Abstract ND08: FAP-LTBR (RO7567132): a first-in-class bi-specific stromal immunomodulatory agonist designed to enable and enhance efficacy of cancer immunotherapies

Abstract RO7567132 is a novel bispecific antibody that binds bivalently to the lymphotoxin beta receptor (LTBR) and monovalently to the fibroblast activation protein (FAP). LTBR is a member of the tumor necrosis factor receptor superfamily, expressed by various cells including stromal cells. Activation of LTBR upon engagement with its ligands leads to the upregulation of genes involved in the attraction of immune cells and the development and maintenance of secondary lymphoid organs and high endothelial venules (HEVs). FAP is highly prevalent in various solid tumors, making it a suitable target for drugs intended to accumulate within the tumor stroma. By restricting LTBR activation specifically to the tumor microenvironment (TME) via FAP targeting, RO7567132 is designed to modulate the tumor stroma to induce HEV differentiation, increase immune cell infiltration via upregulation of adhesion molecules and chemokines and and induce the formation of tertiary lymphoid structures (TLS) specifically at the tumor site, while avoiding widespread LTBR activation and minimizing toxicity. Clinical evidence shows that an increased immune infiltrate, the presence of TLS or the presence of HEVs correlate with better prognosis and better response to cancer immunotherapies in several tumor indications. RO7567132 induced a dose-dependent and FAP-dependent increase in the expression of adhesion molecules on the surface of endothelial cells, as well as an increase in the secretion of immune cell-attracting chemokines in vitro. In preclinical mouse models, the murine surrogate of RO7567132 induced the activation of tumor blood vessels, their differentiation into HEVs and the upregulation of inflammatory and immune pathways that resulted in increased infiltration of T and B cells into the tumor and elevated serum levels of CXCL13. Treatment with the murine surrogate of RO7567132 led to tumor growth inhibition in a breast cancer model and showed greater efficacy when combined with the murine surrogate of atezolizumab in both breast cancer and fibrosarcoma models. Additionally, in a slow-growing orthotopic mouse colorectal cancer model, treatment with the murine surrogate of RO7567132 increased the content of immune cells (T and B cells) and HEVs in tumors and induced the formation of immune cell niches resembling TLS. RO7567132 was well tolerated in both a 2-week non-GLP Maximum tolerated dose/Dose range-finding (MTD/DRF) study and a 4-week GLP toxicology study in cynomolgus monkeys at doses up to 10 mg/kg, with no associated adverse findings. RO7567132 is currently being tested in an open-label, multicenter, dose-escalation, randomized, phase1 study (NCT06537310) to evaluate safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of RO7567132, as a single agent and in combination with atezolizumab in participants with advanced and/or metastatic solid tumours. Citation Format: Roberta Bianchi, Leo Kunz, Michelle Brydon, Dario Speziale, Ralf Hosse, Juliana Bessa, Christophe Boetsch, Ana De Oliviera Rodrigues Amorim, Petra Schwalie, Alberto Valdeolivas Urbelz, Nadine Kumpesa, Christine Trumpfheller, Ashley Lakner, Pablo Umana, Meher Majety. FAP-LTBR (RO7567132): a first-in-class bi-specific stromal immunomodulatory agonist designed to enable and enhance efficacy of cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND08.