Exploiting the internalization feature of an antibody against the glycosphingolipid SSEA‐4 to deliver immunotoxins in breast cancer cells

Abstract

The stage‐specific embryonic antigen‐4 (SSEA‐4) is a cell surface glycosphingolipid antigen expressed in early stages of human development. This surface marker is downregulated during the differentiation process but is found re‐expressed in several types of tumors, including breast cancer. This feature makes SSEA‐4 an attractive target for the development of therapeutic antibodies against tumors. In this work, we first studied the binding and intracellular fate of the monoclonal antibody MC‐813‐70 directed against SSEA‐4. MC‐813‐70 was found to be rapidly internalized into triple‐negative breast cancer cells following binding to its target at the plasma membrane, and to accumulate in acidic organelles, most likely lysosomes. Given the internalization feature of MC‐813‐70, we next tested whether the antibody was able to selectively deliver the saporin toxin inside SSEA‐4‐expressing cells. Results show that the immunotoxin complex was properly endocytosed and able to reduce cell viability of breast cancer cells in vitro, either alone or in combination with chemotherapeutic drugs. Our findings indicate that the MC‐813‐70 antibody has the potential to be developed as an alternative targeted therapeutic agent for cancer cells expressing the SSEA‐4 glycolipid.

Probing the Internalization and Efficacy of Antibody‐Drug Conjugate via Site‐Specific Fc‐Glycan Labelling of a Homogeneous Antibody Targeting SSEA‐4 Bearing Tumors

“…After longer incubation, the majority of chMC813-70-AF488 moved to the intracellular space. This result showed that the glycoengineered chMC-813-70 antibody is internalized by MDA-MB-231 cells, which is consistent with a previous report by Daniotti et al [23]…”

Golgi Phosphoprotein 3 Regulates the Physical Association of Glycolipid Glycosyltransferases

“…Additionally, qualitative and quantitative changes in the glycosylation of glycolipids are a hallmark of tumors contributing to their development and progression [ 2 , 3 , 4 ]. Thus, the aberrant glycolipid expression reported in tumors is emerging as an attractive target to deliver specific therapies [ 2 , 5 ]. These molecules are synthesized by a complex membrane-bound machinery formed by glycolipid glycosyltransferases (GGTs) at the Golgi complex [ 6 , 7 ] ( Figure 1 ).…”

Stage-specific Embryogenic Antigen-4 Expression in Castration-resistant Prostate Cancer and its Correlation With the Androgen Receptor

“…In recent years, SSEA-4 has been suggested to be a novel therapeutic target in a variety of malignancies (42)(43)(44). For example, a mAb directed against SSEA-4 (MC-813-70) has been suggested as a potential therapeutic agent for triplenegative breast cancer cells expressing SSEA-4 (43).…”