Abstract 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.
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Aug 19, 2024
Chávez-Chavira Grecia + 2
Open Access