O-linked glycosylation, so MUC1* is missed by antibodies that target aberrant glycans. Importantly, therapeutics that target full-length MUC1 could increase tumorigenesis by enriching for cells expressing the tumorigenic MUC1* growth factor receptor. Minerva’s anti-MUC1* antibody, huMNC2, binds to the conformational epitope that is unmasked when MUC1 is cleaved to MUC1*. MMP9, which has been linked to poor prognosis and metastasis, cleaves MUC1 to a tumor-associated growth factor receptor form of MUC1*. huMNC2 and onco-embryonic growth factor NME7AB compete for binding to the s