Tribody: Robust Self-Assembled Trimeric Targeting Ligands with High Stability and Significantly Improved Target-Binding Strength

Kim, Dong-Wook; Kim, Sang Kyun; Valencia, C. Alexander; Liu, Rihe

doi:10.1021/bi400716w

Cited by 10 publications

(10 citation statements)

References 29 publications

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“…4a ). The trimeric trap, which is efficiently formed from the monomeric trap through self-assembly, binds to mouse PD-L1 with a K d of 219 pM, a binding affinity more than a thousand times higher than that between monomeric PD-1 and PD-L1 24 , 25 . This high affinity allows to efficiently disrupt the otherwise extensive cell surface interactions between endogenous PD-1 on T-cells and PD-L1 on cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap

et al. 2018

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Although great success has been obtained in the clinic, the current immune checkpoint inhibitors still face two challenging problems: low response rate and immune-related adverse effects (irAEs). Here we report the combination of immunogenic chemotherapy and locally expressed PD-L1 trap fusion protein for efficacious and safe cancer immunotherapy. We demonstrate that oxaliplatin (OxP) boosts anti-PD-L1 mAb therapy against murine colorectal cancer. By design of a PD-L1 trap and loading its coding plasmid DNA into a lipid-protamine-DNA nanoparticle, PD-L1 trap is produced transiently and locally in the tumor microenvironment, and synergizes with OxP for tumor inhibition. Significantly, unlike the combination of OxP and anti-PD-L1 mAb, the combination of OxP and PD-L1 trap does not induce obvious Th17 cells accumulation in the spleen, indicating better tolerance and lower tendency to irAEs. The reports here may highlight the potential of applying PD-L1 inhibitor, especially locally expressed PD-L1 trap, in cancer therapy following OxP-based chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap

et al. 2018

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“…33 Typically, trivalent traps that bind to a target of interest with low nM to pM binding affinities can be efficiently generated from monomeric domains that are 1000 times weaker. 34 The mouse sequence of this trimerization domain is highly homologous to that of human CMP1, making it easy to switch to the human version if translational application is desired. As the trimeric trap is formed through self-assembly of three identical monomers (Figure 1A), it only requires a relatively small gene that codes for the monomeric trap, making the gene to be delivered much shorter and easier to encapsulate (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer

et al. 2017

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Pancreatic tumors are known to be resistant to immunotherapy due to the extensive immune suppressive tumor microenvironment (TME). We hypothesized that CXCL12 and PD-L1 are two key molecules controlling the immunosuppressive TME. Fusion proteins, called traps, designed to bind with these two molecules with high affinity (Kd = 4.1 and 0.22 nM, respectively) were manufactured and tested for specific binding with the targets. Plasmid DNA encoding for each trap was formulated in nanoparticles and intravenously injected to mice bearing orthotopic pancreatic cancer. Expression of traps was mainly seen in the tumor, and secondarily, accumulations were primarily in the liver. Combination trap therapy shrunk the tumor and significantly prolonged the host survival. Either trap alone only brought in a partial therapeutic effect. We also found that CXCL12 trap allowed T-cell penetration into the tumor, and PD-L1 trap allowed the infiltrated T-cells to kill the tumor cells. Combo trap therapy also significantly reduced metastasis of the tumor cells to other organs. We conclude that the trap therapy significantly modified the immunosuppressive TME to allow the host immune system to kill the tumor cells. This can be an effective therapy in clinical settings.

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“…Affibody Z 1907 does not influence on cell proliferation (Ekerljung et al, 2012), so we tested it as a ligand module. Based on the findings of earlier studies (Kim et al, 2012;Kim et al, 2013), we placed the affibody on the N-terminus of the MNT. Therefore, another reason of creating the new MNT was a palette extension, which would expand the possibility of modification of the MNT with additional functional modules.…”

Section: Introductionmentioning

confidence: 99%

Targeted Delivery of 111In Into the Nuclei of EGFR Overexpressing Cells via Modular Nanotransporters With Anti-EGFR Affibody

et al. 2020

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Since cell nucleus is one of the most vulnerable compartments, the maximum therapeutic effect from a variety of locally acting agents, such as photosensitizers, alfa-emitters, Auger electron emitters, will be expected when they get there. Therefore, the targeted delivery of these agents into the nuclei of target tumor cells is necessary for their anticancer effects and minimization of side effects. Modular nanotransporters (MNT) are artificial polypeptides comprising several predefined modules that recognize target cell, launching their subsequent internalization, escape from endosomes, and transport the drug load to the nucleus. This technology significantly enhances the cytotoxicity of locally acting drugs in vitro and in vivo. Epidermal growth factor receptors (EGFR) are useful molecular targets as they are overexpressed in glioblastoma, head-and-neck cancer, bladder cancer, and other malignancies. Here, we examined the possibility of using internalizable anti-EGFR affibody as an EGFR-targeting MNT module for drug transport into the cancer cell nuclei. It binds to both murine and human EGFR facilitating preclinical studies. We showed that MNT with affibody on the N-terminus (MNT N-affibody ) effectively delivered the Auger electron emitter 111 In to target cell nuclei and had pronounced cytotoxic efficacy against EGFR-overexpressing human A431 epidermoid carcinoma cells. Using EGFR-expressing human adenocarcinoma MCF-7 cells, we demonstrated that in contrast to MNT with N-terminal epidermal growth factor (EGF), MNT N-affibody and MNT with EGF on the C-terminus did not stimulate cancer cell proliferation.

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Tribody: Robust Self-Assembled Trimeric Targeting Ligands with High Stability and Significantly Improved Target-Binding Strength

Cited by 10 publications

References 29 publications

Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap

Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap

Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer

Targeted Delivery of 111In Into the Nuclei of EGFR Overexpressing Cells via Modular Nanotransporters With Anti-EGFR Affibody

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