Abstract 14P
Background
Dipeptidyl Peptidase 4 (DPP4 or CD26) is a membrane glycoprotein involved in chemotactic and inflammatory responses, via its enzymatic activities. DPP4 is frequently overexpressed in primary tumors and metastases where its role remains still poorly understood. Recently, DPP4 has been identified as a novel biomarker of senescent cells. In cancers, the harmful effect of senescent tumor cells is well recognized and mediated by the Senescence Associated Secretory Phenotype (SASP) which can be induced by many chemotherapy and radiation treatments. This deleterious induction promotes tumor growth, invasion and neo-angiogenesis which can lead to treatment resistance, relapses, and poor prognosis in many cancers, especially at advanced stages.
Methods
STX-1 is a first-in-class Antibody-Drug Conjugate (ADC) coupling a chimeric anti-DPP4 monoclonal antibody with a topoisomerase I inhibitor (Exatecan/DAR8) payload via an enzymatically cleavable cathepsin-dipeptide linker.
Results
STX-1 was assessed for in vitro and in vivo anti-tumor activities. Using several human cancer cell lines and radiation-induced senescence, we validated the targeting of STX-1 and its cytotoxic effect on cells (at nM ranges). Furthermore, preliminary efficacy is demonstrated in vivo on tumor xenograft models of various histological origins associated with DPP4 positive expressions at doses ranging from 2.5 to 10 mg/kg. The safety of STX-1 has been evaluated in a transgenic human DPP4+ mice model with no significant side effects observed at high-dose injections (up to 100 mg/kg).
Conclusions
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. Our results highlight that STX-1 is a first-in-class ADC suitable for the therapeutic targeting of several cancer indications alone and using synergistic combinations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
StarkAge Therapeutics.
Funding
StarkAge Therapeutics.
Disclosure
B. Le Calvé, D. Dayde, V. Lelarge, G. Jouffroy, J. Choeur: Financial Interests, Institutional, Full or part-time Employment: StarkAge Therapeutics. E. Angevin: Financial Interests, Personal, Advisory Board: Starkaget therapeutics.