Foram Dave, Poonam Vaghela, Bryony Heath, Zuzana Dunster, Elena Dubinina, Dhruma Thakker, Katie Mann, Joe Chadwick, Gaelle Cane, Bubacarr G Kaira, Omar J Mohammed, Ruhul Choudhury, Samantha Paston, Tina Parsons, Mireille Vankemmelbeke, Lindy Durrant
{"title":"SC134-TCB 靶向岩藻糖基-GM1 的 T 细胞参与抗体,在临床前小细胞肺癌模型中具有强大的抗肿瘤活性。","authors":"Foram Dave, Poonam Vaghela, Bryony Heath, Zuzana Dunster, Elena Dubinina, Dhruma Thakker, Katie Mann, Joe Chadwick, Gaelle Cane, Bubacarr G Kaira, Omar J Mohammed, Ruhul Choudhury, Samantha Paston, Tina Parsons, Mireille Vankemmelbeke, Lindy Durrant","doi":"10.1158/1535-7163.MCT-24-0187","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"SC134-TCB targeting fucosyl-GM1, a T cell engaging antibody with potent anti-tumour activity in preclinical small-cell lung cancer models.\",\"authors\":\"Foram Dave, Poonam Vaghela, Bryony Heath, Zuzana Dunster, Elena Dubinina, Dhruma Thakker, Katie Mann, Joe Chadwick, Gaelle Cane, Bubacarr G Kaira, Omar J Mohammed, Ruhul Choudhury, Samantha Paston, Tina Parsons, Mireille Vankemmelbeke, Lindy Durrant\",\"doi\":\"10.1158/1535-7163.MCT-24-0187\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":18791,\"journal\":{\"name\":\"Molecular Cancer Therapeutics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1535-7163.MCT-24-0187\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1535-7163.MCT-24-0187","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
SC134-TCB targeting fucosyl-GM1, a T cell engaging antibody with potent anti-tumour activity in preclinical small-cell lung cancer models.
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.
期刊介绍:
Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.