Precision glycocalyx editing as a strategy for cancer immunotherapy

Abstract

Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody-sialidase conjugates that enhance tumor cell susceptibility to antibodydependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody-sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody-enzyme conjugates is therefore a promising avenue for cancer immune therapy.cancer immune therapy | trastuzumab | sialic acid | Siglec | ADCC

Engineering and physical sciences in oncology: challenges and opportunities

“…Approaches are now being explored for targeted removal of glycocalyx components to enhance NK cell-mediated tumour killing. For example, therapeutic conjugates consisting of the HER2-specific antibody trastuzumab fused to a recombinant sialidase removed sialylated glycans from tumour cells and induced potent NK cell cytotoxic activity 84 .…”

Tailoring Natural Killer cell immunotherapy to the tumour microenvironment

“…Therapeutic interventions designed to target tumour-associated sialosides or block inhibitory Siglec function may provide a promising new avenue for cancer immunotherapy. To this end, a recent study showed that recombinant sialidase fused to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab desialylated tumour cells in a HER2-dependent manner, reduced tumour cell binding to inhibitory NK cell Siglecs, and enhanced ADCC [30]. Yet another approach has been to synthesise small sialic acid derivatives that bind with high affinity to Siglec-7, although it remains unclear whether these molecules can block Siglec receptor function in cytotoxicity assays [31].…”

Marine Lectins DlFBL and HddSBL Fused with Soluble Coxsackie-Adenovirus Receptor Facilitate Adenovirus Infection in Cancer Cells BUT Have Different Effects on Cell Survival

“…Meanwhile, increased sialylation was often associated with poor prognosis in cancer patients [13]. A recent study showed that desialylation of cancer cells reduced natural killer cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and increased natural killer cell activating receptor natural killer group 2D (NKG2D), suggesting a precise sialylation editing method for cancer targeting immune therapy [26]. …”