Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy

Su, Yu-Cheng; Burnouf, Pierre-Alain; Chuang, Kai‐Hsiang; Chen, Bing Mae; Tian, Chen; Roffler, Steve R.

doi:10.1038/ncomms15507

Cited by 57 publications

(41 citation statements)

References 67 publications

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“…specifically to PEG for universal detection and quantification of PEGylated drugs by anti-PEG sandwich enzymelinked immunosorbent assay (ELISA) [6,7]. The anti-PEG antibodies have been further engineered for cancertargeting therapy to universally deliver PEGylated nanoparticles to tumors by using bispecific PEG-binding antibodies that simultaneously bind to PEG on the nanomedicines and to membrane receptors (e.g., epidermal growth factor receptor, or EGFR) on the cancer cells [8][9][10]. Because the underlying mechanism for specific PEG binding has not been elucidated, by solving complex crystal structures of the anti-PEG Fab with PEG and by analyzing their interactions, we provide a possible basis for designing improved anti-PEG antibodies with higher affinity.…”

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confidence: 99%

Structural basis of polyethylene glycol recognition by antibody

Lee

et al. 2020

J Biomed Sci

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Background: Polyethylene glycol (PEG) is widely used in industry and medicine. Anti-PEG antibodies have been developed for characterizing PEGylated drugs and other applications. However, the underlying mechanism for specific PEG binding has not been elucidated. Methods: The Fab of two cognate anti-PEG antibodies 3.3 and 2B5 were each crystallized in complex with PEG, and their structures were determined by X-ray diffraction. The PEG-Fab interactions in these two crystals were analyzed and compared with those in a PEG-containing crystal of an unrelated anti-hemagglutinin 32D6-Fab. The PEG-binding stoichiometry was examined by using analytical ultracentrifuge (AUC).Results: A common PEG-binding mode to 3.3 and 2B5 is seen with an S-shaped core PEG fragment bound to two dyad-related Fab molecules. A nearby satellite binding site may accommodate parts of a longer PEG molecule. The core PEG fragment mainly interacts with the heavy-chain residues D31, W33, L102, Y103 and Y104, making extensive contacts with the aromatic side chains. At the center of each half-circle of the S-shaped PEG, a water molecule makes alternating hydrogen bonds to the ether oxygen atoms, in a similar configuration to that of a crown ether-bound lysine. Each satellite fragment is clamped between two arginine residues, R52 from the heavy chain and R29 from the light chain, and also interacts with several aromatic side chains. In contrast, the nonspecifically bound PEG fragments in the 32D6-Fab crystal are located in the elbow region or at lattice contacts. The AUC data suggest that 3.3-Fab exists as a monomer in PEG-free solution but forms a dimer in the presence of PEG-550-MME, which is about the size of the S-shaped core PEG fragment. Conclusions:The differing amino acids in 3.3 and 2B5 are not involved in PEG binding but engaged in dimer formation. In particular, the light-chain residue K53 of 2B5-Fab makes significant contacts with the other Fab in a dimer, whereas the corresponding N53 of 3.3-Fab does not. This difference in the protein-protein interaction between two Fab molecules in a dimer may explain the temperature dependence of 2B5 in PEG binding, as well as its inhibition by crown ether.

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confidence: 99%

Structural basis of polyethylene glycol recognition by antibody

Lee

et al. 2020

J Biomed Sci

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“…Our CD20 Ab × mPEG scFv rst targets the liquid tumor cells and induces the ADCC and CDC effects, then the BsAbs remain on the liquid tumor cell membranes until crosslinked with the mPEG part of PLD. There are around 4528 mPEG-DSPEs on a 100 nm liposome [27,28] and many PEGs on the liposome like "Hedgehog" or multiple epitopes which can trigger endocytosis after the PLD has attached mPEG scFv of BsAb [29]. In liquid tumors, our CD20 Ab × mPEG scFv prove that BsAbs combined with PLD can enhance the internalization rate from 10.6-60.5% via receptormediated internalization (Fig.…”

Section: Discussionmentioning

confidence: 66%

Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab×mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity

Chen

Cheng

et al. 2020

Preprint

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Background Tumor-targeted nanoparticles hold great promise as new tools for therapy of liquid cancers. Furthermore, the therapeutic efficacy of nanoparticles can be improved by enhancing the cancer cellular internalization. Methods In this study, we developed a humanized bispecific antibody (BsAbs: CD20 Ab×mPEG scFv) which retains the clinical anti-CD20 whole antibody (Ofatumumab) and is fused with anti-mPEG single chain antibodies (scFv) that can target the systemic liquid tumor cells. This combination achieves the therapeutic function and simultaneously “grabs” PEGylated liposomal doxorubicin (PLD) to enhance the cellular internalization and anticancer activity of PLD. Results We successfully constructed the CD20 Ab×mPEG scFv and proved that CD20 Ab×mPEG scFv can target CD20-expressing Raji cells and simultaneously grab PEGylated liposomal DiD increasing the internalization ability up to 60% in 24 h. We further showed that the combination of CD20 Ab×mPEG scFv and PLD successfully led to a 9-fold increase in tumor cytotoxicity (LC 50 : 0.38 nM) compared to the CD20 Ab×DNS scFv and PLD (lC 50 : 3.45 nM) in vitro . Importantly, a combination of CD20 Ab×mPEG scFv and PLD had greater anti-liquid tumor efficacy ( P = 0.0005) in Raji-bearing mice than CD20 Ab×DNS scFv and PLD. Conclusion Our results indicate that this “double-attack” strategy using CD20 Ab×mPEG scFv and PLD can retain the tumor targeting ( first attack ) and confer PLD tumor-selectivity ( second attack ) to enhance PLD internalization and improve therapeutic efficacy in liquid tumors.

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“…Intriguingly, although intercellular adhesion molecule I (ICAM-I) alone did not induce endocytosis, nanoparticles covered with ICAM-I were internalized through endocytosis due to cross-linking. 49) Moreover, bispecific humanized antibody with a particular affinity for EGFR and PEG (i.e., PEG engager EGFR ) formed the cross-linking between PEGylated liposome containing doxorubicin (i.e., Doxisome) and EGFRs (Fig. 8).…”

Section: Ligand-receptor Clusteringmentioning

confidence: 99%

Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

Tashima¹

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Discriminatory drug delivery into target cells is essential to effectively elicit the drug activity and to avoid off-target side effects; however, transporting drugs across the cell membrane is difficult due to factors such as molecular size, hydrophilicity, intercellular adhesiveness, and efflux transporters, particularly, in the brain capillary endothelial cells. Drug delivery into the brain is blocked by the blood-brain barrier (BBB). Thus, developing drugs for the central nervous system (CNS) diseases remains a challenge. The approach based on receptor-mediated transcytosis (RMT) can overcome this impassable problem at the BBB. Well-designed molecules for RMT form conjugates with the ligand and drugs via linkers or nanoparticles. Cell penetrating peptides (CPPs), receptor-targeting peptides, and monoclonal antibodies (mAbs) are often used as ligands. The binding of ligand to the receptor on the endothelial cell surface induces endocytosis. Existing exosomes comprising the conjugates move in the cytoplasm and fuse with the opposite plasma membrane to release them. Subsequently, the transcytosed conjugate-loaded drugs or released drugs from the conjugates elicit activity in the brain. As receptors, transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (InsR) have been used to intendedly induce transcytosis. Presently, several clinical trials on CNS drugs for Alzheimer's and Parkinson disease are hindered due to poor drug distribution into the brain. Therefore, this strategy based on RMT is a promising method for CNS drugs to be transported into the brain. In this review, I introduce the practicality and possibility of drug delivery into brain across the BBB using RMT.

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Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy

Cited by 57 publications

References 67 publications

Structural basis of polyethylene glycol recognition by antibody

Structural basis of polyethylene glycol recognition by antibody

Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab×mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity

Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

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