Advertisement

Clinical Trials and Commercialization Using CPPs

  • Ülo Langel
Chapter

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.

Keywords

Commercialization Protein mimicry New modalities Antisense 

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. Bode, S. A., & Lowik, D. (2017). Constrained cell penetrating peptides. Drug discovery today. Technologies, 26, 33–42.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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
  9. 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.CrossRefGoogle Scholar
  10. 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
  11. Camarero, J. A. (2017). Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. Bioorganic & Medicinal Chemistry Letters, 27, 5089–5099.CrossRefGoogle Scholar
  12. 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
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. Clinicaltrial ClinicalTrial Database: NCT00907387. www.clinicaltrials.gov/ct2/show/NCT00907387?term=Rt001&rank=2.
  16. 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.CrossRefGoogle Scholar
  17. 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
  18. Craik, D. J., & Du, J. (2017). Cyclotides as drug design scaffolds. Current Opinion in Chemical Biology, 38, 8–16.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. Dougherty, P. G., Qian, Z., & Pei, D. (2017). Macrocycles as protein-protein interaction inhibitors. Biochemical Journal, 474, 1109–1125.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. Gould, A., & Camarero, J. A. (2017). Cyclotides: Overview and biotechnological applications. ChemBioChem, 18, 1350–1363.CrossRefGoogle Scholar
  31. Guidotti, G., Brambilla, L., & Rossi, D. (2017). Cell-Penetrating Peptides: From Basic Research to Clinics. Trends in Pharmacological Sciences, 38, 406–424.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. Isakov, N. (2017). Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Seminars in cancer biology.Google Scholar
  36. Jakobsson, P. J., Göransson, U., Svensson, C., Klareskog, L. & Gunasekera, S. (2015). Novel sfti and cyclotide based peptides. Google Patents.Google Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. Johnson, R. M., Harrison, S. D., & Maclean, D. (2011). Therapeutic applications of cell-penetrating peptides. Methods in Molecular Biology, 683, 535–551.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. Kohl, J. (2006). Drug evaluation: The C5a receptor antagonist PMX-53. Current Opinion in Molecular Therapeutics, 8, 529–538.PubMedGoogle Scholar
  42. Köhl, J. 2007. Drug evaluation: The C5a receptor antagonist PMX-53.Google Scholar
  43. 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
  44. 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.CrossRefGoogle Scholar
  45. 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.CrossRefGoogle Scholar
  46. 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
  47. 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.CrossRefGoogle Scholar
  48. 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
  49. 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
  50. 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.CrossRefGoogle Scholar
  51. 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
  52. 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.CrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. 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.CrossRefGoogle Scholar
  55. 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
  56. 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.CrossRefGoogle Scholar
  57. 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
  58. Skrlec, K., Strukelj, B., & Berlec, A. (2015). Non-immunoglobulin scaffolds: A focus on their targets. Trends in Biotechnology, 33, 408–418.CrossRefGoogle Scholar
  59. Smith, A. B., Daly, N. L., & Craik, D. J. (2011). Cyclotides: A patent review. Expert Opinion on Therapeutic Patents, 21, 1657–1672.CrossRefGoogle Scholar
  60. 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
  61. 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.CrossRefGoogle Scholar
  62. 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.CrossRefGoogle Scholar
  63. 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
  64. 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.CrossRefGoogle Scholar
  65. Vasconcelos, L., Pärn, K., & Langel, Ü. (2013). Therapeutic potential of cell-penetrating peptides. Ther Deliv, 4, 573–591.CrossRefGoogle Scholar
  66. Vives, E., Schmidt, J., & Pelegrin, A. (2008). Cell-penetrating and cell-targeting peptides in drug delivery. Biochimica et Biophysica Acta, 1786, 126–138.PubMedGoogle Scholar
  67. 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.CrossRefGoogle Scholar
  68. 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.CrossRefGoogle Scholar
  69. 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.CrossRefGoogle Scholar
  70. 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.CrossRefGoogle Scholar
  71. 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.CrossRefGoogle Scholar
  72. 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.CrossRefGoogle Scholar
  73. Yudin, A. K. (2015). Macrocycles: Lessons from the distant past, recent developments, and future directions. Chemical Science, 6, 30–49.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Ülo Langel
    • 1
    • 2
  1. 1.Department of Biochemistry and BiophysicsStockholm UniversityStockholmSweden
  2. 2.Institute of TechnologyUniversity of TartuTartuEstonia

Personalised recommendations