Bioconjugated Antibody‐Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two‐Step Immunomodulation of Myeloid Cells

Abstract

AbstractCurrent immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll‐like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid‐derived suppressor cells (MDSCs) and tumor‐associated M2 macrophages, and boost dendritic cell (DC)‐based T‐cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two‐step activation strategy via Antibody‐Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti‐SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody‐mediated endocytosis. ATICC blocks the CD47‐SIRPα (“don't eat me” signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross‐presentation by DCs, resulting in antigen‐specific CD8+ T‐cell generation in tumor‐draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen‐specific CD8+ T cells, and antibody‐dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.