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Clinical Trials and Commercialization Using CPPs

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CPP, Cell-Penetrating Peptides

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Abstract

Below, a brief summary of the clinical trials and commercialization using the CPP approaches for the delivery of pharmaceuticals is presented. I feel that, due to protective reasons, the available information is not always very clear or well defined. Additionally, the information concerning the initiation and finalization of clinical trials is difficult to obtain and, hence, sometimes the situation in clinical trials is not timely, which is a nightmare for the updated summary of the field.

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References

  • Bae, D. G., Kim, T. D., Li, G., Yoon, W. H., & Chae, C. B. (2005). Anti-flt1 peptide, a vascular endothelial growth factor receptor 1-specific hexapeptide, inhibits tumor growth and metastasis. Clinical Cancer Research, 11, 2651–2661.

    Article  CAS  Google Scholar 

  • Bates, E., Bode, C., Costa, M., Gibson, C. M., Granger, C., Green, C., et al. (2008). Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation, 117, 886–896.

    Article  Google Scholar 

  • Bennett, G., Harrison, H., Campbell, S., Teufel, D., Langford, G., Watt, A., et al. (2017). Development of BT1718, a Bicycle Drug Conjugate® (BDC) targeting MT1-MMP for treatment of solid tumours. European Journal of Cancer, 69, S21.

    Article  Google Scholar 

  • Betts, C. A., & Wood, M. J. (2013). Cell penetrating peptide delivery of splice directing oligonucleotides as a treatment for Duchenne muscular dystrophy. Current Pharmaceutical Design, 19, 2948–2962.

    Article  CAS  Google Scholar 

  • Bird, G. H., Mazzola, E., Opoku-Nsiah, K., Lammert, M. A., Godes, M., Neuberg, D. S., et al. (2016). Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices. Nature Chemical Biology, 12, 845–852.

    Article  CAS  Google Scholar 

  • Bode, S. A., & Lowik, D. (2017). Constrained cell penetrating peptides. Drug discovery today. Technologies, 26, 33–42.

    Article  CAS  Google Scholar 

  • Borsello, T., Clarke, P. G., Hirt, L., Vercelli, A., Repici, M., Schorderet, D. F., et al. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Medicine, 9, 1180–1186.

    Article  CAS  Google Scholar 

  • Brandt, F., O’connell, C., Cazzaniga, A. & Waugh, J. M. (2010). Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. Dermatologic surgery: Official publication for American Society for Dermatologic Surgery [et al.], 36(Suppl 4), 2111–2118.

    Google Scholar 

  • Bright, R., Raval, A. P., Dembner, J. M., Perez-Pinzon, M. A., Steinberg, G. K., Yenari, M. A., et al. (2004). Protein kinase C delta mediates cerebral reperfusion injury in vivo. Journal of Neuroscience, 24, 6880–6888.

    Article  CAS  Google Scholar 

  • Bruzzoni-Giovanelli, H., Alezra, V., Wolff, N., Dong, C.-Z., Tuffery, P. & Rebollo, A. (2017). Interfering peptides targeting protein–protein interactions: The next generation of drugs? Drug Discov Today.

    Google Scholar 

  • Camarero, J. A. (2017). Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. Bioorganic & Medicinal Chemistry Letters, 27, 5089–5099.

    Article  CAS  Google Scholar 

  • Chatterjee, S., Behnam Azad, B. & Nimmagadda, S. (2014). Chapter two—The intricate role of CXCR4 in cancer. In Pomper, M. G. & Fisher, P. B. (Eds.), Advances in Cancer Research. Academic Press.

    Google Scholar 

  • Chen, L., Hahn, H., Wu, G., Chen, C. H., Liron, T., Schechtman, D., et al. (2001). Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC. Proceedings of the National Academy of Sciences of the U S A, 98, 11114–11119.

    Article  CAS  Google Scholar 

  • Cirak, S., Arechavala-Gomeza, V., Guglieri, M., Feng, L., Torelli, S., Anthony, K., et al. (2011). Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. The Lancet, 378, 595–605.

    Article  CAS  Google Scholar 

  • Clinicaltrial ClinicalTrial Database: NCT00907387. www.clinicaltrials.gov/ct2/show/NCT00907387?term=Rt001&rank=2.

  • Coriat, R., Faivre, S. J., Mir, O., Dreyer, C., Ropert, S., Bouattour, M., et al. (2016). Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: A Phase I study. International Journal of Nanomedicine, 11, 6207–6216.

    Article  CAS  Google Scholar 

  • Cousins, M. J., Pickthorn, K., Huang, S., Critchley, L. & Bell, G. (2013). The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (epsilonPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: A crossover study design. Pain Medicine (Malden, Mass.), 14, 533–540.

    Google Scholar 

  • Craik, D. J., & Du, J. (2017). Cyclotides as drug design scaffolds. Current Opinion in Chemical Biology, 38, 8–16.

    Article  CAS  Google Scholar 

  • Datta, G., Chaddha, M., Garber, D. W., Chung, B. H., Tytler, E. M., Dashti, N., et al. (2000). The receptor binding domain of apolipoprotein E, linked to a model class A amphipathic helix, enhances internalization and degradation of LDL by fibroblasts. Biochemistry, 39, 213–220.

    Article  CAS  Google Scholar 

  • de Coupade, C., Fittipaldi, A., Chagnas, V., Michel, M., Carlier, S., Tasciotti, E., et al. (2005). Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochemical Journal, 390, 407–418.

    Article  Google Scholar 

  • Deloche, C., Lopez-Lazaro, L., Mouz, S., Perino, J., Abadie, C., & Combette, J. M. (2014). XG-102 administered to healthy male volunteers as a single intravenous infusion: A randomized, double-blind, placebo-controlled, dose-escalating study. Pharmacology Research and Perspectives, 2, e00020.

    Article  Google Scholar 

  • Desmet, J., Verstraete, K., Bloch, Y., Lorent, E., Wen, Y., Devreese, B., et al. (2014). Structural basis of IL-23 antagonism by an Alphabody protein scaffold. Nature Communications, 5, 5237.

    Article  CAS  Google Scholar 

  • Dinca, A., Chien, W. M., & Chin, M. T. (2016). Intracellular delivery of proteins with cell-penetrating peptides for therapeutic uses in human disease. International Journal of Molecular Sciences, 17, 263.

    Article  Google Scholar 

  • Dougherty, P. G., Qian, Z., & Pei, D. (2017). Macrocycles as protein-protein interaction inhibitors. Biochemical Journal, 474, 1109–1125.

    Article  CAS  Google Scholar 

  • El Andaloussi, S. A., Hammond, S. M., Mager, I., & Wood, M. J. (2012). Use of cell-penetrating-peptides in oligonucleotide splice switching therapy. Current Gene Therapy, 12, 161–178.

    Article  CAS  Google Scholar 

  • El Zaoui, I., Touchard, E., Berdugo, M., Abadie, C., Kowalczuk, L., Deloche, C., et al. (2015). Subconjunctival injection of XG-102, a c-Jun N-terminal kinase inhibitor peptide, in the treatment of endotoxin-induced uveitis in rats. Journal of Ocular Pharmacology and Therapeutics, 31, 17–24.

    Article  CAS  Google Scholar 

  • Flynn, C. R., Cheung-Flynn, J., Smoke, C. C., Lowry, D., Roberson, R., Sheller, M. R., et al. (2010). Internalization and intracellular trafficking of a PTD-conjugated anti-fibrotic peptide, AZX100, in human dermal keloid fibroblasts. Journal of Pharmaceutical Sciences, 99, 3100–3121.

    Article  CAS  Google Scholar 

  • Gao, X., Stanger, K., Kaluarachchi, H., Maurer, T., Ciepla, P., Chalouni, C., et al. (2016). Cellular uptake of a cystine-knot peptide and modulation of its intracellular trafficking. Scientific Reports, 6, 35179.

    Article  CAS  Google Scholar 

  • Glogau, R., Blitzer, A., Brandt, F., Kane, M., Monheit, G. D., & Waugh, J. M. (2012). Results of a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a botulinum toxin type A topical gel for the treatment of moderate-to-severe lateral canthal lines. Journal of drugs in dermatology: JDD, 11, 38–45.

    CAS  PubMed  Google Scholar 

  • Gould, A., & Camarero, J. A. (2017). Cyclotides: Overview and biotechnological applications. ChemBioChem, 18, 1350–1363.

    Article  CAS  Google Scholar 

  • Guidotti, G., Brambilla, L., & Rossi, D. (2017). Cell-Penetrating Peptides: From Basic Research to Clinics. Trends in Pharmacological Sciences, 38, 406–424.

    Article  CAS  Google Scholar 

  • Hewitt, W. M., Leung, S. S., Pye, C. R., Ponkey, A. R., Bednarek, M., Jacobson, M. P., et al. (2015). Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. Journal of the American Chemical Society, 137, 715–721.

    Article  CAS  Google Scholar 

  • Hirt, L., Badaut, J., Thevenet, J., Granziera, C., Regli, L., Maurer, F., et al. (2004). D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia. Stroke, 35, 1738–1743.

    Article  CAS  Google Scholar 

  • Inagaki, K., Chen, L., Ikeno, F., Lee, F. H., Imahashi, K.-I., Bouley, D. M., et al. (2003). Inhibition of δ-Protein Kinase C Protects Against Reperfusion Injury of the Ischemic Heart In Vivo. Circulation, 108, 2304–2307.

    Article  CAS  Google Scholar 

  • Isakov, N. (2017). Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Seminars in cancer biology.

    Google Scholar 

  • Jakobsson, P. J., Göransson, U., Svensson, C., Klareskog, L. & Gunasekera, S. (2015). Novel sfti and cyclotide based peptides. Google Patents.

    Google Scholar 

  • Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A. Y., et al. (2013). In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. Journal of the American Chemical Society, 135, 11623–11633.

    Article  CAS  Google Scholar 

  • Jia, L., Gorman, G. S., Coward, L. U., Noker, P. E., McCormick, D., Horn, T. L., et al. (2011). Preclinical pharmacokinetics, metabolism, and toxicity of azurin-p28 (NSC745104) a peptide inhibitor of p53 ubiquitination. Cancer Chemotherapy and Pharmacology, 68, 513–524.

    Article  CAS  Google Scholar 

  • Johnson, R. M., Harrison, S. D., & Maclean, D. (2011). Therapeutic applications of cell-penetrating peptides. Methods in Molecular Biology, 683, 535–551.

    Article  CAS  Google Scholar 

  • Jones, P. M., & George, A. M. (2016). Computational analysis of the MCoTI-II plant defence knottin reveals a novel intermediate conformation that facilitates trypsin binding. Scientific Reports, 6, 23174.

    Article  CAS  Google Scholar 

  • Kohl, J. (2006). Drug evaluation: The C5a receptor antagonist PMX-53. Current Opinion in Molecular Therapeutics, 8, 529–538.

    CAS  PubMed  Google Scholar 

  • Köhl, J. 2007. Drug evaluation: The C5a receptor antagonist PMX-53.

    Google Scholar 

  • Lee, J., Kennedy, P. & Waugh, J. M. (2015). Experiences with CPP-based self assembling peptide systems for topical delivery of botulinum toxin. Methods in Molecular Biology, 2806-4_27.

    Google Scholar 

  • Lopes, L. B., Furnish, E. J., Komalavilas, P., Flynn, C. R., Ashby, P., Hansen, A., et al. (2009). Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-beta1-induced CTGF expression in keloid fibroblasts. Journal of Investigative Dermatology, 129, 590–598.

    Article  CAS  Google Scholar 

  • McGee, J. H., Shim, S. Y., Lee, S. J., Swanson, P. K., Jiang, S. Y., Durney, M. A., et al. (2018). Exceptionally high-affinity Ras binders that remodel its effector domain. Journal of Biological Chemistry, 293, 3265–3280.

    Article  CAS  Google Scholar 

  • Meric-Bernstam, F., Saleh, M. N., Infante, J. R., Goel, S., Falchook, G. S., Shapiro, G., et al. (2017). Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. Journal of Clinical Oncology, 35, 2505–2505.

    Google Scholar 

  • Meyer-Losic, F., Nicolazzi, C., Quinonero, J., Ribes, F., Michel, M., Dubois, V., et al. (2008). DTS-108, a novel peptidic prodrug of SN38: in vivo efficacy and toxicokinetic studies. Clinical Cancer Research, 14, 2145–2153.

    Article  CAS  Google Scholar 

  • Moodie, J. E., Bisley, E. J., Huang, S., Pickthorn, K. & Bell, G. (2013). A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain. Pain medicine (Malden, Mass.), 14, 916–924.

    Google Scholar 

  • Moscetti, I., Cannistraro, S. & Bizzarri, A. R. 2017. Surface Plasmon Resonance Sensing of Biorecognition Interactions within the Tumor Suppressor p 53 Network. Sensors (Basel), 17.

    Google Scholar 

  • Naylor, M. R., Bockus, A. T., Blanco, M.-J., & Lokey, R. S. (2017). Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Current Opinion in Chemical Biology, 38, 141–147.

    Article  CAS  Google Scholar 

  • Omotehara, Y., Hakuba, N., Hato, N., Okada, M. & Gyo, K. (2011). Protection against ischemic cochlear damage by intratympanic administration of AM-111. Otology & neurotology: Official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 32, 1422–1427.

    Google Scholar 

  • Over, B., Matsson, P., Tyrchan, C., Artursson, P., Doak, B. C., Foley, M. A., et al. (2016). Structural and conformational determinants of macrocycle cell permeability. Nature Chemical Biology, 12, 1065–1074.

    Article  CAS  Google Scholar 

  • Rothbard, J. B., Garlington, S., Lin, Q., Kirschberg, T., Kreider, E., McGrane, P. L., et al. (2000). Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nature Medicine, 6, 1253–1257.

    Article  CAS  Google Scholar 

  • Shabanpoor, F., Hammond, S. M., Abendroth, F., Hazell, G., Wood, M. J. A., & Gait, M. J. (2017). Identification of a peptide for systemic brain delivery of a morpholino oligonucleotide in mouse models of spinal muscular atrophy. Nucleic Acid Therapeutics, 27, 130–143.

    Article  CAS  Google Scholar 

  • Shimo, T., Maruyama, R. & Yokota, T. (2018). Designing effective antisense oligonucleotides for exon skipping. In Bernardini, C. (Ed.), Duchenne Muscular Dystrophy: Methods and Protocols. New York, NY: Springer New York.

    Google Scholar 

  • Shin, S.-M., Choi, D.-K., Jung, K., Bae, J., Kim, J.-S., Park, S.-W., et al. (2017). Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nature Communications, 8, 15090.

    Article  Google Scholar 

  • Sho, E., Jin, Z., Begley, R., Chen, L., Harrison, S. & Mendel, D. (2008). Protein kinase C-δ inhibitor protects against ischemic stroke by inhibing cellular injury and inflammation and promoting astrocyte proliferation. Presented at: International Stroke Conference 2008. New Orleans, LA, USA, February 20–22.

    Google Scholar 

  • Skrlec, K., Strukelj, B., & Berlec, A. (2015). Non-immunoglobulin scaffolds: A focus on their targets. Trends in Biotechnology, 33, 408–418.

    Article  CAS  Google Scholar 

  • Smith, A. B., Daly, N. L., & Craik, D. J. (2011). Cyclotides: A patent review. Expert Opinion on Therapeutic Patents, 21, 1657–1672.

    Article  CAS  Google Scholar 

  • Suckfuell, M., Lisowska, G., Domka, W., Kabacinska, A., Morawski, K., Bodlaj, R., Klimak, P., Kostrica, R. & Meyer, T. (2014). Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: A double-blind, randomized, placebo-controlled phase II study. Otology & neurotology: Official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 35, 1317–1326.

    Google Scholar 

  • Touchard, E., Omri, S., Naud, M. C., Berdugo, M., Deloche, C., Abadie, C., et al. (2010). A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis. Investigative Ophthalmology & Visual Science, 51, 4683–4693.

    Article  Google Scholar 

  • Valeur, E., Gueret, S. M., Adihou, H., Gopalakrishnan, R., Lemurell, M., Waldmann, H., et al. (2017a). New modalities for challenging targets in drug discovery. Angewandte Chemie (International ed. in English), 56, 10294–10323.

    Article  CAS  Google Scholar 

  • Valeur, E. & Jimonet, P. (2018). New modalities, technologies, and partnerships in probe and lead generation: Enabling a mode-of-action centric paradigm. Journal of Medicinal Chemistry.

    Google Scholar 

  • Valeur, E., Knerr, L., Olwegard-Halvarsson, M., & Lemurell, M. (2017b). Targeted delivery for regenerative medicines: an untapped opportunity for drug conjugates. Drug Discov Today, 22, 841–847.

    Article  CAS  Google Scholar 

  • Vasconcelos, L., Pärn, K., & Langel, Ü. (2013). Therapeutic potential of cell-penetrating peptides. Ther Deliv, 4, 573–591.

    Article  CAS  Google Scholar 

  • Vives, E., Schmidt, J., & Pelegrin, A. (2008). Cell-penetrating and cell-targeting peptides in drug delivery. Biochimica et Biophysica Acta, 1786, 126–138.

    CAS  PubMed  Google Scholar 

  • Wang, J., van de Water, T. R., Bonny, C., de Ribaupierre, F., Puel, J. L., & Zine, A. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. Journal of Neuroscience, 23, 8596–8607.

    Article  CAS  Google Scholar 

  • Warso, M. A., Richards, J. M., Mehta, D., Christov, K., Schaeffer, C., Rae Bressler, L., et al. (2013). A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours. British Journal of Cancer, 108, 1061–1070.

    Article  CAS  Google Scholar 

  • White, T. R., Renzelman, C. M., Rand, A. C., Rezai, T., McEwen, C. M., Gelev, V. M., et al. (2011). On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nature Chemical Biology, 7, 810–817.

    Article  CAS  Google Scholar 

  • Wu, B., Lu, P., Cloer, C., Shaban, M., Grewal, S., Milazi, S., et al. (2012). Long-Term Rescue of Dystrophin Expression and Improvement in Muscle Pathology and Function in Dystrophic mdx Mice by Peptide-Conjugated Morpholino. The American Journal of Pathology, 181, 392–400.

    Article  CAS  Google Scholar 

  • Yamada, T., Mehta, R. R., Lekmine, F., Christov, K., King, M. L., Majumdar, D., et al. (2009). A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells. Molecular Cancer Therapeutics, 8, 2947–2958.

    Article  CAS  Google Scholar 

  • Yonezawa, T., Kurata, R., Kimura, M., & Inoko, H. (2009). PKC delta and epsilon in drug targeting and therapeutics. Recent Patents on DNA & Gene Sequences, 3, 96–101.

    Article  CAS  Google Scholar 

  • Yudin, A. K. (2015). Macrocycles: Lessons from the distant past, recent developments, and future directions. Chemical Science, 6, 30–49.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholms Län, Sweden

    Ülo Langel

  2. Institute of Technology, University of Tartu, Tartu, Estonia

    Ülo Langel

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Langel, Ü. (2019). Clinical Trials and Commercialization Using CPPs. In: CPP, Cell-Penetrating Peptides. Springer, Singapore. https://doi.org/10.1007/978-981-13-8747-0_11

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