Cancer-specific sialylation of insulin-like growth factor 1 receptor impairs therapeutic antibody binding and efficacy

Despite extensive efforts to develop insulin-like growth factor (IGF1R)-targeted therapies for various malignancies, none has received clinical approval in the past two decades. Here, we reveal that N-glycan sialylation significantly decreases recognition by the humanized monoclonal anti-IGF1R antibody ganitumab across various cancer types, reducing its efficacy both in vitro and in vivo. Sialoforms of IGF1R are virtually absent in normal cells, indicating that the modification is tumor-specific. Pharmacological inhibition of sialyltransferases significantly sensitizes metastatic tumors to ganitumab in a ganitumab-resistant ovarian cancer model. Enzymatic removal of sialic acids from tissue sections resulted in marked enhancement in antibody binding to ovarian cancer patient tumors, but not normal tissues. Upregulation of 2-6 sialyltransferase ST6GAL1 in tumor tissues was found to be responsible for sialylation of IGF1R. Consequently, ST6GAL1-high tumors were more likely to benefit from desialylation-mediated enhancement of ganitumab binding. Furthermore, through comprehensive glycoproteomics analysis, structural prediction, and molecular dynamics simulation, we identify Asn-607 (N607) as a crucial site harboring sialylated glycans. Mechanistically, N607 glycosylation destabilizes the IGF1R-ganitumab complex. Overexpression of IGF1R Asn-607-Gln (N607Q) mutant in IGF1R-knockout cancer cells increases ganitumab efficacy compared to wild-type IGF1R in vivo. Taken together, these findings highlight sialylation as a common barrier in IGF1R-targeted therapies and provide crucial insights for therapy enhancement in cancer and patient stratification for future clinical trials. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/682592v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@17c6d5corg.highwire.dtl.DTLVardef@1efe2f7org.highwire.dtl.DTLVardef@1dd05aorg.highwire.dtl.DTLVardef@159fb23_HPS_FORMAT_FIGEXP M_FIG C_FIG Synopsis2-6 sialylation of IGF1R Asn-607 by ST6GAL1 is prevalent in cancer. This modification disrupts the interaction of IGF1R with therapeutic mAb ganitumab. Removal of sialylation augments ganitumab efficacy.