Development of a T cell engager against IGFBPL1: A novel target for small cell lung cancer and other neuroendocrine cancers

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.