Bifunctional Janus Particles as Multivalent Synthetic Nanoparticle Antibodies (SNAbs) for Selective Depletion of Target Cells

Abstract

Monoclonal antibodies (mAb) have had a transformative impact on treating cancers and immune disorders. However, their use is limited by high development time and monetary cost, manufacturing complexities, suboptimal pharmacokinetics, and availability of disease-specific targets. To address some of these challenges, we developed an entirely synthetic, multivalent, Janus nanotherapeutic platform, called Synthetic Nanoparticle Antibodies (SNAbs). SNAbs, with phage-display-identified cell-targeting ligands on one “face” and Fc-mimicking ligands on the opposite “face”, were synthesized using a custom, multistep, solid-phase chemistry method. SNAbs efficiently targeted and depleted myeloid-derived immune-suppressor cells (MDSCs) from mouse-tumor and rat-trauma models, ex vivo. Systemic injection of MDSC-targeting SNAbs efficiently depleted circulating MDSCs in a mouse triple-negative breast cancer model, enabling enhanced T cell and Natural Killer cell infiltration into tumors. Our results demonstrate that SNAbs are a versatile and effective functional alternative to mAbs, with advantages of a plug-and-play, cell-free manufacturing process, and high-throughput screening (HTS)-enabled library of potential targeting ligands.

Nanoparticle-Mediated Targeted Drug Delivery to Remodel Tumor Microenvironment for Cancer Therapy

“…In order to circumvent the immunosuppressive TME caused by MDSCs, Liu et al constructed an entirely synthetic, multivalent, Janus nano-therapeutic platform called synthetic nanoparticle antibodies (SNAbs), which is a type of MDSC-targeting NPs for the effective depletion of MDSCs in TME. 68 In contrast to other cell types in TME, MDSCs express tenfold higher cell surface S100A8/A9 proteins, and either G3 peptide or G3* peptide conjugated in the NPs shows excellent binding affinity to S100A8/A9 proteins. In vitro and in vivo experiments based on 4T1 mouse breast cancer model demonstrated that this NPs significantly reduced the viability and the total amount of MDSCs.…”

Myeloid-Derived Suppressor Cells in Solid Tumors

“…Synthetic Nanoparticle Antibodies (SNAbs) were developed to efficiently deplete MDSCs. The systemic injection of MDSC-targeting SNAbs in a mouse triple-negative breast cancer model was affirmed to selectively lower the circulating MDSCs and promote T cell and NK cell infiltration into the tumor [ 152 ].…”

Targeting the innate immune system with nanoparticles for cancer immunotherapy

“…168,169 For elimination of MDSCs, a study has found that systemic injection of MDSC-targeting multivalent synthetic nanoparticle antibodies (SNAbs) can efficiently deplete circulating MDSCs in a mouse triple-negative breast cancer model, enabling enhanced T cell and NK cell infiltration into tumors. 170 It has been found that intravenous administration of cargo-free PLGA nanoparticles can result in internalization by MDSCs and monocytes. Combined with the anti-PD-1 antibody, these cargo-free PLGA nanoparticles have been found to significantly decrease the abundance of MDSCs in the circulation and in the lungs, and slow tumor growth and result in a survival benefit in the 4T1 mouse model of metastatic triple-negative breast cancer.…”