Atigotatug

Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012–mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti–PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178–89. ©2018 AACR.

Certain lung cancer patients express elevated Fucosyl Monosialoganglioside (Fuc‐GM1) in circulation compared to control groups. Several sensitive methods involving characterization of Fuc‐GM1 have been reported. However, a highly specific and sensitive method for quantifying multiple potential Fuc‐GM1 biomarkers present in various biological matrices has not been reported to date.

Individual Fuc‐GM1 analogs in a commercially obtained standard mixture were characterized using HPLC/UV/MS and high‐resolution mass spectrometry (HRMS). Proprietary antibodies, mAb1 and mAb2, were used to selectively capture and pre‐concentrate the soluble and drug‐bound forms of Fuc‐GM1 molecules present in human serum and whole blood, eliminating the background matrix components. Immunocapture extraction (ICE) followed by HPLC/MS/MS was used to quantify specific Fuc‐GM1 analogs in biological matrices.

The concentration of individual Fuc‐GM1 analogs in the standard mixture was estimated to be 7–34%, using HPLC/UV/MS. Using the standard mixture spiked into the biological matrices (100 μL), the lower limit of quantification (LLOQ) of each analog was 0.2–0.4 ng/mL with a dynamic range of up to 200 ng/mL. The applicability of the ICE‐HPLC/MS/MS method was demonstrated by detecting endogenous Fuc‐GM1 analogs present in rat blood and in several lung cancer cell lines.

This highly specific and sensitive HPLC/MS/MS method for quantifying individual potential Fuc‐GM1 biomarkers in serum and whole blood can play a critical role in patient stratification strategies and during drug treatment. This method can be employed for monitoring both free (soluble) form and antibody drug‐bound Fuc‐GM1.