Abstract CT034: GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors

作者：Jason J. Luke, Melissa M. Johnson, Anthony W. Tolcher, Christopher T. Chen, Tong Dai, Brendan D. Curti, Anthony B. El-Khoueiry, Mario Sznol, Brian S. Henick, Christine E. Horak, Pushpa Jayaraman, Christopher B. Cole, Dawn K. Wilson, Lizhi Cao, Li Peng, David Feltquate, Deanne Lathers, Manish Sharma · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-ct034 · 被引用次数：13 · 研究领域：Cancer Research and Treatments、Glycosylation and Glycoproteins Research、Cancer, Hypoxia, and Metabolism

Abstract Background: Hypersialylation (excessive sialoglycans) on tumor cells has been known to be associated with poorer cancer outcomes for more than 40 years. Sialoglycans are immune suppressive and promote tumor immune evasion by binding to sialoglycan receptors (e.g. Siglecs) expressed on immune cells. However, redundant immune cell expression among Siglecs has posed a challenge for receptor-targeting therapeutic approaches. E-602 is a first-in-class fusion protein of engineered human sialidase (Neu2) and a human IgG1 Fc region. The dimeric sialidase moieties of E-602 circumvent the redundancy of this biology by directly cleaving terminal sialic acid residues from sialoglycans on immune and tumor cells. In preclinical studies, E-602 enhanced immune function by augmenting antigen-specific priming and activation of T cells and restoring function of exhausted-like T cells, and E-602 demonstrated antitumor activity as monotherapy in multiple mouse tumor models. Methods: A Phase 1/2 first-in-human dose escalation study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of E-602 in patients with advanced cancers. Eligible patients with select advanced solid tumors were treated with E-602 IV once weekly at dose levels between 1 and 30 mg/kg. Circulating immune cells were analyzed for changes in sialylation and immunophenotyping by flow cytometry. Changes in circulating cytokines were measured by immunoassays. Results: As of January 6,...