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Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains. Of note, checkpoint inhibition (CPI) therapy has been largely ineffective in HER2-expressing tumors, likely due to the absence of T cell infiltrate. We show here, however, that a large fraction of HER2-expressing tumors is replete with resident myeloid cells despite lacking T cells. Intratumoral activation of myeloid cells could be beneficial in breast cancer, as suggested by clinical studies with demonstrated responses in cutaneous breast cancer metastases after topical application of imiquimod, a relatively weak TLR agonist. Local administration, the typical delivery route used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. SBT6050 is a HER2-directed monoclonal antibody conjugated to a potent TLR8 agonist, allowing for systemic delivery of a myeloid cell agonist with activity localized to HER2-expressing tumor sites. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positivetumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. As previously described, SBT6050 is designed to drive tumor immunity through intratumoral pan-myeloid activation by inducing direct macrophage-mediated killing of tumor cells, repolarizing suppressive myeloid cell populations to a pro-immunogenic phenotype, augmenting dendritic cell priming of tumor-specific CTL responses, and facilitating tumor recruitment and infiltration of immune cell types, including T cells. Here, we present preclinical studies that provide additional support for the clinical evaluation of SBT6050 as a monotherapy as well as in combination with trastuzumab. SBT6050 is proficient at ADCC and ADCP and binds to an epitope distinct from trastuzumab. An SBT6050 mouse surrogate shows robust single agent efficacy in several tumor models, including an EMT6 breast cancer model, known to be CPI refractory due to low T cell infiltrate, engineered to express huHER2. Tumor-bearing mice treated with the SBT6050 surrogate had durable cures and were resistant to tumor rechallenge, indicating development of immunological memory. The SBT6050 surrogate was also more efficacious than unconjugated anti-HER2 mAb in HER2-positive xenograft models conducted in T cell deficient, but myeloid competent, mouse strains. These data demonstrate the benefit of tumor-directed myeloid cell activation, even in the absence of T cells. As trastuzumab and SBT6050 bind to distinct epitopes on HER2, we evaluated the combination of trastuzumab with SBT6050 in vitro or SBT6050 surrogate in vivo for enhanced activity. In vitro, SBT6050 did not impede trastuzumab’s blockade of HER2 signaling as evidenced by cell death of HER2-positive tumor cell lines. Furthermore, SBT6050 potently activates myeloid cells in a HER2-dependent manner in the presence of trastuzumab. In vivo studies assessing the combination of the SBT6050 surrogate with trastuzumab in HER2- positive xenograft models will support evaluating the combination in the clinic. SBT6050 is currently in preclinical development and is projected to enter the clinic in 2020. Citation Format: Valerie H Odegard, Kara Moyes, Monica Childs, Jamie Brevik, Damion Winship, Ty Brender, Heather Metz, Jenny R Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Sean W Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum. Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2-expressing tumors that lack pre-existing T cell infiltrate [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-09.

Background SBT6290 is a novel therapeutic comprised of a selective TLR8 agonist conjugated to a Nectin-4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells. Nectin-4 is a cell surface adhesion molecule that is overexpressed in multiple solid tumor types including triple negative breast, head and neck, lung, and urothelial cancers, with limited expression in normal tissues. Many solid tumors, including those expressing Nectin-4, are resistant to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors, however, are often replete with myeloid cells. Activation of these cells 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 DCs and macrophages. Agonism of TLR8 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 potently activates human myeloid cells in a Nectin-4-dependent manner and that a mouse surrogate confers single agent anti-tumor activity in preclinical studies. These data support the development of SBT6290 for the treatment of patients with Nectin-4-expressing tumors. Methods SBT6290 activity was characterized in vitro using co-culture systems consisting of human immune cells and Nectin-4-expressing tumor cells. The in vivo efficacy of the SBT6290 surrogate was evaluated as a single agent in mouse tumor models expressing Nectin-4. Results Studies with human immune cells show that SBT6290 potently induces multiple anti-tumor immune activities including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. This activity requires the presence of Nectin-4 expressing tumor cells and the engagement of Fc gamma receptors on the surface of the myeloid cells by the conjugate to facilitate delivery of SBT6290 into myeloid cells. Notably, SBT6290 is >100 fold more potent than the free, unconjugated TLR8 agonist. Systemic administration of a SBT6290 surrogate in mice results in robust single agent efficacy in tumor models intrinsically resistant to checkpoint blockade, including the EMT6 model engineered to express human Nectin-4. Conclusions The preclinical data described here show the potential for SBT6290 to drive robust, single agent anti-tumor responses and support the clinical development of SBT6290 for patients with Nectin-4 expressing tumors.

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.

SBT6050, a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody that binds an epitope distinct from trastuzumab, is designed for systemic delivery and tumor-localized activation of human myeloid cells in the presence of moderate and high HER2-expressing tumor cells. Many solid tumors, including those expressing HER2, are refractory to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors frequently contain abundant populations of tumor-associated myeloid cells. Activation of these cells through TLR agonism has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. Unlike other endosomal TLRs such as TLR7 and TLR9, TLR8 is highly expressed in human myeloid cells known to be prevalent in human tumors such as conventional DCs and macrophages. TLR8's restricted myeloid cell expression removes the risk of inducing T cell death or tumor cell proliferation as described for other innate immune activators such as STING. Agonism of TLR8 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. These functions cannot be replicated by a potent TLR7 agonist or with clinical agents such as resiquimod that agonize TLR7 and only weakly engage TLR8. Here we present data demonstrating the superiority of SBT6050 at activating human myeloid cells compared to HER2 antibody conjugates that use either a selective TLR7 agonist or resiquimod. In vitro studies with human immune cells show that SBT6050 potently induces multiple anti-tumor immune activities, including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. Our data indicate the favorable profile of SBT6050 is likely due to efficient engagement of TLR8 in conjugate form and TLR8's unique expression profile, and not due to differences in the potency of the small molecule payloads. Using an SBT6050 mouse surrogate we show in vivo evidence for intratumoral TLR agonist activation of several myeloid driven anti-tumor pathways leading to curative single agent efficacy in both a T cell-excluded syngeneic tumor model and a xenograft model lacking T, B and NK cells. Collectively, these data demonstrate that SBT6050 displays an attractive functional profile unachievable with agonist-based antibody conjugates directed against other innate immune receptors. These data also highlight the potential for SBT6050 to be clinically active as a monotherapy. SBT6050 is projected to enter the clinic in 2020 for patients with moderate or high HER2-expressing tumors. Citation Format: Michael R. Comeau, Ty Brender, Monica Childs, Jamie Brevik, Damion Winship, Heather Metz, Jenny Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Brenda Stevens, Sean W. Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum, Valerie Odegard. SBT6050, a HER2-directed TLR8 ImmunoTAC™therapeutic, is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4537.

3110 Background: Solid tumors are replete with myeloid cells which, when activated, drive potent anti-tumor responses. Clinical development of systemically administered myeloid cell agonists, however, has been hindered by acute toxicities due to peripheral activation of the targeted cell types. Intratumoral administration, the route of delivery typically used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. A systemically delivered myeloid cell agonist with tumor-localized activity has the potential to overcome challenges encountered with other innate immune/myeloid cell agonists in clinical development. Methods: SBT6050 is a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist payload conjugated to a HER2-directed monoclonal antibody. Delivery of the payload into the endosome of human myeloid cells, where TLR8 resides, requires the co-engagement of HER2 on tumor cells and Fc gamma receptor on human myeloid cells. Thus, SBT6050 is designed for systemic delivery and tumor-targeted activation of human myeloid cells. Results: Studies with human immune cells show that SBT6050 potently induces, in a HER2-dependent manner, multiple anti-tumor immune activities due to its direct activation of myeloid cells and the subsequent induction of T and NK cell cytolytic activity. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positive tumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. Tumor-localized activity has been demonstrated in mouse models using a SBT6050 mouse surrogate. Systemic delivery results in robust single agent efficacy in multiple mouse tumor models, even those engineered to lack T cells, without accompanying peripheral cytokine production. Trastuzumab and SBT6050 bind to distinct epitopes on HER2 and enhanced activity is observed when the two agents are combined. Conclusions: SBT6050 is a systemically administered, tumor-targeted myeloid cell agonist that demonstrates single agent efficacy in multiple mouse tumor models without peripheral cytokine production. A first-in-human study with SBT6050 is expected to begin this year for patients with HER2-expressing solid tumors.