Activation of toll-like receptor 8 (TLR8) enhances natural killer(NK-) cell activation, increases antibody-dependent cell-mediated cytotoxicity and induces Th1 polarizing cytokines. TLR8 is highly expressed in myeloid cells that are prevalent in human tumors and TLR8 agonism can potently activate a broad spectrum of anti-tumor immune mechanisms.

SBT6050, a novel ImmunoTAC™ therapeutic being developed by Silverback Therapeutics, includes a HER2-directed antibody conjugated to a potent and specific small molecule toll-like receptor 8 TLR8 agonist, with activity localized to HER2-expressing tumor sites.

The investigational agent is designed to activate human myeloid cells in tumors expressing moderate or high levels of HER2.

Image: SBT6050 is an ImmunoTAC™ Therapeutic Designed for Systemic Administration with TME-Localized Activity. Courtesy: ©2020 Silverback Therapeutics

Myeloid cell activation and reprogramming
Solid tumors, including those resistant to T-cell targeted immunotherapy, are replete with myeloid cells. Activation and reprogramming of myeloid cells drive an innate immune response resulting in direct tumor killing and can also nucleate a T-cell response. Successful activation of myeloid cells can lead to anti-tumor immunity, even in tumors that are resistant to immune checkpoint blockade.

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The approach of myeloid cell activation and reprogramming in the tumor microenvironment has emerged as a promising therapeutic approach.

“SBT6050 is designed for systemic administration and tumor-localized activation of myeloid cells, in order to circumvent toxicities associated with untargeted myeloid cell agonists,” said Valerie Odegard, Ph.D., Silverback’s chief scientific officer.

“In preclinical studies, SBT6050 demonstrated a broad therapeutic window and this profile has enabled the selection of a first-in-human starting dose projected to be pharmacologically active,” Odegard added,

Preclinical data for SBT6050 were presented during the American Association for Cancer Research‘s (AACR) Virtual Annual Meeting 2020 Session II held online June 22 – 24, 2020, demonstrating that the investigational agent displays an attractive functional profile unachievable with agonist-based antibody conjugates directed against other innate immune receptors.[1]

Phase I trial
Dosing has initiated in an open-label, multicenter, dose-escalation, and expansion cohort Phase I clinical study designed to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of SBT6050 in adults with moderate or high HER2-expressing solid tumors.

“Our preclinical data highlight SBT6050’s potential to maximize anti-tumor immune responses, even in tumors lacking T cells. This is important because the majority of cancer patients, including those whose tumors express HER2, do not respond to checkpoint inhibitors,” said Laura Shawver, Ph.D., president, and chief executive officer of Silverback Therapeutics.

“We look forward to working with our investigators to evaluate SBT6050 as an innovative precision immunotherapeutic for these patients.”

Clinical trials
A Study of SBT6050 in Patients With Advanced HER2 Expressing Solid Tumors – NCT04460456

Reference
[1] Comeau MR, Brender T, Childs M, Brevik J, Winship D, Metz H, Chang J, Adamo J, et al. SBT6050, a HER2-Directed TLR8 ImmunoTAC™ Therapeutic is a Potent Human Myeloid Cell Agonist that Provides Opportunity for Single Agent Clinical Activity. In: Proceedings of the 111th Annual Meeting of the American Association for Cancer Research; 2020 June 22-24. Philadelphia (PA): AACR; 2020. Abstract nr 4537 / 5

Featured Image: Scientist in Biomedical Laboratory. Courtesy 2019 Fotolia. used with permission.