Abstract B063: AGB201, a first-in-class LTβR x EDB bispecific antibody, induces EDB-dependent tertiary lymphoid structure formation and robust anti-tumor activity

Abstract Checkpoint immunotherapy has revolutionized solid tumor therapy by reactivating patients’ anti-tumor immunity. Despite this impact, the majority of patients do not show clinical benefit to α-PD1/PDL1 therapy due to immune suppressed or excluded tumor microenvironments (TME). Tertiary lymphoid structures (TLS) are lymph node-like structures that coordinate immune trafficking and organize immune responses in tissues and their presence in the TME of solid tumors has been positively correlated with clinical benefit of checkpoint immunotherapy. The formation of TLS is orchestrated by the tumor necrosis factor receptor superfamily member, lymphotoxin beta receptor (LTβR). We have advanced a highly optimized bispecific antibody (bsAb) platform to conditionally activate LTβR upon tumor-associated antigen binding. AGB201 is a first-in-class α-LTβR bsAb targeting an oncofetal splice variant of fibronectin (EDB) that is an extracellular matrix tumor antigen overexpressed in the proteinaceous stroma of a variety of solid tumors and absent in normal tissues. In vitro, AGB201 induced EDB-dependent activation of NFκB pathway leading to dose-dependent, selective upregulation of chemokines (EC50= 0.1 nM: CCL19, CXCL10, CXCL12) and the cytokine IL12, all linked to TLS formation. In addition, supernatants from AGB201 treated co-cultures promoted EDB-dependent immune cell trafficking of T cells, dendritic cells and NK cells as well as enhanced immune cell extravasation in endothelial transmigration assays. In vivo, AGB201 demonstrated robust monotherapy anti-tumor activity (8/12 complete regressions, p=0.0008 Log-rank, Bonferroni-Holm adjusted p-values) in the syngeneic EDB-expressing Colon26 model whereas the non-redirecting LTβR x null isotype control, as well as α-PD1 or α-CLTA4 treatment showed no appreciable response. When AGB201 was combined with α-PD1 or α-CLTA4, nearly all tumor bearing mice demonstrated complete responses (11/12 tumor regressions, p=0.0008). Tumor-free “cured” mice from AGB201 and combination treatments arms were rechallenged with Colon26 cells and showed no tumor regrowth, indicative of AGB201 inducing a specific T cell memory response. Further analysis of AGB201-treated mice revealed the presence of TLS formation in tumor tissue by immunofluorescent staining for CD3 (T cells), CD20 (B cells), and CD31 (high endothelial venules). Preliminary data show acceptable tolerability in mice with repeat dosing and cynomolgus monkeys following a single dose, with favorable PK demonstrated in both species. Our findings support advancing AGB201 into clinical evaluation for EDB expressing tumors, both as a monotherapy and in combination with α-PD1 or α-CTLA4. These data highlight the potential of AGB201 to broaden the effectiveness of checkpoint immunotherapy in solid tumors where current agents largely remain ineffective. Citation Format: Nataša Obermajer, Jessie Richardson, Daniel Maslyar, Karin Thacker, Iqbal S. Grewal, Matthew V. Lorenzi. AGB201, a first-in-class LTβR x EDB bispecific antibody, induces EDB-dependent tertiary lymphoid structure formation and robust anti-tumor activity [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B063.