Ingrid 't Hart

15 Introduc�on 1 Figure 6. ( A ) Altered structures on cancer cell membranes are recognized by immune cells. ( B ) Co-expression of Siglec-7 ligands such as ganglioside DSGb5 on cancer cells, inhibit an immune response. Overexpression of GSLs in cancer cells make them interes�ng targets for an�bodies. These an�bodies can be elicited for treatment purposes, e.g. to block the interac�ons of GSLs with immune receptors. The FDA approved an�body Dinutuximab targets GD2 and is an example of passive immuniza�on. Other targets, such as GM2 or Globo-H, are being tested in the late phases of clinical trials for ac�ve immuniza�on. 47,63,64 Since carbohydrates o�en trigger weak immune responses, immunogenicity is improved by conjuga�on to pep�des or proteins such as keyhole limpet haemocyanin (KLH) or diphtheria toxoid cross-reac�ve material (CRM)197. 65,66,67 Some an�bodies have not reached clinical trials, but show promising results in vitro. As an example, an an�body targe�ng Gb3 demonstrated inhibi�on of tumor development and angiogenesis. 68 Furthermore, GSLs on cancer cells could be targeted to deliver an�cancer drugs more selec�vely. A recent study describes effec�ve toxin delivery to breast cancer cells by an an�body for MSGb5. 69 Immuniza�on of A4GalT deficient mice by GSLs from renal cancer cells not only resulted in monoclonal an�bodies (mAbs) against gangliosides, but also to SGLs. An�-ganglioside mAbs bound both healthy and cancerous renal cells, while an�bodies towards SGLs, such as SM2, SM3 and SM4, showed high specificity for renal cancer cells over healthy cells. 70 Other SGLs have also shown to be ligands for cancer-specific an�bodies. An important cancer-specific an�body, the an�-epiglycanin an�body (AE3, later named HAE3), was raised against epiglycanin from mouse mammary carcinoma cells. 71,72 Sulfoglycolipid SM1a (Fig. 1) strongly bound HAE3 in a carbohydrate microarray study. This was a surprise finding, since HAE3 is known to bind mucin-type glycans and not SGLs. 73 NK-cell Cancer cell Cancer cell Siglec-7 immunostimulating receptor DSGb5 NK-cell