GM1 is an important component of the neuronal membrane and is found in the cell body and nerve endings. It has been reported that a reduction in GM1 in Parkinson's disease patients is a cause of cumulative cellular damage leading to the failure of basic functional processes and ultimately neuronal death. Fucosyl -GM1 is poorly expressed in normal tissues but overexpressed in various cancers, particularly small cell lung cancer, suggesting strong potential for targeted therapy.

Structure and synthesis of Fucosyl-GM1

Ganglioside GM1 is an amphiphilic compound with a carbohydrate head group that balances the hydrophilicity of the lipid moiety (ceramide) and the hydrophilicity of the lipid head group, and inserts into the outer layer of the membrane.

Tumor-associated gangliosides are synthesized from lactosceramide (LacCer) by the GM3 synthase ST3Gal V. ST3Gal V transfers the first sialic acid residue to LacCer, forming GM3 (a precursor of α-gangliosides). GM3 elongation is accomplished sequentially by β4GalNAc T1 and β3Gal T4, forming GM1, which is then further fucosylated by α1,2-fucosyltransferases FUT1 and FUT2 to form Fucosyl-GM1.

(Data source: Groux-Degroote S, et al. Int J Mol Sci. 2021)

Fucosyl-GM1 targeted therapy

Atigotatug (BMS-986012) is a human G1 monoclonal antibody targeting Fucosyl-GM1, developed by Bristol-Myers Squibb, for the treatment of extensive-stage and limited-stage small cell lung cancer (SCLC). As a tumor-targeting innate immune inducer, it binds to Fucosyl-GM1 with high affinity and specificity, inducing tumor cell death through antibody-dependent cytotoxicity, antibody-dependent phagocytosis, and complement-dependent cytotoxicity. Nivolumab is an anti-PD-1 antibody that restores T cell activity and anti-tumor immune responses, driving T cell-mediated cytotoxicity and associated tumor antigen release. The combination of Atigotatug and Nivolumab has been shown to enhance tumor cell death through these different but complementary mechanisms of action, potentially achieving deeper and more durable tumor control. The Phase III TIGOS study evaluated the efficacy of Atigotatug and Nivolumab in combination with chemotherapy in ES-SCLC. The dual innate and adaptive immune activation design is intended to enhance tumor killing.

(Data source: Paz-Ares LG, et al. Clin Lung Cancer. 2026)

SC134-Deruxtecan is a fucose-GM1-targeting adjuvant (ADC) for the treatment of small cell lung cancer (SCLC). SC134 specifically targets FucGM1, exhibits no cross-reactivity with GM1, and possesses nanomolar affinity. Computer simulations of the SC134-FucGM1 binding site revealed a relatively narrow binding pocket occupied by the three terminal glycosyl groups through multiple fucose-binding interactions. Binding of SC134 to FucGM1 leads to efficient internalization, a half-life of 6.9 hours, lysosomal co-localization, and ultimately, sub-nanomolar drug delivery efficiency at various effective loads. Covalent conjugation of SC134 with DAR8 and a cleavable linker demonstrated potent (nanomolar) cytotoxic activity against SCLC cell lines such as DMS79 and DMS153 in vitro, while also exhibiting concentration-dependent bystander-effect cytotoxicity against FucGM1-negative AGS cells. Furthermore, ADCC further enhanced the cytotoxic effect on SCLC cells. Significant in vivo DMS79 xenograft killing effect was observed at a dose of 3 mg/kg SC134-dructenotecan, and the drug was well tolerated.

(Data source: Heath B, et al. J Transl Med. 2025)