Abstract 2605: STX-1, a potent first-in-class ADC directed against DPP4 (CD26) as a biomarker of senescent tumor cells

Abstract Dipeptidyl Peptidase 4 (DPP4/CD26) is a membrane glycoprotein involved in particular chemotactic and inflammatory responses, via its N-terminal protein cleavage enzymatic activities. DPP4 expression is found in various cell types, in certain subsets of lymphocytes and frequently overexpressed in primary tumors and metastases where its role remains still poorly understood. Recently, DPP4 was identified as a novel biomarker of senescent cells. In cancers, the harmful effect of senescent tumor cells is well recognized and mediated by the local production of pro-inflammatory cytokines, soluble immunosuppressive factors and metalloproteinases, called ‘SASP’ phenotype which could be induced by many chemotherapy and radiation regimens. This deleterious microenvironment promotes tumor growth, invasion and neoangiogenesis which can lead to treatment resistance, relapses and poor prognosis in many cancers, especially at advanced stages. STX-1 is a leading first-in-class ADC platform based on a proprietary anti-DPP4 mAb generated after a screen between normal and senescence-induced cells identifying DPP4 as a candidate for cancer targeting. Other biomarkers of interest were also identified as being selectively expressed for further preclinical evaluation. This IgG1/k mAb has potent in vitro activities on DPP4+ cells: i) in a bleomycin-induced senescent fibroblasts model; ii) on DPP4-expressing and chemotherapy- or radiotherapy-induced senescent human tumor cell lines with overexpression of DPP4; iii) binding of the mAb to its target results in its internalization into the endolysosomal compartment of cells. The first formulations of STX-1 are undergoing preclinical evaluation in vitro and in vivo and consist of a classical maleimide-based conjugation, an enzymatically cleavable cathepsin-dipeptide linker comprising a self-immolative spacer and either inhibitor of tubulin (MMAE/DAR4) or topoisomerase I inhibitor (exatecan/DAR8) payloads. Plasma stability and affinity, dose-response potency and permeability bystander activity on human tumor cell lines were evaluated in vitro. Preliminary efficacy is demonstrated in vivo on tumor xenograft models with various DPP4 expressions (constitutive or chemo/radio-induced to senescence) based on a 21-28 days weekly infusion schedule (3 or 5 µg/kg). The indications selected for further therapeutic development are prostate, liver and colorectal carcinoma models. Data on antitumor efficacy, tolerability and pharmacokinetics will be presented. Further studies will include optimization of the best STX-1 formulation, NHP studies and GMP scale-up with planned IND submission expected in Q3-2024. Exploiting the targeting of senescent cells in cancer based on selected biomarkers such as DPP4 constitutes a new therapeutic avenue to counteract tumor dormancy, recurrences and resistance to conventional chemo/radiotherapies. Citation Format: Eric Angevin, Virginie Lelarge, Remi Capelle, Justine Choeur, Thierry Mathieu, Benjamin Le Calvé. STX-1, a potent first-in-class ADC directed against DPP4 (CD26) as a biomarker of senescent tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2605.