Eight LabEx teams join their strengths in the battle against breast cancer

An article published this month in the Journal for ImmunoTherapy of Cancer (IF = 8.4) highlights the joint work of eight MAbImprove teams.

Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies

The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human breast cancer (BC) cells. This study, led by the ‘Proteases, Microenvironment and Cancer’ team, led by Dr Emmanuelle Liaudet-Coopman (IRCM, Inserm U1194), in collaboration with ICM hospital (Montpellier) and 7 Labex MAbImprove teams, explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in triple-negative BC (TNBC). We first validated the potential value of cath-D as a tumor-specific extracellular target in TNBC and its suitability for antibody-based therapy. Then, we generated two human anti-cath-D scFv fragments cloned in the human IgG1 l format (F1 and E2) that efficiently bind to human and mouse cath-D, even at the acidic pH of the TNBC microenvironment (International patent WO2016/188911). F1 and E2 accumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival without apparent toxicity. Using this xenograft model, we found that the Fc function of F1 was essential for maximal tumor inhibition. Mechanistically, F1-based therapy triggered an anti-tumor response via natural killer (NK) cell activation, and antitumor cytokine production. Furthermore, F1 treatment prevented the recruitment of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) within the tumor, a specific effect associated with a less immunosuppressive tumor microenvironment. Finally, F1 inhibited tumor growth of TNBC patient-derived xenografts (PDXs). This preclinical proof-of-concept study validates the feasibility and efficacy of an anti-cath-D immunomodulatory antibody-based strategy to treat patients with TNBC.


To read the article : pubmed/30717773