MRNA Delivery of a Bispecific Single‐Domain Antibody to Polarize Tumor‐Associated Macrophages and Synergize Immunotherapy against Liver Malignancies. Issue 23 (4th May 2021)

• Record Type: Journal Article
• Authors: Wang, Ying; Tiruthani, Karthik; Li, Sirui; Hu, Mengying; Zhong, Guojie; Tang, Yu; Roy, Sourav; Zhang, Lillian; Tan, Jun; Liao, Chengheng; Liu, Rihe
• Is Part Of: Advanced materials. Volume 33:Issue 23(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-04
• Subjects: bispecific single‐domain antibody -- immunotherapy -- liver malignancies -- mRNA‐lipid nanoparticles -- tumor‐associated macrophages; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adma.202007603
• Languages: English
• ISSNs: 0935-9648

Abstract

Abstract: Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor‐associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer‐promoting M2‐phenotype. To reverse this immunosuppressive process, an innovative single‐domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity is directly evolved. mRNA encoding BisCCL2/5i is encapsulated in a clinically approved lipid nanoparticle platform, resulting in a liver‐homing biomaterial that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner. This BisCCL2/5i mRNA nanoplatform significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the tumor microenvironment. The combination of BisCCL2/5i with PD‐1 ligand inhibitor (PD‐Li) achieves long‐term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers. The work provides an effective bispecific targeting strategy that could broaden the PD‐Li therapy to multiple types of malignancies in the human liver. Abstract : An innovative single‐domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) is evolved using yeast surface display. mRNAs encoding BisCCL2/5i or a PD‐1 ligand inhibitor (PD‐Li) are encapsulated and delivered via clinically amenable lipid nanoparticles. Combination of BisCCL2/5i with PD‐Li achieves long‐term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers.