MST-0312: Targeted LTBR agonist designed to induce tertiary lymphoid structures (TLS) and high endothelial venules (HEV) for the treatment of solid tumors

The presence of tertiary lymphoid structures (TLSs) and associated high endothelial venules (HEVs) in tumors is recognized as a hallmark of effective antitumor immunity. Improved prognosis and treatment outcomes across tumor stages and modalities (including immune checkpoint blockade, VEGF/PD1, chemotherapy and radiotherapy) highlight the therapeutic potential of inducing TLS and HEV in solid tumors. TLS are ectopic lymphoid structures, part of normal immune defences, that facilitate local education and activation of immune cells, which together with associated HEVs are proposed to enable a marked increase in immune cell access and activity in tumors. Lymphotoxin-beta receptor (LTBR) activation is a critical pathway driving HEV & TLS formation. MST-0312, a novel FAP-LTBR bispecific antibody, is engineered for tumor-localised LTBR activation, promoting TLS and HEV formation while minimising systemic LTBR activation. MST-0312 is planned to enter a first-in-human Phase 1b study shortly. MST-0312 demonstrates potent activation of LTBR in the presence of FAP in human in vitro using patient-derived cancer-associated fibroblasts (CAFs) co-cultured with tumour cell lines. In patient-derived NSCLC microtumors incubated with autologous tumour-infiltrating lymphocytes (TILs), MST-0312 induced reproducible upregulation of TLS-related chemokines, confirming LTBR activation in human tumor tissue. A murine FAP-LTBR bispecific surrogate molecule showed dose-dependent tumor growth inhibition in a MMTV-PyMT syngeneic tumour model linked to a dose-dependent increase in HEVs and T and B-cell infiltration. Immune profiling revealed restructuring of the tumor microenvironment, including increased infiltration of CD8⁺ and CD4⁺ T cells, B cells, alongside a significant decrease in myeloid-derived suppressor cells. Chemokine profiling indicated upregulation of TLS-associated chemokines, downstream of the LTBR pathway. Combination of the MST-0312 surrogate molecule with either Antibody-Drug-Conjugate (ADC), PD-L1 antibody or peptide vaccine in the EMT-6 model significantly increased immune cell infiltration and tumor control, demonstrating the potential for combining with both immune and cytotoxic agents. MST-0312 and its surrogate were well tolerated, with no evidence of systemic cytokine release or off-target toxicity. In summary, MST-0312 is a novel FAP-LTBR bispecific antibody which induces TLS & HEV formation in the tumor and drives the recruitment, education and activation of anti-tumor immune cells leading to potent anti-tumor responses. TLS & HEV induction represents an exciting new therapeutic class with potential as monotherapy and in combination.