Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity

Abstract

Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely seen in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. We have identified novel antibodies that specifically target with high affinity the STn glycan independent of its carrier protein, affording the potential to recognize a wider array of cancer-specific sialylated proteins. A panel of murine monoclonal anti-STn therapeutic antibodies were generated and their binding specificity and efficacy were characterized in vitro and in in vivo murine cancer models. A subset of these antibodies were conjugated to monomethyl auristatin E (MMAE) to generate antibody-drug conjugates (ADCs). These ADCs demonstrated in vitro efficacy in STn-expressing cell lines and significant tumor growth inhibition in STn-expressing tumor xenograft cancer models with no evidence of overt toxicity.

Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau

“…More importantly, highly glycan-specific anti-STn antibodies conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) as developed in Prendergast et. al, [ 25 ] decreased both OvCa cell viability in vitro and OvCa xenograft tumor volume in vivo , supporting our hypothesis that targeting of STn in ovarian tumors may be an effective clinical strategy.…”

“…Since our analyses suggest that both STn + /CD133 - and STn + /CD133 + OvCa cells exhibit some stem cell like characteristics, we sought to target STn-positive cells by exploiting our novel specific anti-STn antibody [ 25 ]. We developed a cathepsin B-labile maleimidocaproyl-valine-citruline-p-aminobenzyloxycarbonyl-monomethyl auristatin E ADC (MC-vc-PAB-MMAE, referred to as CL-MMAE in the text).…”

“…In earlier studies, we demonstrated that STn levels vary widely across established OvCa cell lines [ 25 ] likely due to heterogeneity among the evaluated lines. In analogous analyses, we and others have reported similar variability in expression of the known CSC marker CD133 [ 28 , 46 ].…”

I-branched carbohydrates as emerging effectors of malignant progression

“…Importantly, through the pioneering efforts to reengage the host immune system to fight cancer, cancer-associated glycans can also be targeted in these revitalized anticancer therapeutic strategies. Development of vaccines, anticarbohydrate-drug conjugate Abs, and chimeric antigen receptor T cells against cancer-specific glycans are rapidly evolving as promising cancer immunotherapeutic approaches (116)(117)(118)(119)(120). As reviewed here, there are several cancer-associated glycan features that can be leveraged to design rational drug or immune system targets.…”

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

“…P value of <0.05 was considered statistically significant4 | D ISCUSS I ONAberrant glycosylation and altered O-glycan biosynthesis machinery have been implicated with the progression of several cancers including PDAC 24,25. Incomplete O-glycosylation results in the expression of truncated O-glycans such as Tn antigen and its sialylated form STn antigen whose expression is highly restricted in normal tissues but is found only on tumour tissues [26][27][28][29]. The presence oftruncated O-glycans in cell surface of tumour tissues is highly associated with tumour progression, metastasis, chemoresistance and poor prognosis which makes STn antigen as an attractive therapeutic target.…”