小细胞肺癌 (SCLC) 是一种侵袭性疾病，治疗选择有限。岩藻糖基-GM1 (FucGM1) 是一种糖脂，在大多数 SCLC 肿瘤中过度表达，但在正常健康组织中几乎不存在。在这里，我们验证了一种靶向 FucGM1 的 T 细胞重定向双特异性抗体 (TCB) 用于治疗 SCLC。超过 80% 的 SCLC 患者来源的异种移植 (PDX) 组织表达 FucGM1，而只有三种正常人体组织：垂体、胸腺和皮肤表达低度和局灶性 FucGM1。基于 Fc 沉默的人源化 h134 抗体的 FucGM1 靶向 TCB (SC134-TCB) 表现出纳摩尔 FucGM1 糖脂和 SCLC 细胞表面结合。 SC134-TCB 对 SCLC 细胞系表现出强大的离体杀伤作用，供体依赖性 EC50 范围为 7.2 pmol/L 至 211.0 pmol/L，有效激活 T 细胞，具有皮摩尔效率，与目标依赖性细胞因子的产生（如干扰素 γ）一致、白细胞介素-2 和肿瘤坏死因子 α 以及 CD4 和 CD8 T 细胞的强劲增殖。离体 SC134-TCB 肿瘤控制活性转化为有效的体内抗 DMS79 肿瘤治疗，在人 PBMC 混合环境中实现 100% 无肿瘤生存，全身给药后总体生存率为 40%（55% 肿瘤生长抑制）人类PBMC。与 Atezolizumab 联合治疗进一步提高生存率和肿瘤生长抑制（高达 73%）。 SC134-TCB 剂量减少十倍后，仍保持了强大的体内抗肿瘤作用，转化为 70% 的总生存率 (P<0.0001)。全血与 SC134-TCB 孵育以及健康人原代细胞分析表明没有靶标独立的细胞因子产生。 SC134-TCB 是一个有吸引力的候选药物，可为 SCLC 患者提供有效的免疫治疗选择。

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.