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Targeted Delivery of Endosomal Escape Peptides to Enhance Immunotoxin Potency and Anti-cancer Efficacy

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Abstract

This work describes use of anti-carcinoembryonic antigen antibodies (10H6, T84.66) for targeted delivery of an endosomal escape peptide (H6CM18) and gelonin, a type I ribosome inactivating protein. The viability of colorectal cancer cells (LS174T, LoVo) was assessed following treatment with gelonin or gelonin immunotoxins, with or without co-treatment with T84.66-H6CM18. Fluorescent microscopy was used to visualize the escape of immunoconjugates from endosomes of treated cells, and efficacy and toxicity were assessed in vivo in xenograft tumor-bearing mice following single- and multiple-dose regimens. Application of 25 pM T84.66-H6CM18 combined with T84.66-gelonin increased gelonin potency by ~ 1,000-fold and by ~ 6,000-fold in LS174T and LoVo cells. Intravenous 10H6-gelonin at 1.0 mg/kg was well tolerated by LS174T tumor-bearing mice, while 10 and 25 mg/kg doses led to signs of toxicity. Single-dose administration of PBS, gelonin conjugated to T84.66 or 10H6, T84.66-H6CM18, or gelonin immunotoxins co-administered with T84.66-H6CM18 were evaluated. The combinations of T84.66-gelonin + 1.0 mg/kg T84.66-H6CM18 and 10H6-gelonin + 0.1 mg/kg T84.66-H6CM18 led to significant delays in LS174T growth. Use of a multiple-dose regimen allowed further anti-tumor effects, significantly extending median survival time by 33% and by 69%, for mice receiving 1 mg/kg 10H6-gelonin + 0.1 mg/kg T84.66-H6CM18 (p = 0.0072) and 1 mg/kg 10H6-gelonin + 1 mg/kg T84.66-H6CM18 (p = 0.0017). Combined administration of gelonin immunoconjugates with antibody-targeted endosomal escape peptides increased the delivery of gelonin to the cytoplasm of targeted cells, increased gelonin cell killing in vitro by 1,000–6,000 fold, and significantly increased in vivo efficacy.

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References

  1. FitzGerald DJ, Kreitman R, Wilson W, Squires D, Pastan I. Recombinant immunotoxins for treating cancer. Int J Med Microbiol. 2004;293(7–8):577–82.

    Article  CAS  PubMed  Google Scholar 

  2. Kreitman RJ. Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies. Curr Pharm Des. 2009;15(23):2652–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Alewine C, Hassan R, Pastan I. Advances in anticancer immunotoxin therapy. Oncologist. 2015;20(2):176–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Frankel AE, Houston LL, Issell BF, Fathman G. Prospects for immunotoxin therapy in cancer. Annu Rev Med. 1986;37:125–42.

    Article  CAS  PubMed  Google Scholar 

  5. Walsh MJ, Dodd JE, Hautbergue GM. Ribosome-inactivating proteins: potent poisons and molecular tools. Virulence. 2013;4(8):774–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. de Virgilio M, Lombardi A, Caliandro R, Fabbrini MS. Ribosome-inactivating proteins: from plant defense to tumor attack. Toxins (Basel). 2010;2(11):2699–737.

    Article  CAS  Google Scholar 

  7. Eiklid K, Olsnes S, Pihl A. Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp Cell Res. 1980;126(2):321–6.

    Article  CAS  PubMed  Google Scholar 

  8. Lambert JM, Blattler WA, McIntyre GD, Goldmacher VS, Scott CF. Immunotoxins containing single chain ribosome-inactivating proteins. In: Frankel AE, editor. Immunotoxins: Kluwer Academic Publishers; 1988. p. 180.

  9. Taylor NS, Pollack M. Purification of Pseudomonas aeruginosa exotoxin by affinity chromatography. Infect Immun. 1978;19(1):66–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lyu MA, Cao YJ, Mohamedali KA, Rosenblum MG. Cell-targeting fusion constructs containing recombinant gelonin. Methods Enzymol. 2012;502:167–214.

    Article  CAS  PubMed  Google Scholar 

  11. Borthakur G, Rosenblum MG, Talpaz M, Daver N, Ravandi F, Faderl S, et al. Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies. Haematologica. 2013;98(2):217–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pirie CM, Hackel BJ, Rosenblum MG, Wittrup KD. Convergent potency of internalized gelonin immunotoxins across varied cell lines, antigens, and targeting moieties. J Biol Chem. 2011;286(6):4165–72.

    Article  CAS  PubMed  Google Scholar 

  13. Yazdi PT, Murphy RM. Quantitative analysis of protein synthesis inhibition by transferrin-toxin conjugates. Cancer Res. 1994;54(24):6387–94.

    CAS  PubMed  Google Scholar 

  14. Copolovici DM, Langel K, Eriste E, Langel U. Cell-penetrating peptides: design, synthesis, and applications. ACS Nano. 2014;8(3):1972–94.

    Article  CAS  PubMed  Google Scholar 

  15. Guidotti G, Brambilla L, Rossi D. Cell-Penetrating Peptides: From Basic Research to Clinics. Trends Pharmacol Sci. 2017;38(4):406–24.

    Article  CAS  PubMed  Google Scholar 

  16. Haas DH, Murphy RM. Design of a pH-sensitive pore-forming peptide with improved performance. J Pept Res. 2004;63(1):9–16.

    Article  CAS  PubMed  Google Scholar 

  17. Li W, Nicol F, Szoka FC Jr. GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Adv Drug Deliv Rev. 2004;56(7):967–85.

    Article  CAS  PubMed  Google Scholar 

  18. Parente RA, Nir S, Szoka FC Jr. Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA. Biochemistry. 1990;29(37):8720–8.

    Article  CAS  PubMed  Google Scholar 

  19. Junghans R, Waldmann T. Metabolism of Tac (IL2Ralpha): physiology of cell surface shedding and renal catabolism, and suppression of catabolism by antibody binding. J Exp Med. 1996;183(4):1587–602.

    Article  CAS  PubMed  Google Scholar 

  20. Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol. 2010;28(11):1203–7.

    Article  CAS  PubMed  Google Scholar 

  21. Chaparro-Riggers J, Liang H, Devay RM, Bai L, Sutton JE, Chen W, et al. Increasing Serum Half-life and Extending Cholesterol Lowering in vivo by Engineering Antibody with pH-sensitive Binding to PCSK9. J Biol Chem. 2012;287(14):11090–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Engler FA, Polli JR, Li T, An B, Otteneder M, Qu J, et al. “Catch-and-Release” Anti-Carcinoembryonic Antigen Monoclonal Antibody Leads to Greater Plasma and Tumor Exposure in a Mouse Model of Colorectal Cancer. J Pharmacol Exp Ther. 2018;366(1):205–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shi ZR, Tsao D, Kim YS. Subcellular distribution, synthesis, and release of carcinoembryonic antigen in cultured human colon adenocarcinoma cell lines. Cancer Res. 1983;43(9):4045–9.

    CAS  PubMed  Google Scholar 

  24. Levin LV, Griffin TW, Childs LR, Davis S, Haagensen DE Jr. Comparison of multiple anti-CEA immunotoxins active against human adenocarcinoma cells. Cancer Immunol Immunother. 1987;24(3):202–6.

    Article  CAS  PubMed  Google Scholar 

  25. Hermanson GT. Bioconjugate techniques. Third edition. ed. London ; Waltham, MA: Elsevier/AP; 2013. xvii, 1146 pages p.

  26. Engler FA, Balthasar JP. Development and validation of an enzyme-linked immunosorbent assay for the quantification of gelonin in mouse plasma. J Immunoassay Immunochem. 2016;37(6):611–22.

    Article  CAS  PubMed  Google Scholar 

  27. Eeftens JM, van der Torre J, Burnham DR, Dekker C. Copper-free click chemistry for attachment of biomolecules in magnetic tweezers. BMC Biophys. 2015;8:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dunn KW, Kamocka MM, McDonald JH. A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol. 2011;300(4):C723–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bolte S, Cordelières FP. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2006;224(Pt 3):213–32.

    Article  CAS  PubMed  Google Scholar 

  30. Salomone F, Breton M, Leray I, Cardarelli F, Boccardi C, Bonhenry D, et al. High-yield nontoxic gene transfer through conjugation of the CM18-Tat11 chimeric peptide with nanosecond electric pulses. Mol Pharm. 2014;11(7):2466–74.

    Article  CAS  PubMed  Google Scholar 

  31. Salomone F, Cardarelli F, Di Luca M, Boccardi C, Nifosì R, Bardi G, et al. A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape. J Control Release. 2012;163(3):293–303.

    Article  CAS  PubMed  Google Scholar 

  32. Del’Guidice T, Lepetit-Stoffaes JP, Bordeleau LJ, Roberge J, Théberge V, Lauvaux C, et al. Membrane permeabilizing amphiphilic peptide delivers recombinant transcription factor and CRISPR-Cas9/Cpf1 ribonucleoproteins in hard-to-modify cells. PLoS One. 2018;13(4):e0195558.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. King HD, Dubowchik GM, Mastalerz H, Willner D, Hofstead SJ, Firestone RA, et al. Monoclonal antibody conjugates of doxorubicin prepared with branched peptide linkers: inhibition of aggregation by methoxytriethyleneglycol chains. J Med Chem. 2002;45(19):4336–43.

    Article  CAS  PubMed  Google Scholar 

  34. Oyama K, Takabayashi M, Takei Y, Arai S, Takeoka S, Ishiwata S, et al. Walking nanothermometers: spatiotemporal temperature measurement of transported acidic organelles in single living cells. Lab Chip. 2012;12(9):1591–3.

    Article  CAS  PubMed  Google Scholar 

  35. Shi B, Huang Q-Q, Birkett R, Doyle R, Dorfleutner A, Stehlik C, et al. SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages. Autophagy. 2017;13(2):285–301.

    Article  CAS  PubMed  Google Scholar 

  36. Scott CF Jr, Goldmacher VS, Lambert JM, Chari RV, Bolender S, Gauthier MN, et al. The antileukemic efficacy of an immunotoxin composed of a monoclonal anti-Thy-1 antibody disulfide linked to the ribosome-inactivating protein gelonin. Cancer Immunol Immunother. 1987;25(1):31–40.

    Article  CAS  PubMed  Google Scholar 

  37. Scott CF Jr, Lambert JM, Goldmacher VS, Blatter WA, Sobel R, Schlossman SF, et al. The pharmacokinetics and toxicity of murine monoclonal antibodies and of gelonin conjugates of these antibodies. Int J Immunopharmacol. 1987;9(2):211–25.

    Article  CAS  PubMed  Google Scholar 

  38. Moolten FL, Cooperband SR. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science. 1970;169(3940):68–70.

    Article  CAS  PubMed  Google Scholar 

  39. Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ. Immunotoxin therapy of cancer. Nat Rev Cancer. 2006;6(7):559–65.

    Article  CAS  PubMed  Google Scholar 

  40. Akbari B, Farajnia S, AhdiKhosroshahi S, Safari F, Yousefi M, Dariushnejad H, et al. Immunotoxins in cancer therapy: Review and update. Int Rev Immunol. 2017;36(4):207–19.

    Article  CAS  PubMed  Google Scholar 

  41. Bordeau BM, Balthasar JP. Strategies to enhance monoclonal antibody uptake and distribution in solid tumors. Cancer Biol Med. 2021;18(3):649–64.

    Article  CAS  PubMed Central  Google Scholar 

  42. Shan L, Liu Y, Wang P. Recombinant Immunotoxin Therapy of Solid Tumors: Challenges and Strategies. J Basic Clin Med. 2013;2(2):1–6.

    PubMed  PubMed Central  Google Scholar 

  43. Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ. Immunotoxin Treatment of Cancer. Annu Rev Med. 2007;58(1):221–37.

    Article  CAS  PubMed  Google Scholar 

  44. Posey JA, Khazaeli MB, Bookman MA, Nowrouzi A, Grizzle WE, Thornton J, et al. A Phase I Trial of the Single-Chain Immunotoxin SGN-10 (BR96 sFv-PE40) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2002;8(10):3092–9.

    CAS  PubMed  Google Scholar 

  45. Marcil J, Ravindranath N, Sairam MR. Cytotoxic activity of lutropin-gelonin conjugate in mouse Leydig tumor cells: Potentiation of the hormonotoxin activity by different drugs. Mol Cell Endocrinol. 1993;92(1):83–90.

    Article  CAS  PubMed  Google Scholar 

  46. Mujoo K, Reisfeld RA, Cheung L, Rosenblum MG. A potent and specific immunotoxin for tumor cells expressing disialoganglioside GD2. Cancer Immunol Immunother. 1991;34(3):198–204.

    Article  CAS  PubMed  Google Scholar 

  47. Davol PA, Bizuneh A, Frackelton AR. Wortmannin, a phosphoinositide 3-kinase inhibitor, selectively enhances cytotoxicity of receptor-directed-toxin chimeras in vitro and in vivo. Anticancer Res. 1999;19(3A):1705–13.

    CAS  PubMed  Google Scholar 

  48. Shin MC, Zhao J, Zhang J, Huang Y, He H, Wang M, et al. Recombinant TAT-gelonin fusion toxin: synthesis and characterization of heparin/protamine-regulated cell transduction. J Biomed Mater Res A. 2015;103(1):409–19.

    Article  PubMed  CAS  Google Scholar 

  49. Berstad MB, Cheung LH, Berg K, Peng Q, Fremstedal ASV, Patzke S, et al. Design of an EGFR-targeting toxin for photochemical delivery: in vitro and in vivo selectivity and efficacy. Oncogene. 2015;34(44):5582–92.

    Article  CAS  PubMed  Google Scholar 

  50. Berg K, Høgset A, Prasmickaite L, Weyergang A, Bonsted A, Dietze A, et al. Photochemical internalization (PCI): A novel technology for activation of endocytosed therapeutic agents. Med Laser Appl. 2006;21(4):239–50.

    Article  Google Scholar 

  51. Dietze A, Peng Q, Selbo PK, Kaalhus O, Müller C, Bown S, et al. Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin. Br J Cancer. 2005;92(11):2004–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Selbo PK, Sivam G, Fodstad Ø, Sandvig K, Berg K. In vivo documentation of photochemical internalization, a novel approach to site specific cancer therapy. Int J Cancer. 2001;92(5):761–6.

    Article  CAS  PubMed  Google Scholar 

  53. Bull-Hansen B, Berstad MB, Berg K, Cao Y, Skarpen E, Fremstedal AS, et al. Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer. Oncotarget. 2015;6(14):12436–51.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Weyergang A, Fremstedal AS, Skarpen E, Peng Q, Mohamedali KA, Eng MS, et al. Light-enhanced VEGF121/rGel: A tumor targeted modality with vascular and immune-mediated efficacy. J Control Release. 2018;288:161–72.

    Article  CAS  PubMed  Google Scholar 

  55. Shin MC, Zhang J, Min KA, He H, David AE, Huang Y, et al. PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In vivo Proof-of-Concept Study. Pharm Res. 2015;32(8):2690–703.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Pirie CM, Liu DV, Wittrup KD. Targeted cytolysins synergistically potentiate cytoplasmic delivery of gelonin immunotoxin. Mol Cancer Ther. 2013;12(9):1774–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Salomone F, Breton M, Leray I, Cardarelli F, Boccardi C, Bonhenry D, et al. High-yield nontoxic gene transfer through conjugation of the CM(1)(8)-Tat(1)(1) chimeric peptide with nanosecond electric pulses. Mol Pharm. 2014;11(7):2466–74.

    Article  CAS  PubMed  Google Scholar 

  58. Salomone F, Cardarelli F, Di Luca M, Boccardi C, Nifosi R, Bardi G, et al. A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape. J Control Release. 2012;163(3):293–303.

    Article  CAS  PubMed  Google Scholar 

  59. Del Guidice T, Lepetit-Stoffaes JP, Bordeleau LJ, Roberge J, Theberge V, Lauvaux C, et al. Membrane permeabilizing amphiphilic peptide delivers recombinant transcription factor and CRISPR-Cas9/Cpf1 ribonucleoproteins in hard-to-modify cells. Plos One. 2018;13(4).

  60. Dubowchik GM, Firestone RA, Padilla L, Willner D, Hofstead SJ, Mosure K, et al. Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity. Bioconjug Chem. 2002;13(4):855–69.

    Article  CAS  PubMed  Google Scholar 

  61. Dubowchik GM, Mosure K, Knipe JO, Firestone RA. Cathepsin B-sensitive dipeptide prodrugs. 2. Models of anticancer drugs paclitaxel (Taxol), mitomycin C and doxorubicin. Bioorg Med Chem Lett. 1998;8(23):3347–52.

    Article  CAS  PubMed  Google Scholar 

  62. Abuqayyas L, Balthasar JP. Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer. J Pharmacokinet Pharmacodyn. 2012;39(6):683–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mujoo K, Cheung L, Murray JL, Rosenblum MG. Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin. Cancer Immunol Immunother. 1995;40(5):339–45.

    Article  CAS  PubMed  Google Scholar 

  64. Fujimori K, Covell DG, Fletcher JE, Weinstein JN. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J Nucl Med. 1990;31(7):1191–8.

    CAS  PubMed  Google Scholar 

  65. Bordeau BM, Yang Y, Balthasar JP. Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy. Cancer Res. 2021;81(15):4145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bordeau BM, Abuqayyas L, Nguyen TD, Chen P, Balthasar JP. Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier. Front Pharmacol. 2022;13.

  67. Caron PC, Jurcic JG, Scott AM, Finn RD, Divgi CR, Graham MC, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood. 1994;83(7):1760–8.

    Article  CAS  PubMed  Google Scholar 

  68. Urva SR, Yang VC, Balthasar JP. Physiologically based pharmacokinetic model for T84.66: a monoclonal anti-CEA antibody. J Pharm Sci. 2010;99(3):1582–600.

    Article  CAS  PubMed  Google Scholar 

  69. Shin MC, Zhang J, Ah Min K, Lee K, Moon C, Balthasar JP, et al. Combination of antibody targeting and PTD-mediated intracellular toxin delivery for colorectal cancer therapy. J Control Release. 2014;194:197–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Blumenthal RD, Osorio L, Hayes MK, Horak ID, Hansen HJ, Goldenberg DM. Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft. Cancer Immunol Immunother. 2005;54(4):315–27.

    Article  CAS  PubMed  Google Scholar 

  71. Vassileva V, Rajkumar V, Mazzantini M, Robson M, Badar A, Sharma S, et al. Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer. J Nucl Med. 2015;56(8):1239–45.

    Article  CAS  PubMed  Google Scholar 

  72. Kato J, Futamura M, Kanematsu M, Gaowa S, Mori R, Tanahashi T, et al. Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status. Int J Cancer. 2016;138(6):1516–27.

    Article  CAS  PubMed  Google Scholar 

  73. Saridaki Z, Georgoulias V, Souglakos J. Mechanisms of resistance to anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer. World J Gastroenterol. 2010;16(10):1177–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Jacobs School of Medicine and Biomedical Sciences for the use of Leica DMi 8 inverted fluorescence microscope for live cell imaging.

Funding

This work was supported by the National Cancer Institute of National Institutes of Health (grant numbers CA204192 and CA246785).

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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, 14214, USA

    Joseph Ryan Polli, Ping Chen, Brandon M. Bordeau & Joseph P. Balthasar

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Contributions

J.R.P. and J.P.B. contributed to conceptualization; J.R.P. and P.C. contributed to methodology; J.R.P and P.C. contributed to investigation; J.R.P. contributed to writing—original draft preparation; J.R.P., P.C., B.M.B. and J.P.B. contributed to writing—review and editing; J.P.B. contributed to funding acquisition; J.P.B. provided the resources; J.P.B. contributed to supervision.

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Correspondence to Joseph P. Balthasar.

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Conflict of Interest Disclosure Statement

J.P.B. serves as the Director of the University at Buffalo Center for Protein Therapeutics, which is supported by an industry consortium. Through the consortium, J.P.B. has received research support, for work unrelated to this report, from Abbvie, Amgen, CSL-Behring, Eli Lilly, Genentech, GSK, Janssen, Merck, Roche, and Sanofi. During the course of this work, J.P.B. has received consulting fees from companies involved with the development of cancer therapies, including: Abbvie, Amgen, Eli Lilly, Merck, and Pfizer

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Protocols for animal experiments were approved by the Institutional Animal Use and Care Committee of the University at Buffalo (PHC44086Y).

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Polli, J.R., Chen, P., Bordeau, B.M. et al. Targeted Delivery of Endosomal Escape Peptides to Enhance Immunotoxin Potency and Anti-cancer Efficacy. AAPS J 24, 47 (2022). https://doi.org/10.1208/s12248-022-00698-x

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