Antibodies against sialoglycolipids two sides of the same coin

JOSÉ L. DANIOTTI; FERNANDO M. RUGGIERO; ALDO A. VILCAES; VANINA TORRES DEMICHELIS

San Pablo

Workshop; Sao Paulo School for Advanced Science in Cell Biology; 2018

Faculdade de Ciências Farmacêuticas, Universidade de São Paulo

Introduction: Sialoglycolipidsare a sialic acid bearing family of glycolipids ubiquitously distributed on theouter leaflet of vertebrate plasma membranes (PM). Most of them are known asgangliosides. Ganglioside expression is tightly regulated in a tissue anddevelopment fashion and changes under several physiological and pathologicalconditions. A wide spectrum of pathological processes is associated withgangliosides, being receptors for viruses, toxins and antibodies. Antibodiesto gangliosides (ATGs) have been associated with a wide rangeof neuropathological syndromes. ATGs GM1 and GD1a are key mediatorsof peripheral nerve damage in Guillain-Barre syndrome. On the other hand, the abnormalglycosylation of gangliosides on the surface of different cancer cells hasreceived considerable attention as a convenient immunotherapeutic target forcancer treatment through ATGs.Objectives: Thebinding and fate of ATGs are critical for both, their role in induction of celldamage and for potential therapeutic use. In our laboratory, we are interestedin understanding the molecular mechanisms involved in ganglioside expression aswell as the internalization and intracellular trafficking of ATGs after bindingtheir target gangliosides at the PM.Results and conclusions: Previousfindings from our laboratory demonstrated that the kinetics of cellular internalizationand fate of ATGs are quite different and seem to be unique for each cell-ATGsystem. This knowledge allows us to selectively target and to potentiallyablate the cell population that express the target ganglioside. Those ATGs thatare internalized could be used to selectively deliver cytotoxic agents into thetarget cells. On the other hand, ATGs that are not actively internalized butremain associated to the PM could potentially be used to engage a cellular/humoralresponse against those target cells. We took advantage of the internalizationfeature of an antibody that recognizes GD3 to selectively deliver saporin toxinto GD3-expressing melanoma cells, which caused a drastic growth inhibition. Now,we are characterizing the cellular behavior of an antibody to SSEA4, anupregulated sialoglycolipid in triple negative breast cancer cells that constitutea promising antigen to specifically target this cancer subtype.