mRNA-based therapy is considered as a revolutionary approach that could “disrupt the drug industry”, as exemplified by the recent success in developing mRNA vaccines against SARS-CoV-2. One of the urgent unmet need in cancer treatment is how to expand the immune checkpoint blockade (ICB) to a broader range of cancer types. Conceptually, mRNA therapeutics promise to turn the liver of patients into immunotherapeutic-making factories with minimal irAES.<br/>To identify critical targets that are involved the immunosuppression in the liver malignancies, we performed correlation gene signature analysis and IHC studies in HCC patients’ samples and found that CCL2 and CCL5 are two major chemokines responsible for attracting TAM infiltration and inducing their polarization towards cancer-promoting M2-phenotype. We applied directed molecular evolution to develop a humanized single-domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity. We encapsulated the mRNA encoding BisCCL2/5i in a clinically approved lipid nanoparticle (LNP) platform, resulting in a liver-homing mRNA nanoplatform that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner (<i>Advanced Materials</i>, in revision; Figure 1). This BisCCL2/5i mRNA therapeutic significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the TME, with a superior antitumor efficacy as demonstrated in the mouse models of various liver malignancies. Our work provides an effective strategy that can be used to address numerous mechanistic and translational questions in the fields of biological chemistry.

mRNA delivery of an evolved bispecific single domain antibody to synergize the immune checkpoint blockade therapy

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.