Preclinical data for the ImmunoTAC™ candidate SBT6050, being developed by Silverback Therapeutics, presented during the American Association for Cancer Research‘s (AACR) Virtual Annual Meeting 2020 Session II held online June 22 – 24, 2020, shows that the drug displays an attractive functional profile unachievable with agonist-based antibody conjugates directed against other innate immune receptors.
Silverback’s ImmunoTAC™ platform strategically pairs antigen-binding domains with disease pathway-modulating payloads to create molecules that enable innovative therapeutic approaches for oncology, virology, and fibrosis.
The data also highlight the potential for SBT6050 to be clinically active as a monotherapy.
Solid tumors, including tumors expressing human epidermal growth factor receptor 2 (HER2), are refractory to immunotherapy due to immune-suppressive mechanisms, loss of HLA (Human Leukocyte Antigen), low neoantigen availability, and/or minimal T-cell infiltrates. However, these tumors are replete with tumor-associated myeloid cells.
Myeloid cells play a major role in tumor growth through nurturing cancer stem cells by providing growth factors and metabolites, increasing angiogenesis, and promoting immune evasion through the creation of an immune-suppressive microenvironment. Immunosuppression in the tumor microenvironment is achieved by preventing critical anti-tumor immune responses by natural killer and T-cells within the primary tumor and in metastatic niches.
Succesful activation and reprogramming of these myeloid cells in malignancies may drive an innate immune response resulting in direct tumor killing and can also nucleate a T-cell response, even in tumors that are resistant to immune checkpoint blockade. As a result, the activation of myeloid cells through TLR agonism has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies.
Endosomal TLRs play an important role in innate immune response as well as in autoimmune processes. But 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 dendritic cells 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 (stimulator of interferon genes, also known as transmembrane protein 173 or TMEM173)
Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including pro-inflammatory cytokine production, inflammasome activation, repolarization of suppressive myeloid cells, and the priming of CTL responses and the indirect activation of cytolytic activity associated with T and NK cells.
Uniquely, these functions cannot be replicated by a potent TLR7 agonist or with clinical agents such as resiquimod, an analogue of imiquimod, a modifier of immune response reported being dose-dependently induce some cytokines including IFN, TNF, IL-1β and IL-6 in human peripheral blood mononuclear (PBMCs) that agonize TLR7 and only weakly engage TLR8.
SBT6050 is a novel therapeutic comprised of a potent toll-like receptor 8 agonist conjugated to a HER2-directed monoclonal antibody that binds an epitope distinct from trastuzumab (Herceptin®, Genentech/Roche).
In contrast to Checkpoint inhibition therapy which has largely been ineffective against HER2-expressing tumors (2+ and 3+ by IHC), likely due to the absence of T-cell infiltrate, scientists at Silverback designed a novel agent for systemic delivery and tumor-localized activation of human myeloid cells in the presence of moderate and high HER2-expressing tumor cells.
The data shows that SBT6050 is a highly specific TLR8 agonist, allowing for systemic delivery of a myeloid cell agonist with activity localized to HER2-expressing tumor sites, the functional profile was not replicated with conjugates comprised of TLR7-specific or resiquimod-derived agonists.
Robust, durable single-agent activity is observed with the SBT6050 mouse surrogate in multiple tumor models, including those with low tumor-infiltrating lymphocytes. In a human xenograft model lacking T, B, and NK cells, the SBT6050 mouse surrogate is curative as a single agent, demonstrating the ability of myeloid cells to mediate strong anti-tumor activity.
“TLR8’s robust expression and functional profile in human myeloid cells uniquely positions SBT6050 to potentiate anti-tumor responses through the activation of these innate immune cells present in tumors,” explained Valerie Odegard, Ph.D., Silverback’s chief scientific officer.
“Our preclinical data highlight SBT6050’s potential to maximize anti-tumor immune responses, even in tumors lacking T cells. We are excited to be developing much-needed immunotherapies for patients with HER2-expressing disease and will enter the clinic later this year,” Odegard concluded.
Clinical investigation of SBT6050 is expected to begin in the second half of 2020.
|Summary of Key data|
A Study of SBT6050 in Patients With Advanced HER2 Expressing Solid Tumors – NCT04460456
 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
 Chaib M, Chauhan SC, Makowski L. Friend or Foe? Recent Strategies to Target Myeloid Cells in Cancer. Front Cell Dev Biol. 2020;8:351. Published 2020 May 19. doi:10.3389/fcell.2020.00351
 Gibson SJ, Imbertson LM, Wagner TL, Testerman TL, Reiter MJ, Miller RL, Tomai MA.Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res. 1995 Jun; 15(6):537-45.
Featured image: Before the pandemic – the annual meeting of the AACR/American Association for Cancer Research: Photo courtesy: 2015 AACR/Todd Buchanan.