Immunotoxins: From Design to Clinical Application
Conflicts of Interest
References
- Moolten, F.L.; Cooperband, S.R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 1970, 169, 68–70. [Google Scholar] [CrossRef] [PubMed]
- Thorpe, P.E.; Ross, W.C.; Cumber, A.J.; Hinson, C.A.; Edwards, D.C.; Davies, A.J. Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin. Nature 1978, 271, 752–755. [Google Scholar] [CrossRef] [PubMed]
- Casellas, P.; Brown, J.P.; Gros, O.; Gros, P.; Hellstrom, I.; Jansen, F.K.; Poncelet, P.; Roncucci, R.; Vidal, H.; Hellstrom, K.E. Human melanoma cells can be killed in vitro by an immunotoxin specific for melanoma-associated antigen p97. Int. J. Cancer 1982, 30, 437–443. [Google Scholar] [CrossRef] [PubMed]
- Thorpe, P.E.; Cumber, A.J.; Williams, N.; Edwards, D.C.; Ross, W.C.; Davies, A.J. Abrogation of the non-specific toxicity of abrin conjugated to anti-lymphocyte globulin. Clin. Exp. Immunol. 1981, 43, 195–200. [Google Scholar]
- FitzGerald, D.J.P.; Waldmann, T.A.; Willingham, M.C.; Pastan, I. Pseudomonas exotoxin-Anti-Tac: Cell specific immunotoxin active against cells expressing the human T cell growth factor receptor. J. Clin. Investig. 1984, 74, 966–971. [Google Scholar] [CrossRef]
- Thomas, P.B.; Delatte, S.J.; Sutphin, A.; Frankel, A.E.; Tagge, E.P. Effective targeted cytotoxicity of neuroblastoma cells. J. Pediatr Surg 2002, 37, 539–544. [Google Scholar] [CrossRef]
- Cawley, D.B.; Herschman, H.R.; Gilliland, D.G.; Collier, R.J. Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic. Cell 1980, 22, 563–570. [Google Scholar] [CrossRef]
- Krolick, K.A.; Villemez, C.; Isakson, P.; Uhr, J.W.; Vitetta, E.S. Selective killing of normal or neoplastic B cells by antibodies coupled to the A chain of ricin. Proc. Natl. Acad. Sci. USA 1980, 77, 5419–5423. [Google Scholar] [CrossRef] [Green Version]
- Kondo, T.; FitzGerald, D.; Chaudhary, V.K.; Adhya, S.; Pastan, I. Activity of immunotoxins constructed with modified Pseudomonas exotoxin A lacking the cell recognition domain. J. Biol. Chem. 1988, 263, 9470–9475. [Google Scholar] [CrossRef]
- Kozak, R.W.; Loberboum-Galski, H.; Jones, L.; Puri, R.K.; Willingham, M.C.; Malek, T.; FitzGerald, D.J.; Waldmann, T.A.; Pastan, I. IL-2-PE40 prevents the development of tumors in mice injected with IL-2 receptor expressing EL4 transfectant tumor cells. J. Immunol. 1990, 145, 2766–2771. [Google Scholar]
- Bacha, P.; Williams, D.P.; Waters, C.; Williams, J.M.; Murphy, J.R.; Strom, T.B. Interleukin 2 receptor-targeted cytotoxicity: Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein. J. Exp. Med. 1988, 167, 612–622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kreitman, R.J.; Siegall, C.B.; FitzGerald, D.J.P.; Epstein, J.; Barlogie, B.; Pastan, I. Interleukin-6 fused to a mutant form of Pseudomonas exotoxin kills malignant cells from patients with multiple myeloma. Blood 1992, 79, 1775–1780. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kreitman, R.J.; Puri, R.K.; Pastan, I. A circularly permuted recombinant interleukin 4 toxin with increased activity. Proc. Natl. Acad. Sci. USA 1994, 91, 6889–6893. [Google Scholar] [CrossRef] [Green Version]
- Antignani, A.; Ho, E.C.H.; Bilotta, M.T.; Qiu, R.; Sarnvosky, R.; FitzGerald, D.J. Targeting Receptors on Cancer Cells with Protein Toxins. Biomolecules 2020, 10, 1331. [Google Scholar] [CrossRef]
- Chaudhary, V.K.; Queen, C.; Junghans, R.P.; Waldmann, T.A.; FitzGerald, D.J.; Pastan, I. A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 1989, 339, 394–397. [Google Scholar] [CrossRef] [PubMed]
- Kreitman, R.J.; Chaudhary, V.K.; Waldmann, T.; Willingham, M.C.; FitzGerald, D.J.; Pastan, I. The recombinant immunotoxin anti-Tac(Fv)-Pseuodomonas exotoxin 40 is cytotoxic toward peripheral blood malignant cells from patients with adult T-cell leukemia. Proc. Natl. Acad. Sci. USA 1990, 87, 8291–8295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Robbins, D.H.; Margulies, I.; Stetler-Stevenson, M.; Kreitman, R.J. Hairy cell leukemia, a B-cell neoplasm which is particularly sensitive to the cytotoxic effect of anti-Tac(Fv)-PE38 (LMB-2). Clin. Cancer Res. 2000, 6, 693–700. [Google Scholar]
- Kreitman, R.J.; Wilson, W.H.; Robbins, D.; Margulies, I.; Stetler-Stevenson, M.; Waldmann, T.A.; Pastan, I. Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood 1999, 94, 3340–3348. [Google Scholar] [CrossRef]
- Kreitman, R.J.; Wilson, W.H.; White, J.D.; Stetler-Stevenson, M.; Jaffe, E.S.; Waldmann, T.A.; Pastan, I. Phase I trial of recombinant immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol. 2000, 18, 1614–1636. [Google Scholar] [CrossRef]
- Kreitman, R.J. Getting plant toxins to fuse. Leuk. Res. 1997, 21, 997–999. [Google Scholar] [CrossRef]
- Xu, B.; Deng, C.; Wu, X.; Ji, T.; Zhao, L.; Han, Y.; Yang, W.; Qi, Y.; Wang, Z.; Yang, Z.; et al. CCR9 and CCL25: A review of their roles in tumor promotion. J. Cell Physiol 2020, 235, 9121–9132. [Google Scholar] [CrossRef]
- Tu, Z.; Xiao, R.; Xiong, J.; Tembo, K.M.; Deng, X.; Xiong, M.; Liu, P.; Wang, M.; Zhang, Q. CCR9 in cancer: Oncogenic role and therapeutic targeting. J. Hematol. Oncol. 2016, 9, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rezaie, E.; Amani, J.; Bidmeshki Pour, A.; Mahmoodzadeh Hosseini, H. A new scfv-based recombinant immunotoxin against EPHA2-overexpressing breast cancer cells; High in vitro anti-cancer potency. Eur. J. Pharmacol. 2020, 870, 172912. [Google Scholar] [CrossRef] [PubMed]
- Kreitman, R.J.; Pastan, I. Development of recombinant immunotoxins for hairy cell leukemia. Biomolecules 2020, 10, 1140. [Google Scholar] [CrossRef] [PubMed]
- Bachanova, V.; Frankel, A.E.; Cao, Q.; Lewis, D.; Grzywacz, B.; Verneris, M.R.; Ustun, C.; Lazaryan, A.; McClune, B.; Warlick, E.D.; et al. Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. Clin. Cancer Res. 2015, 21, 1267–1272. [Google Scholar] [CrossRef] [Green Version]
- Oh, F.; Modiano, J.F.; Bachanova, V.; Vallera, D.A. Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors. Biomolecules 2020, 10, 956. [Google Scholar] [CrossRef]
- Borgatti, A.; Koopmeiners, J.S.; Sarver, A.L.; Winter, A.L.; Stuebner, K.; Todhunter, D.; Rizzardi, A.E.; Henriksen, J.C.; Schmechel, S.; Forster, C.L.; et al. Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Mol. Cancer Ther. 2017, 16, 956–965. [Google Scholar] [CrossRef] [Green Version]
- Hessler, J.L.; Kreitman, R.J. An early step in Pseudomonas exotoxin action is removal of the terminal lysine residue, which allows binding to the KDEL receptor. Biochemistry 1997, 36, 14577–14582. [Google Scholar] [CrossRef] [PubMed]
- Kreitman, R.J.; Pastan, I. Importance of the glutamate residue of KDEL in increasing the cytotoxicity of Pseudomonas exotoxin derivatives and for increased binding to the KDEL receptor. Biochem J. 1995, 307, 29–37. [Google Scholar] [CrossRef]
- Oh, S.; Tsai, A.K.; Ohlfest, J.R.; Panoskaltsis-Mortari, A.; Vallera, D.A. Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. J. Neurosurg 2011, 114, 1662–1671. [Google Scholar] [CrossRef] [Green Version]
- Waldron, N.N.; Oh, S.; Vallera, D.A. Bispecific targeting of EGFR and uPAR in a mouse model of head and neck squamous cell carcinoma. Oral Oncol. 2012, 48, 1202–1207. [Google Scholar] [CrossRef] [Green Version]
- Borgatti, A.; Fieberg, A.; Winter, A.L.; Stuebner, K.; Taras, E.; Todhunter, D.; Masyr, A.; Rendhal, A.; Vallera, D.A.; Koopmeiners, J.S.; et al. Impact of repeated cycles of EGF bispecific angiotoxin (eBAT) administered at a reduced interval from doxorubicin chemotherapy in dogs with splenic haemangiosarcoma. Vet. Comp. Oncol. 2020, 18, 664–674. [Google Scholar] [CrossRef]
- Fleming, B.D.; Ho, M. Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update. Biomolecules 2020, 10, 934. [Google Scholar] [CrossRef] [PubMed]
- Jia, H.L.; Ye, Q.H.; Qin, L.X.; Budhu, A.; Forgues, M.; Chen, Y.; Liu, Y.K.; Sun, H.C.; Wang, L.; Lu, H.Z.; et al. Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin. Cancer Res. 2007, 13, 1133–1139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ho, M.; Kim, H. Glypican-3: A new target for cancer immunotherapy. Eur. J. Cancer 2011, 47, 333–338. [Google Scholar] [CrossRef] [Green Version]
- Gao, W.; Tang, Z.; Zhang, Y.F.; Feng, M.; Qian, M.; Dimitrov, D.S.; Ho, M. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat. Commun. 2015, 6, 6536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Feng, M.; Gao, W.; Wang, R.; Chen, W.; Man, Y.G.; Figg, W.D.; Wang, X.W.; Dimitrov, D.S.; Ho, M. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, E1083–E1091. [Google Scholar] [CrossRef] [Green Version]
- Li, N.; Wei, L.; Liu, X.; Bai, H.; Ye, Y.; Li, D.; Li, N.; Baxa, U.; Wang, Q.; Lv, L.; et al. A Frizzled-Like Cysteine-Rich Domain in Glypican-3 Mediates Wnt Binding and Regulates Hepatocellular Carcinoma Tumor Growth in Mice. Hepatology 2019, 70, 1231–1245. [Google Scholar] [CrossRef]
- Wang, C.; Gao, W.; Feng, M.; Pastan, I.; Ho, M. Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget 2017, 8, 32450–32460. [Google Scholar] [CrossRef] [Green Version]
- Fleming, B.D.; Urban, D.J.; Hall, M.D.; Longerich, T.; Greten, T.F.; Pastan, I.; Ho, M. Engineered Anti-GPC3 Immunotoxin, HN3-ABD-T20, Produces Regression in Mouse Liver Cancer Xenografts Through Prolonged Serum Retention. Hepatology 2020, 71, 1696–1711. [Google Scholar] [CrossRef]
- Chang, K.; Pai, L.H.; Batra, J.K.; Pastan, I.; Willingham, M.C. Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium. Cancer Res. 1992, 52, 181–186. [Google Scholar] [PubMed]
- Chang, K.; Pastan, I.; Willingham, M.C. Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int. J. Cancer 1992, 50, 373–381. [Google Scholar] [CrossRef] [PubMed]
- Chang, K.; Pastan, I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc. Natl. Acad. Sci. USA 1996, 93, 136–140. [Google Scholar] [CrossRef] [Green Version]
- Argani, P.; Iacobuzio-Donahue, C.; Ryu, B.; Rosty, C.; Goggins, M.; Wilentz, R.E.; Murugesan, S.R.; Leach, S.D.; Jaffee, E.; Yeo, C.J.; et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: Identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin. Cancer Res. 2001, 7, 3862–3868. [Google Scholar]
- Hassan, R.; Wu, C.; Brechbiel, M.W.; Margulies, I.; Kreitman, R.J.; Pastan, I. 111Indium-labeled Monoclonal antibody K1: Biodistribution study in nude mice bearing a human carcinoma xenograft expressing mesothelin. Int. J. Cancer 1999, 80, 559–563. [Google Scholar] [CrossRef]
- Hassan, R.; Viner, J.; Wang, Q.C.; Kreitman, R.J.; Pastan, I. Anti-tumor activity of K1-LysPE38QQR, an immunotoxin targeting mesothelin, a cell-surface antigen overexpressed in ovarian cancer and malignant mesothelioma. J. Immunother. 2000, 23, 473–479. [Google Scholar] [CrossRef] [PubMed]
- Chowdhury, P.S.; Viner, J.L.; Beers, R.; Pastan, I. Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity. Proc. Natl. Acad. Sci. USA 1998, 95, 669–674. [Google Scholar] [CrossRef] [Green Version]
- Kreitman, R.J.; Hassan, R.; FitzGerald, D.J.; Pastan, I. Phase I Trial of Continuous Infusion Anti-Mesothelin Recombinant Immunotoxin SS1P. Clin. Cancer Res. 2009, 15, 5274–5279. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Bullock, S.; Premkumar, A.; Kreitman, R.J.; Kindler, H.; Willingham, M.; Pastan, I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin. Cancer Res. 2007, 13, 5144–5149. [Google Scholar] [CrossRef] [Green Version]
- Hassan, R.; Miller, A.C.; Sharon, E.; Thomas, A.; Reynolds, J.C.; Ling, A.; Kreitman, R.J.; Miettinen, M.M.; Steinberg, S.M.; Fowler, D.H.; et al. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci. Transl. Med. 2013, 5, 208ra147. [Google Scholar] [CrossRef]
- Hassan, R.; Sharon, E.; Thomas, A.; Zhang, J.; Ling, A.; Miettinen, M.; Kreitman, R.J.; Steinberg, S.M.; Hollevoet, K.; Pastan, I. Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer 2014, 120, 3311–3319. [Google Scholar] [CrossRef] [PubMed]
- Hagerty, B.L.; Pegna, G.J.; Xu, J.; Tai, C.H.; Alewine, C. Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors. Biomolecules 2020, 10, 973. [Google Scholar] [CrossRef] [PubMed]
- Jiang, Q.; Ghafoor, A.; Mian, I.; Rathkey, D.; Thomas, A.; Alewine, C.; Sengupta, M.; Ahlman, M.A.; Zhang, J.; Morrow, B.; et al. Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models. Sci. Transl. Med. 2020, 12. [Google Scholar] [CrossRef]
- Alewine, C.; Ahmad, M.; Peer, C.J.; Hu, Z.I.; Lee, M.J.; Yuno, A.; Kindrick, J.D.; Thomas, A.; Steinberg, S.M.; Trepel, J.B.; et al. Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma. Clin. Cancer Res. 2020, 26, 828–836. [Google Scholar] [CrossRef] [PubMed]
- Dieffenbach, M.; Pastan, I. Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy. Biomolecules 2020, 10, 979. [Google Scholar] [CrossRef]
- Zhang, Y.; Chertov, O.; Zhang, J.; Hassan, R.; Pastan, I. Cytotoxic activity of immunotoxin SS1P is modulated by TACE-dependent mesothelin shedding. Cancer Res. 2011, 71, 5915–5922. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Xiang, L.; Hassan, R.; Pastan, I. Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors. Proc. Natl. Acad. Sci. USA 2007, 104, 17099–17104. [Google Scholar] [CrossRef] [Green Version]
- Pasetto, M.; Antignani, A.; Ormanoglu, P.; Buehler, E.; Guha, R.; Pastan, I.; Martin, S.E.; FitzGerald, D.J. Whole-genome RNAi screen highlights components of the endoplasmic reticulum/Golgi as a source of resistance to immunotoxin-mediated cytotoxicity. Proc. Natl. Acad. Sci. USA 2015, 112, E1135–E1142. [Google Scholar] [CrossRef] [Green Version]
- Seetharam, S.; Chaudhary, V.K.; FitzGerald, D.; Pastan, I. Increased cytotoxic activity of Pseudomonas exotoxin and two chimeric toxins ending in KDEL. J. Biol. Chem. 1991, 266, 17376–17381. [Google Scholar] [CrossRef]
- Phan, L.D.; Perentesis, J.P.; Bodley, J.W. Saccharomyces cerevisiae elongation factor 2. Mutagenesis of the histidine precursor of diphthamide yields a functional protein that is resistant to diphtheria toxin. J. Biol. Chem. 1993, 268, 8665–8668. [Google Scholar] [CrossRef]
- Webb, T.R.; Cross, S.H.; McKie, L.; Edgar, R.; Vizor, L.; Harrison, J.; Peters, J.; Jackson, I.J. Diphthamide modification of eEF2 requires a J-domain protein and is essential for normal development. J. Cell Sci. 2008, 121, 3140–3145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bera, T.K. Anti-BCMA Immunotoxins: Design, Production, and Preclinical Evaluation. Biomolecules 2020, 10, 1387. [Google Scholar] [CrossRef]
- Joseph, N.S.; Tai, Y.T.; Anderson, K.C.; Lonial, S. Novel Approaches to Treating Relapsed and Refractory Multiple Myeloma with a Focus on Recent Approvals of Belantamab Mafodotin and Selinexor. Clin. Pharmacol. 2021, 13, 169–180. [Google Scholar] [CrossRef] [PubMed]
- Bera, T.K.; Abe, Y.; Ise, T.; Oberle, A.; Gallardo, D.; Liu, X.F.; Nagata, S.; Binder, M.; Pastan, I. Recombinant immunotoxins targeting B-cell maturation antigen are cytotoxic to myeloma cell lines and myeloma cells from patients. Leukemia 2018, 32, 569–572. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kreitman, R.J.; Pastan, I. Immunotoxins: From Design to Clinical Application. Biomolecules 2021, 11, 1696. https://doi.org/10.3390/biom11111696
Kreitman RJ, Pastan I. Immunotoxins: From Design to Clinical Application. Biomolecules. 2021; 11(11):1696. https://doi.org/10.3390/biom11111696
Chicago/Turabian StyleKreitman, Robert J., and Ira Pastan. 2021. "Immunotoxins: From Design to Clinical Application" Biomolecules 11, no. 11: 1696. https://doi.org/10.3390/biom11111696