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SBT6290 is a novel product candidate comprised of a selective TLR8 agonist conjugated to a Nectin4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells. Nectin4 is a cell surface adhesion molecule that is overexpressed in multiple solid tumor types including bladder, triple negative breast, squamous head and neck, and non-small cell lung cancers, with limited expression in normal tissues. Nectin4-expressing solid tumors display substantial myeloid cell infiltrate. Activation of these myeloid cells in the tumor microenvironment has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. TLR8 is highly expressed in myeloid cell types prevalent in human tumors, including conventional dendritic cells (DCs) and macrophages. TLR8 agonism in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells, and the priming of CTL responses. Here, we show that SBT6290 activates human myeloid cells by SBT6290 in a Nectin4-dependent manner and that a SBT6290 mouse surrogate confers single agent anti-tumor activity in preclinical studies. In vitro studies with human immune cells demonstrate that SBT6290 induces multiple anti-tumor immune mechanisms including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect activation of T and NK cell cytolytic activity. This activity is Nectin4-specific and requires SBT6290 engagement of Fcγ receptors on the surface of myeloid cells to facilitate uptake of the conjugate into myeloid cells. Notably, SBT6290 is >100-fold more active than free, unconjugated TLR8 agonist and demonstrates activity on tumor cells with Nectin4 overexpression that correlates with levels found in primary tumor samples. Nectin4 was recently described to be a ligand for T cell immunoreceptor with Ig and ITIM domains (TIGIT), an inhibitory receptor considered to be a promising new target for cancer immunotherapy (J Immunother Cancer. 2020; 8(1): e000266). The SBT6290 binding domain blocks the interaction between TIGIT and Nectin4, potentially contributing to the T and NK cell activation induced by SBT6290. Systemic administration of a SBT6290 surrogate in mice bearing Nectin4-expressing tumors results in intra-tumoral myeloid and T cell activation and increased overall survival. The preclinical data described here demonstrate the potential for SBT6290 to drive anti-tumor responses and support continued preclinical development of SBT6290 for Nectin4-expressing tumors. Citation Format: Michael R. Comeau, Heather Metz, Brenda Stevens, Damion Winship, Jamie Brevik, Marcus Rhodehamel, Monica Childs, Elsa Hay, Jenny Chang, Li-Qun Fan, Hengyu Xu, Jonathan Grey, Jeffrey Adamo, Ben Setter, Ray Carillo, Sean W. Smith, Phil Tan, Robert Dubose, Yvette Latchman, Peter Baum, Valerie Odegard. SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1858.

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Tissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture.