Localized Immune Activation by Systemic TLR8 Agonist in HER2-Positive Tumor Therapy

The development of myeloid cell agonists for systemic administration has faced challenges due to acute toxicities related to peripheral cell activation. A new class of composition, ImmunoTAC, has been introduced to enable systemic delivery of immune modulators with localized activity to tumor sites and secondary lymphoid structures. TLR8 agonism in human myeloid cells has been shown to stimulate anti-tumor immunity through various mechanisms, including macrophage-mediated tumor cell killing and the promotion of dendritic cells to elicit tumor-specific CTL responses.

SBT6050, an ImmunoTAC, consists of a potent TLR8 agonist linked to a HER2-targeting monoclonal antibody. It is designed to activate human monocytes and macrophages in the presence of HER2-positive tumor cells with moderate or high expression levels, relying on the Fc domain's interaction with Fcγ receptors on myeloid cells. SBT6050 also strongly activates conventional dendritic cells, which drive a Th1/CTL program in T cells.

In mice, systemic administration of a SBT6050 surrogate demonstrated significant single-agent efficacy in tumor models resistant to checkpoint blockade, such as the HER2+ CT26 syngeneic model. The intratumoral immune response included activation of tumor-associated myeloid cells, neutrophil infiltration, sustained increases in local cytokine and chemokine production, reduction in Treg infiltrate, and the development of a potent, neo-Ag specific anti-tumor CTL response. Mice cured with single-agent treatment exhibited resistance to tumor rechallenge, indicating the induction of long-lived immunological memory.

Unlike small molecule TLR8 agonists, ImmunoTAC does not induce peripheral cytokine production or associated toxicities in mice, reflecting its localized activity. Silverback's lead candidate, SBT6050, is in preclinical development for patients with tumors expressing moderate or high levels of HER2. The data presented illustrate a novel therapeutic approach that allows for the systemic administration of immune modulators with tissue-specific activity.