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- W4308395719 abstract "<h3>Background</h3> Agonist antibodies targeting 4-1BB (CD137) effectively costimulate cytotoxic T cells and are active in preclinical models of cancer. However, clinical development of these agents has been hampered by limited efficacy and/or poor tolerability at active doses.<sup>1,2</sup> To overcome the efficacy and safety limitations of this approach, SGN-BB228, a first-in-class, investigational CD228/4-1BB Antibody Anticalin® bispecific was created. SGN-BB228 targets CD228 (melanotransferrin, p97), a glycosylphosphatidylinositol-anchored membrane protein with limited normal tissue expression, but high and prevalent expression in melanoma, mesothelioma, lung cancer and other tumor types.<sup>3,4</sup> SGN-BB228 is designed to provide a potent costimulatory bridge between tumor-specific T cells and tumor cells, improving and constraining T cell mediated cytotoxicity to tumors, potentially expanding the therapeutic window for 4-1BB agonism. <h3>Methods</h3> Here we describe the expression profile of CD228 in cancer and normal tissues and preclinical activity of SGN-BB228 across reporter cell and primary T cell-based assays. <h3>Results</h3> SGN-BB228 is comprised of a hinge-stabilized (S228P), Fc-null (FALA) fully human IgG4 antibody specific for CD228 connected to 4-1BB-targeting Anticalin® proteins<sup>5</sup> via C-terminal heavy-chain fusions. The proposed mechanism of action (MOA) for SGN-BB228 is CD228-conditional clustering of 4-1BB on antigen experienced tumor-specific T cells, resulting in enhanced activation and cellular cytotoxicity. Expression analysis across cancer and normal tissues demonstrates CD228 is a tumor associated antigen prevalent in melanoma, mesothelioma, lung cancer and other tumor types with minimal normal tissue expression. Preclinical testing of SGN-BB228 in vitro shows potent CD228-conditional 4-1BB stimulation and cytotoxic T cell activation across a range of assay systems. In the presence of CD228-expressing tumor cells, but not CD228-negative tumor cells, SGN-BB228 drove dose-dependent amplification of NFkB signaling using a 4-1BB reporter cell system. SGN-BB228 also consistently drove potent CD228-conditional costimulatory activity in assays using primary T cells or whole peripheral blood mononuclear cells (PBMCs) receiving different forms of T cell receptor stimulation. The CD228-conditional activity of SGN-BB228 consistently outperformed a clinical benchmark antibody, even in the presence of antibody-clustering FcgRs expressed by PBMC. <h3>Conclusions</h3> Together these data introduce 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 future clinical study of SGN-BB228 in a first-in-human Phase 1 trial. <h3>References</h3> Segal NH, Logan TF, Hodi FS, <i>et al</i>. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. <i>Clin Cancer Res</i>. 2017;<b>23</b>(8):1929–36. Segal NH, He AR, Doi T,<i> et al</i>. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. <i>Clin Cancer Res</i> 2018;<b>24</b>(8):1816–23. Brown JP, Nishiyama K, Hellström I, Hellström KE. Structural characterization of human melanoma-associated antigen p97 with monoclonal antibodies. <i>J Immunol</i> 1981;<b>127</b>(2):539–546. Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PJ. Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. <i>Mol Cancer Ther</i> 2006;<b>5</b>(6):1474–1482. Hinner MJ, Aiba RSB, Jaquin TJ, <i>et al</i>. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. <i>Clin Cancer Res</i>. 2019;<b>25</b>(19):5878–89." @default.
- W4308395719 created "2022-11-11" @default.
- W4308395719 creator A5016696344 @default.
- W4308395719 date "2022-11-01" @default.
- W4308395719 modified "2023-09-30" @default.
- W4308395719 title "1201 SGN-BB228 is a first-in-class CD228-targeted costimulatory antibody anticalin<sup>®</sup>bispecific delivering potent and conditional 4–1BB costimulation to tumor-specific T cells" @default.
- W4308395719 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1201" @default.
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