Precision glycocalyx editing as a strategy for cancer immunotherapy

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 anti...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 37; pp. 10304 - 10309
Main Authors Xiao, Han, Woods, Elliot C., Vukojicic, Petar, Bertozzi, Carolyn R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 13.09.2016
SeriesFrom the Cover
Subjects
Biological Sciences
Cancer
Carbohydrates
Enzymes
Glycoproteins
Immunotherapy
Physical Sciences
Tumors
trastuzumab
cancer immune therapy
Siglec
sialic acid
ADCC
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Summary: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 antibody-dependent 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.
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Author contributions: H.X., E.C.W., and C.R.B. designed research; H.X., E.C.W., and P.V. performed research; H.X., E.C.W., and C.R.B. contributed new reagents/analytic tools; H.X., E.C.W., P.V., and C.R.B. analyzed data; and H.X., E.C.W., and C.R.B. wrote the paper.
Edited by Laura L. Kiessling, University of Wisconsin-Madison, Madison, WI, and approved July 11, 2016 (received for review May 24, 2016)
1H.X. and E.C.W. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1608069113