Activating innate immunity against breast cancer

Silverback Therapeutics’ SBT6050 shows promise in HER2-expressing tumors

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SEATTLE—The latest news to emerge from biopharmaceutical company Silverback Therapeutics seems to reinforce the promise of SBT6050, their anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2-expressing tumors.
Silverback issued periodic positive updates throughout 2019, indicating SBT6050’s ability to drive activation of both innate and adaptive immune responses, resulting in single-agent efficacy in mouse models. Working as a TLR8 agonist conjugated to a HER2-directed monoclonal antibody, SBT6050 seems to activate myeloid cells only in the presence of HER2-expressing tumor cells with moderate-to-high expression levels. Due to localized activation of myeloid cells, TLR conjugates do not cause an overproduction of peripheral cytokines in preclinical models, thus minimizing cytotoxicity found in other approaches to these tumors.
“TLR8 activation of tumor-resident myeloid cells results in potent anti-tumor immune responses, but effective delivery has been the key challenge,” said Dr. Valerie Odegard, Silverback’s chief scientific officer. “Our preclinical studies demonstrate that systemic delivery of a TLR agonist with tumor-localized activity dramatically rewires the tumor microenvironment, resulting in durable, single-agent efficacy in tumors refractory to checkpoint blockade.”
According to Dr. Peter Thompson, Silverback’s co-founder, chairman and CEO, what led the company to explore the innate immunity offered by myeloids was the intent to take the known potent tumor agonist TLR8 and identify a way to apply it locally. SBT6050 is Silverback’s novel immune-modulatory conjugate that utilizes cell surface expression of HER2 to localize activation of TLR8 (toll-like receptor 8) for the treatment of HER2-expressing tumors, delivering a heavy immune payload distinct from the cytotoxicity found by activating T cells and lymphocytes.
“Our data show the successful, specific delivery of a TLR agonist to HER2-expressing tumor cells upon systemic administration—thereby addressing a fundamental challenge previously limiting use of innate immune agonists to topical and intratumoral administration, largely due to toxicity arising from widespread myeloid cell activation with systemic use of these agents,” stated Thompson. “Unlike other innate immune agonists that have been limited to topical or intratumoral administration, SBT6050 is designed for systemic delivery and tumor-localized activity. With this validating data in hand, we are applying our technology to a broad range of targets and diseases.”
What is most exciting to Thompson is the ability to utilize the more primitive element of the immune mechanism even in patients showing no signs of an intact adaptive immune response to a tumor. He explained that they specifically wanted to look at those patients who showed no functioning T cell response to test how effective the innate immune response of just the myeloid systems could be. Because tumors are not heterogenic and differ from site to site, they were also hoping to find a composition class that could be activated systemically rather than locally. Likewise, they sought an agent that did not react to normal, heathy tissue that features small amounts of HER2 or HER3 expression. In all facets, SBT6050 is showing very promising results.
“SBT6050’s ability to drive a broad spectrum of anti-tumor immune responses through localized and potent activation of human myeloid cells has not been achieved by other cancer immunotherapies,” Odegard remarked. “Our preclinical data continue to highlight the potential for single-agent clinical activity with SBT6050, even in settings with diminished or absent T cell infiltrates, and now demonstrate the opportunity for enhanced activity in combination with trastuzumab. We are excited to rapidly advance SBT6050 into the clinic.”
Dr. Naomi Hunder, Silverback’s senior vice president of clinical development, added “Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains, and immune checkpoint inhibitors have demonstrated activity in only a subset of these patients. Preclinical data indicate SBT6050 may be useful as a single-agent therapeutic or in combination with trastuzumab-based therapies, providing a much-needed immunotherapeutic option for patients with HER2-expressing disease. We plan to initiate clinical investigation of SBT6050 in 2020.”

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