SC134-TCB targeting fucosyl-GM1, a T cell engaging antibody with potent anti-tumour activity in preclinical small-cell lung cancer models

• Published in: Molecular cancer therapeutics
• Main Authors: Dave, am, Vaghela, Poonam, Heath, Bryony, Dunster, Zuzana, Dubinina, Elena, Thakker, Dhruma, Mann, Katie, Chadwick, Joe, Cane, Gaelle, Kaira, Bubacarr G, Mohammed, Omar J, Choudhury, Ruhul, Paston, Samantha, Parsons, Tina, Vankemmelbeke, Mireille, Durrant, Lindy
• Format: Journal Article
• Language: English
• Published: 26.08.2024
• ISSN: 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-24-0187

Small-cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Fucosyl-GM1 (FucGM1) is a glycolipid overexpressed in the majority of SCLC tumours, but virtually absent from normal healthy tissues. Here, we validate a FucGM1-targeting T cell redirecting bispecific antibody (TCB) for the treatment of SCLC. Over 80% of SCLC patient-derived xenograft (PDX) tissues expressed FucGM1, whilst only three normal human tissues: pituitary, thymus and skin expressed low and focal FucGM1. A FucGM1-targeting TCB (SC134-TCB), based on the Fc-silenced humanised h134 antibody exhibited nanomolar FucGM1 glycolipid and SCLC cell surface binding. SC134-TCB showed potent ex vivo killing of SCLC cell lines with donor-dependent EC50 ranging from 7.2 pmol/L up to 211.0 pmol/L, effectively activating T cells, with picomolar efficiency, coinciding with target-dependent cytokine production such as interferon gamma, interleukin-2 and tumour necrosis factor alpha and robust proliferation of both CD4 and CD8 T cells. The ex vivo SC134-TCB tumour controlling activity translated into an effective in vivo anti-DMS79 tumour therapy, resulting in 100% tumour-free survival in a human PBMC admixed setting and 40% overall survival (55% tumour growth inhibition) with systemically administered human PBMC. Combination treatment with Atezolizumab further enhanced survival and tumour growth inhibition (up to 73%). A ten-fold SC134-TCB dose reduction maintained the strong in vivo anti-tumour impact, translating into 70% overall survival (P<0.0001). Whole blood incubation with SC134-TCB, as well as healthy human primary cells analysis, revealed no target-independent cytokine production. SC134-TCB presents an attractive candidate to deliver an effective immunotherapy treatment option for SCLC patients.Small-cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Fucosyl-GM1 (FucGM1) is a glycolipid overexpressed in the majority of SCLC tumours, but virtually absent from normal healthy tissues. Here, we validate a FucGM1-targeting T cell redirecting bispecific antibody (TCB) for the treatment of SCLC. Over 80% of SCLC patient-derived xenograft (PDX) tissues expressed FucGM1, whilst only three normal human tissues: pituitary, thymus and skin expressed low and focal FucGM1. A FucGM1-targeting TCB (SC134-TCB), based on the Fc-silenced humanised h134 antibody exhibited nanomolar FucGM1 glycolipid and SCLC cell surface binding. SC134-TCB showed potent ex vivo killing of SCLC cell lines with donor-dependent EC50 ranging from 7.2 pmol/L up to 211.0 pmol/L, effectively activating T cells, with picomolar efficiency, coinciding with target-dependent cytokine production such as interferon gamma, interleukin-2 and tumour necrosis factor alpha and robust proliferation of both CD4 and CD8 T cells. The ex vivo SC134-TCB tumour controlling activity translated into an effective in vivo anti-DMS79 tumour therapy, resulting in 100% tumour-free survival in a human PBMC admixed setting and 40% overall survival (55% tumour growth inhibition) with systemically administered human PBMC. Combination treatment with Atezolizumab further enhanced survival and tumour growth inhibition (up to 73%). A ten-fold SC134-TCB dose reduction maintained the strong in vivo anti-tumour impact, translating into 70% overall survival (P<0.0001). Whole blood incubation with SC134-TCB, as well as healthy human primary cells analysis, revealed no target-independent cytokine production. SC134-TCB presents an attractive candidate to deliver an effective immunotherapy treatment option for SCLC patients.