mRNA Delivery of a Bispecific Single‐Domain Antibody to Polarize Tumor‐Associated Macrophages and Synergize Immunotherapy against Liver Malignancies

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.

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

“…11 ). The mRNA-LNP-based delivery system can be applied to other TAM-enriched cancer types [ 164 ]. In recent studies, researchers also focused on CCL19 or macrophage inflammatory protein 3 beta (MIP-3β) to enhance the interaction among immune responses using the targeted gene delivery system with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), methoxy poly (ethylene glycol)-poly (lactide) (MPEG-PLA), and folic acid-modified poly (ethylene glycol)-poly(ε-caprolactone) (FA-PEG-PCL) (FDMCA) to polarize macrophages toward M1, inhibiting tumor growth and metastasis in mouse models [ 165 ].…”

The Role of Chemokines in Cervical Cancers

“…To summarize the 27 different members of this subgroup that have been reported for mammals, referred to as CC chemokine ligands (CCL)-1 to -28, CCL-2 is the most investigated chemokine within this group of chemokines. Interestingly, macrophages/dendritic cells also seem to produce their own CCL2 in the cervical cancer environment, and, therefore, this chemokine together with others like CCL5 may be responsible for attracting tumor associated macrophages (TAM), their infiltration, and inducing their polarization toward cancer-promoting M2-phenotype [86]. The dominant member of the CXC chemokine subfamily concerning cervical cancer is CXCL12 resulting in 52 PubMed hits.…”

Emerging Nanoparticle Strategies for Modulating Tumor-Associated Macrophage Polarization

“…In addition, cytokine and chemokine therapies, which also benefited from nanocarriers, are candidates for reprogramming TAMs because of their powerful roles in tuning cellular signal pathways and phenotypes. In a recent report, one kind of clinical-approved liposome was used to deliver mRNA, which edited a bispecific antibody to neutralize CCL2 and CCL5 ( Figure 2 ) [ 73 ]. The nanomedicine down regulated IL-10, ARG1, MRC1 and CD206 and suppressed liver cancer growth in mice together with PD-1 antibody treatment [ 73 ].…”

“…In a recent report, one kind of clinical-approved liposome was used to deliver mRNA, which edited a bispecific antibody to neutralize CCL2 and CCL5 ( Figure 2 ) [ 73 ]. The nanomedicine down regulated IL-10, ARG1, MRC1 and CD206 and suppressed liver cancer growth in mice together with PD-1 antibody treatment [ 73 ]. Anujan Ramesh’s lab constructed a liposome to carry BLZ945 and SHP099 (inhibitors of CSF1R and CD47-SIRPα signal pathway, respectively,) and the nanoparticle significantly down regulated the expression of CD206 in a macrophage cell line Raw264.7 from ~75% to ~10%, increasing the M1/M2 ratio by six times [ 74 ].…”

“…( c ) In vivo bioluminescence of tumor-bearing mice on days 5 and 14. Reproduced with permission [ 73 ]. Copyright 2021 Wiley-VCH.…”