Abstract 5676: SGN-BB228, a CD228-directed costimulatory antibody anticalin® bispecific provides potent and conditional 4-1BB costimulation to T cells in vivo and in an in vitro model of T cell exhaustion

Agonist antibodies targeting 4-1BB (CD137) effectively costimulate cytotoxic T cells and are active in preclinical models of cancer. However, the clinical development of these agents has been hampered by limited efficacy and/or poor tolerability at active doses. To overcome the efficacy and safety limitations of this approach, SGN-BB228, a first-in-class, investigational CD228 × 4-1BB costimulatory Antibody Anticalin® bispecific (MabcalinTM) was created. SGN-BB228 is designed to target CD228 (melanotransferrin), a GPI-anchored oncofetal membrane protein with limited normal tissue expression, but high prevalence and expression in melanoma, mesothelioma, lung cancer, and other tumor types. SGN-BB228 is designed to provide a potent costimulatory bridge between tumor-specific T cells and tumor cells, improving and limiting T cell-mediated cytotoxicity to tumors, potentially expanding the therapeutic window for 4-1BB agonism. Here we describe the anti-tumor activity and pharmacodynamic effects of SGN-BB228 in vivo using humanized mouse tumor models, and the in vitro costimulatory effect of SGN-BB228 in a tumor cell line-based model of functional T cell exhaustion. In vivo, SGN-BB228 improved the quality and magnitude of the cytotoxic T cell response within CD228-expressing tumors, augmenting anti-tumor immunity. In vitro, 4-1BB costimulation provided by SGN-BB228 elicited proliferation, and cytokine production from functionally exhausted human T cells when in culture with CD228-expressing tumor cell lines engineered to engage the T cell receptor. Functionally exhausted T cells in this system are a mixed population that share phenotypic markers and single cell transcriptional signatures associated with either progenitor exhausted T cells (TPEX) or terminally exhausted T cells (TEX). Interestingly, in this system, anti-PD-1 (nivolumab) failed to reinvigorate functionally exhausted T cells despite high PD-L1 expression by tumor cells. The unique ability of 4-1BB costimulation provided by SGN-BB228 to improve T cell activity in this model suggests the potential to drive immunomodulation in circumstances where PD-1 blockade fails. Together these data highlight SGN-BB228, a first-in-class, investigational CD228 × 4-1BB costimulatory Antibody Anticalin® bispecific with potent and CD228-conditional 4-1BB costimulatory activity with therapeutic potential in multiple solid tumor types. These data support the first-in-human phase 1 clinical trial of SGN-BB228 in advanced