Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Simón‐Gracia, Lorena; Savier, Eric; Parizot, Christophe; Brossas, Jean-Yves; Loisel, Séverine; Teesalu, Tambet; Conti, Filoména; Förster, Charlotte; Scatton, Olivier; Aoudjehane, Lynda; Rebollo, Angelita

doi:10.1002/adtp.202000131

Cited by 14 publications

(24 citation statements)

References 53 publications

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“…We saw no increase in Crea or ALAT (Fig. 3F) following OximUNO administration compared to the values reported in the literature 51 or the reference values for the female Balb/c reported in the Mouse Phenome Database by…”

Section: Oximuno Enhances the Cytotoxicity Of Dox On M2 Macrophages In Vitrosupporting

confidence: 55%

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Lepland

Malfanti

Haljasorg

et al. 2021

Preprint

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Chemotherapy is the standard of care for patients with triple negative breast cancer (TNBC), an aggressive breast cancer subtype with a poor prognosis. In many solid tumours, M2-skewed tumour-associated macrophages (TAMs) are known to promote progression, immunosuppression, relapse, and dissemination of the malignant disease. Although TAM depletion has been explored as an anticancer strategy, the currently available TAM depleting compounds suffer from poor efficacy and dose-limiting side effects. Here, we develop of a novel TAM-depleting agent that specifically targets CD206+ macrophages and show that it is efficacious as an anti-TNBC agent and well tolerated. This new TAM-depleting compound, called “OximUNO”, is a star-shaped polyglutamate decorated with the CD206-targeting peptide mUNO and carrying doxorubicin through a pH-responsive linker. In the orthotopic and experimental metastases of TNBC, fluorescent reporter mUNO-guided polyglutamate construct homed to CD206+ macrophages in the primary cancer lesions and at the sites of metastases. OximUNO displayed enhanced cytotoxicity towards primary M2 macrophages in vitro and exhibited no acute liver or kidney toxicity in vivo. In TNBC mouse models, OximUNO reduced the progression of primary breast cancer lesions and metastatic dissemination of malignant cells. Treatment with OximUNO had an immunomodulatory effect on the tumour microenvironment: besides reducing the number of CD206+ TAMs, it resulted in increased ratio of the CD8/FOXP3 expression. These studies suggest the potential utility of OximUNO based CD206+ TAM depletion strategies for the treatment of TNBC, and possibly, other types of solid tumours.

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Section: Oximuno Enhances the Cytotoxicity Of Dox On M2 Macrophages In Vitrosupporting

confidence: 55%

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Lepland

Malfanti

Haljasorg

et al. 2021

Preprint

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“…Another example of a tumor penetrating peptide is TT1 (sequence: disulfide-cyclized CKRGARSTC) and its linear version linTT1 (AKRGARSTA). These peptides target p32 (HABP1/gC1qR), a protein that is upregulated and aberrantly expressed on the surface of malignant cells and activated macrophages in solid tumors and in atherosclerotic plaques [ 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 ].…”

Section: From In Vitro To In Vivomentioning

confidence: 99%

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

et al. 2021

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Cationic liposomes (CLs) are effective carriers of a variety of therapeutics. Their applications as vectors of nucleic acids (NAs), from long DNA and mRNA to short interfering RNA (siRNA), have been pursued for decades to realize the promise of gene therapy, with approvals of the siRNA therapeutic patisiran and two mRNA vaccines against COVID-19 as recent milestones. The long-term goal of developing optimized CL-based NA carriers for a broad range of medical applications requires a comprehensive understanding of the structure of these vectors and their interactions with cell membranes and components that lead to the release and activity of the NAs within the cell. Structure–activity relationships of lipids for CL-based NA and drug delivery must take into account that these lipids act not individually but as components of an assembly of many molecules. This review summarizes our current understanding of how the choice of the constituting lipids governs the structure of their CL–NA self-assemblies, which constitute distinct liquid crystalline phases, and the relation of these structures to their efficacy for delivery. In addition, we review progress toward CL–NA nanoparticles for targeted NA delivery in vivo and close with an outlook on CL-based carriers of hydrophobic drugs, which may eventually lead to combination therapies with NAs and drugs for cancer and other diseases.

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“…PEPscan seems of particular interest when the structure of the partners in interaction is not known, and when in silico analyses cannot reliably be conducted. This is the case in numerous pathologies, such as various cancers, for which identifying a peptide can benefit from the coupling with cell-penetrating peptides [ 31 ], and more recently from tumor-addressing peptides [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Pepscan Approach for the Identification of Protein–Protein Interfaces: Lessons from Experiment

2021

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PEPscan is an old approach that has recently gained renewed interest for the identification of interfering peptides (IPs), i.e., peptides able to interfere with protein–protein interactions (PPIs). Its principle is to slice a protein sequence as a series of short overlapping peptides that are synthesized on a peptide array and tested for their ability to bind a partner, with positive spots corresponding to candidate IPs. PEPscan has been applied with a rather large success in various contexts, but the structural determinants underlying this success remain obscure. Here, we analyze the results of 14 PEPscan experiments, and confront the in vitro results with the available structural information. PEPscan identifies candidate IPs in limited numbers that in all cases correspond to solvent-accessible regions of the structures, their location at the protein–protein interface remaining to be further demonstrated. A strong point of PEPscan seems to be its ability to identify specific IPs. IPs identified from the same protein differ depending on the target PPI, and correspond to patches not frequently involved in the interactions seen in the 3D structures available. Overall, PEPscan seems to provide a cheap and rapid manner to identify candidate IPs, that also comes with room for improvement.

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Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Cited by 14 publications

References 53 publications

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

Pepscan Approach for the Identification of Protein–Protein Interfaces: Lessons from Experiment

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