PO.IM01.16 · 免疫学
针对IGFBPL1的T细胞衔接器的开发：小细胞肺癌及其他神经内分泌癌的新靶点
Development of a T cell engager against IGFBPL1: A novel target for small cell lung cancer and other neuroendocrine cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
小细胞肺癌（SCLC）是一种侵袭性神经内分泌恶性肿瘤，因治疗耐药而临床预后极差。靶向DLL3的T细胞衔接器tarlatamab获FDA批准，为复发性疾病患者提供了新的治疗选择，并激发了人们对T细胞衔接器及其他DLL3靶向疗法用于SCLC的热情。值得注意的是，SCLC在转录层面复杂，具有多种分子亚型。对于DLL3阴性患者以及应对与瘤内异质性相关的获得性耐药，还需要更多的治疗选择。胰岛素样生长因子结合蛋白样1（IGFBPL1）是胰岛素样生长因子结合蛋白（IGFBP）家族的成员，该家族为调节胰岛素样生长因子（IGF）生物活性的分泌型蛋白。IGFBPL1在健康成人组织中通常处于沉默状态，但在SCLC以及其他神经内分泌表型癌症中高表达，这已在人类细胞系和患者样本中得到证实。利用Retained Display（ReD™）技术，我们分离出多个完全人源的单链可变片段（scFv），可特异性识别由HLA-A*02:01（全球最常见的HLA等位基因之一）呈递的源自IGFBPL1的肽段。我们基于一个先导候选scFv生成了一种半衰期延长的T细胞衔接器，其对靶点IGFBPL1/HLA-A*02:01复合物展现出皮摩尔范围的结合。体外观察到对天然表达IGFBPL1的HLA-A*02:01阳性SCLC细胞系的强效杀伤，包括HLA表面表达低的模型——这是SCLC的常见特征。我们目前正在对IGFBPL1在总蛋白和表面肽水平的表达进行表征，此外，体内疗效评估及其他IND支持性研究也在进行中。我们的数据支持基于IGFBPL1靶向开发一种新型SCLC T细胞衔接器。这种潜在疗法为临床中和研究中的DLL3靶向疗法提供了另一种选择，以克服这一具有挑战性且极具破坏性的疾病。
查看英文原文 English abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal clinical outcomes defined by treatment resistance. FDA approval of tarlatamab, a T cell engager targeting DLL3, has delivered a new treatment option for patients with relapsed disease and spurred enthusiasm for T cell engagers and other DLL3-targeted therapies for SCLC. Notably, SCLC is transcriptionally complex with multiple molecular subtypes. Additional treatment options are required for DLL3-negative patients and to combat acquired resistance associated with intratumoral heterogeneity. Insulin growth factor binding protein-like 1 (IGFBPL1) is a member of the insulin-like growth factor binding protein (IGFBP) family, secreted proteins regulating the biological activity of insulin-like growth factors (IGFs). IGFBPL1 is normally silenced in healthy adult tissues, but is highly expressed in SCLC, as well as other neuroendocrine-phenotype cancers, as shown in human cell lines and patient samples. Using Retained Display (ReD TM ) technology, we isolated several fully human single chain variable fragments (scFvs) specifically recognising a peptide derived from IGFBPL1 presented by HLA-A*02:01, one of the most common HLA alleles worldwide. We generated a half-life extended T cell engager based on a lead candidate scFv displaying picomolar range binding to the target IGFBPL1/HLA-A*02:01 complex. Potent killing of HLA-A*02:01-positive SCLC cell lines naturally expressing IGFBPL1 was observed in vitro, including models with low HLA surface expression - a common feature of SCLC. We are currently characterising IGFBPL1 expression at the total protein and surface peptide level, in addition to evaluation of in vivo efficacy and other IND enabling studies in progress. Our data support development of a novel T cell engager for SCLC based on IGFBPL1 targeting. This potential therapy provides another option to DLL3-targeting therapies in the clinic and under investigation, to overcome this challenging and devastating disease.
利益披露 Disclosure
L. A. Pitt,
Immunome, Inc Stock.
E. Leung, None..
R. Kannan, None..
S. Jabar, None..
N. Church, None..
Z. Rosenes, None..
B. Kiefel, None..
M. Beasley, None.