Chimeric toxins in cancer treatment

Bibliography

• LANDIS SH, MURRAY T, BOLDEN S, WINGO PA: Cancer Statistics, 1999. CA Cancer J. Clin. (1999) 49:8–31.
   PubMed Web of Science ®Google Scholar
• YAMAIZUMI M, MEKADA E, UCHIDA T, OKADA Y: One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell (1978) 15:245–250.
   PubMed Web of Science ®Google Scholar
• FRANKEL AE, HALL PD, BURBAGE C, et al.: Modulation of the apoptotic response of human myeloid leukaemia cells to a diphtheria toxin granulocyte-macrophage colony-stimulating factor fusion protein. Blood (1997) 90:3654–3661.
   PubMed Web of Science ®Google Scholar
• ENDO Y, MITSUI K, MOTIZUKI M, TSURUGI K: Themechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. J. Biol. Chem. (1987) 262:5908–5912.
   PubMed Web of Science ®Google Scholar
• CARROLL SF, COLLIER RJ: Active site of Pseudomonas aeruginosa exotoxin A. Glutamic acid 553 is photola-belled by NAD and shows functional homology with glutamic acid 148 of diphtheria toxin. J. Biol. Chem. (1987) 262:8707–8711.
   PubMed Web of Science ®Google Scholar
• SIEGALL CB, CHAUDHARY VK, FITZGERALD DJ, PASTAN I: Functional analysis of domains II, Ib, and III of Pseudomonas exotoxin. J. Biol. Chem. (1989) 264:14256–14261.
   PubMed Web of Science ®Google Scholar
• KREITMAN RJ, PASTAN I Recombinant toxinscontaining human granulocyte-macrophage colony-stimulating factor and either Pseudomonas exotoxin or diphtheria toxin kill gastrointestinal cancer and leukaemia cells. Blood (1997) 90:252–259.
   PubMed Web of Science ®Google Scholar
• •Recombinant fusion toxins were produced containing human GM-CSF and either truncated diphtheria toxin (DT388) or truncated Pseudomonas exotoxin (PE38KDEL). DT388-GM-CSF was very cytotoxic toward haematologic tumour cells and GM-CSF-PE38KDEL was very cytotoxic toward gastrointestinal malignancies. DT388-GM-CSF was developed further for the treatment of AML.
   Google Scholar
• WILLIAMS DP, SNIDER CE, STROM TB, MURPHY JR:Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. J. Biol. Chem. (1990) 265:11885–11889.
   PubMed Web of Science ®Google Scholar
• WILLIAMS DP, WEN Z, WATSON RS, BOYD J, STROM TB,MURPHY JR: Cellular processing of the interleukin-2 fusion toxin DAB486-IL-2 and efficient delivery of diphtheria fragment A to the cytosol of target cells requires Arg194. J. Biol. Chem. 1990, 265:20673–20677.
   PubMed Web of Science ®Google Scholar
• OGATA M, FRYLING CM, PASTAN I, FITZGERALD DJ: Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and G1y28° generates the enzymatically active fragment which translocates to the cytosol. J. Biol. Chem. (1992) 267:25396–25401.
   PubMed Web of Science ®Google Scholar
• KREITMAN RJ, PASTAN I: Importance of the glutamateresidue of KDEL in increasing the cytotoxicity of Pseudomonas exotoxin derivatives and for increased binding to the KDEL receptor. Biochem. J. (1995) 307:29–37.
   PubMed Web of Science ®Google Scholar
• PAI LH, WITTES R, SETSER A, WILLINGHAM MC, PASTAN I: Treatment of advanced solid tumours with immuno-toxin LMB-1: an antibody linked to Pseudomonas exotoxin. Nature Med. (1996) 2:350–3.
   PubMed Web of Science ®Google Scholar
• ••This was the first clinical trial of a chemical conjugatecontaining a truncated form of Pseudomonas exotoxin and a mAb. Objective antitumour activity was observed in five patients, with a PR in colon cancer and a CR in breast cancer. These were the first major responses reported for an immunotoxin in solid tumours.
   Google Scholar
• BUCHNER J, PASTAN I, BRINKMANN U: A method forincreasing the yield of properly folded recombinant fusion proteins: single-chain immunotoxins from renaturation of bacterial inclusion bodies. Anal. Biochem. (1992) 205:263–270.
   PubMed Web of Science ®Google Scholar
• ••Solving the problem of how to renature recombinant toxinsfrom inclusion bodies of E. coil was a major advance in allowing clinical trials to be accomplished in recombinant immunotoxins, agents which contain an Fv fragment fused to a truncated toxin. This method was later applied to the production of DT388-GM-CSF, allowing that agent to enter clinical testing.
   Google Scholar
• KREITMAN RJ, PASTAN I: Using cytokine receptors to target leukaemia and lymphoma with fusion toxins. Methods Mol. Med.; Drug Targeting (March, 2000) (In Press).
   Google Scholar
• LEMAISTRE CF, SALEH MN, KUZEL TM, et al.: Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood (1998) 91:399–405.
   PubMed Web of Science ®Google Scholar
• ••In a Phase I trial, 73 patients with haematologic malignan-cies were treated with the recombinant fusion toxinDAB389IL-2. This trial identified CTCL as a particularly sensitive disease, with 5 CRs and 8 PRs occurring in 38 CTCL patients. The maximum tolerated dose was identified at 27 1.1g/kg/day x 5. This trial as well as the follow-up Phase III study led to the approval of this agent for the salvage treatment of CTCL, the first approval of an immunotoxin as an anticancer drug.
   Google Scholar
• AMLOT PL, STONE MJ, CUNNINGHAM D, et al.: A Phase Istudy of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy. Blood (1993) 82:2624–2633.
   PubMed Web of Science ®Google Scholar
• •This was the first Phase I trial of RFB4-dgA, a chemical conjugate of the anti-CD22 mAb RFB4 with deglycosylated ricin A-chain. The agent was administered by 4 h iv. infusions every 48 h. The DLT was caused by VLS, including weight gain, oedema, hypoalbuminaemia and pulmonary oedema. 1 CR and 5 PRs were observed out of 24 patients.
   Google Scholar
• SAUSVILLE EA, HEADLEE D, STETLER-STEVENSON M, et al.: Continuous infusion of the anti-CD22 immuno-toxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a Phase I study. Blood (1995) 85:3457–3465.
   PubMed Web of Science ®Google Scholar
• •To determine if RFB4-dgA would result in more efficacy and less toxicity if administered by continuous infusion, patients in this Phase I trial received 8-day continuous iv. infusions. Four PRs out of 18 patients were observed. This study again showed VLS to be dose-limiting, and the therapeutic index was not noticeably improved compared to the 4 h infusion.
   Google Scholar
• SENDEROWICZ AM, VITETTA E, HEADLEE D, et al.:Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann. Intern. Med. (1997) 126:882–885.
   PubMed Web of Science ®Google Scholar
• GHETIE V, SWINDELL E, UHR JW, VITETTA ES: Purifica-tion and properties of immunotoxins containing one vs. two deglycosylated ricin A chains. J. Immunol. Methods (1993) 166:117–122.
   PubMed Web of Science ®Google Scholar
• KREITMAN RJ, WANG QC, FITZGERALD DJP, PASTAN I:Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by Cynomolgus monkeys. Int. J. Cancer (1999) 81:148–155.
   PubMed Web of Science ®Google Scholar
• •RFB4(dsFv)-PE38 (BL22) is a recombinant immunotoxin containing the variable domains of the anti-CD22 mAb RFB4 fused to truncated Pseudomonas exotoxin. In this preclinical study BL22 resulted in complete regression of human CD22+ xenografts in mice either by bolus injection or by continuous ip. infusion. Monkeys were extremely resistant to the toxic effects of BL22 and a recent study showed that doses of to 2 mg/kg iv. q.o.d. x 3 were well-tolerated. These studies led to the Phase I trial now underway in patients with CD22+ B-cell leukaemia and lymphoma.
   Google Scholar
• KUAN C, PAI LH, PASTAN I: Immunotoxins containing Pseudomonas exotoxin targeting Le' damage human endothelial cells in an antibody-specific mode: relevance to vascular leak syndrome. Clin. Cancer Res. (1995) 1:1589–1594.
   PubMed Web of Science ®Google Scholar
• STONE MJ, SAUSVILLE EA, FAY JAN, et al.: A Phase I study of bolus versus continuous infusion of the anti-CD 19 immunotoxin, IgG-HD 37-dgA, in patients with B-cell lymphoma. Blood (1996) 88:1188–1197.
   Google Scholar
• CONRY RM, KHAZAELI MB, SALEH MN, et al.: Phase I trial of an Anti-CD19 deglycosylated ricin A chain immuno-toxin in non-Hodgkin's lymphoma: effect of an intensive schedule of administration. J. Immunother. (1995) 18:231–241.
   PubMed Web of Science ®Google Scholar
• MULTANI PS, ODAY S, NADLER LM, GROSSBARD ML: Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma. Clin. Cancer Res. (1998) 4:2599–2604.
   PubMed Web of Science ®Google Scholar
• •Responses were previously reported to the immunotoxin chemical conjugate anti-B4-bR, but in this Phase II trial sustained major responses were not seen in 16 patients. Poor penetration into solid lymphomatous masses was identified as a factor limiting clinical efficacy.
   Google Scholar
• SCADDEN DT, SCHENKEIN DP, BERNSTEIN Z, et al: Immunotoxin combined with chemotherapy for patients with AIDS-related non-Hodgkin's lymphoma. Cancer (1998) 83:2580–2587.
   PubMed Web of Science ®Google Scholar
• •This study indicates the feasibility of combining chimeric toxins with chemotherapy. Whether this will result in improved response rates must await clinical testing.
   Google Scholar
• JANSEN B, KERSEY JH, JASZCZ WB, et al.: Effective immunochemotherapy of human t (4;11) leukaemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide. Leukaemia (1993) 7:290–297.
   PubMed Web of Science ®Google Scholar
• KODAKA T, UCHIYAMA T, ISHIKAWA T, et al.: Interleukin-2 receptor 0-chain (p70-75) expressed on leukaemic cells from adult T cell leukaemia patients. Jpn. J. Cancer Res. (1990) 81:902–908.
   PubMedGoogle Scholar
• YAGURA H, TAMAKI T, FURITSU T, et al.: Demonstration of high-affinity interleukin-2 receptors on B-chronic lymphocytic leukaemia cells: functional and structural characterisation. Blood (1990) 60:181–186.
   Google Scholar
• SHEIBANI K, WINBERG CD, VELDE SVD, BLAYNEY DW, RAPPAPORT H: Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin's disease, and non-Hodgkin's lymphomas: an immunohisto-logic study of 300 cases. Am. J Pathol. (1987) 127:27–37.
   PubMed Web of Science ®Google Scholar
• ROBB RJ, GREENE WC, RUSK CM: Low and high affinity cellular receptors for interleukin 2. J. Exp. Med. (1984) 160:1126–1146.
   PubMed Web of Science ®Google Scholar
• RE GG, WATERS C, POISSON L, WILLINGHAM MC, SUGAMURA K, FRANKEL AE: Interleukin 2 (IL-2) receptor expression and sensitivity to diphtheria fusion toxin DAB(389)11-2 in cultured haematopoietic cells. Cancer Res. (1996) 56:2590–2595.
   PubMed Web of Science ®Google Scholar
• DUVIC M, KUZEL T, OLSEN E, et al.: Quality of life is significantly improved in CTCL patients who responded to DAB38911-2 (ONTAK) fusion protein. Blood (1998) 92\(Suppl. 1):2572a.
   Google Scholar
• ••For Phase III testing of DAB389IL-2, 71 CTCL patientsreceived either 9 or 18 1.1g/kg iv. q.o.d. x 5. The overall response rate was 30%, not significantly different between the two arms. Quality of life analysis showed a trend towardmore benefit from the higher dose level for patients with more advance disease (p = 0.07). Mild VLS was observed in 10% of patients. This pivotal Phase III trial led to the approval of this agent for the salvage therapy of CTCL. This is the first and only chimeric toxin so far to be approved for use for cancer.
   Google Scholar
• KREITMAN RJ, BAILON P, CHAUDHARY VK, FITZGERALD DJP, PASTAN I: Recombinant immunotoxins containing anti-Tac(Fv) and derivatives of Pseudo-monas exotoxin produce complete regression in mice of an interleukin-2 receptor-expressing human carcinoma. Blood (1994) 83:426–434.
   PubMed Web of Science ®Google Scholar
• KREITMAN RJ, WILSON WH, ROBBINS D, et al: Responses in refractory hairy cell leukaemia to a recombinant immunotoxin. Blood (1999) 94: (3340–3348).
   PubMed Web of Science ®Google Scholar
• ••The recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2)was administered to 35 patients with chemotherapy-refractory haematologic malignancies, and of 20 patients receiving > 60m/kg/cycle total dose, 8 patients (40%) had major responses. All 4 (100%) patients with HCL had major responses, including a CR which is ongoing after 18 months. PRs were observed in patients with CLL, ATL, CTCL and HD. Toxicity was reversible and most commonly included transaminase elevations and fever. 6 of 35 patients made high levels of neutralising antibodies after one cycle, allowing the majority of patients not to be excluded from additional cycles because of immunogenicity. This is the first example of an agent containing an Fv fragment inducing major responses in cancer.
   Google Scholar
• MAVROUDIS DA, JIANG YZ, HENSEL N, et al.: Specific depletion of alloreactivity against haplotype mismatched related individuals: a new approach to graft-versus-host disease prophylaxis in haploiden-tical bone marrow transplantation. Bone Marrow Transplant. (1996) 17:793–799.
   PubMed Web of Science ®Google Scholar
• SCHNELL R, VITETTA E, SCHINDLER J, et al.: Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin's lymphoma. Leuk. Lymphoma (1998) 30:525.
   PubMed Web of Science ®Google Scholar
• •The chemical conjugate containing dgA and the anti-CD25 mAb RFT5 was used to treat 20 patients with HD, resulting in 2 responses in this Phase I trial. Immunogenicity was detected in 7 out of 15 patients, which allowed retreatment. The DLT was VLS.
   Google Scholar
• MONTAGNA D, YVON E, CALCATERRA V: Depletion ofalloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukaemia and antiviral activity. Blood (1999) 93:3550–3557.
   PubMed Web of Science ®Google Scholar
• HOGGE DE, WILLMAN CL, KREITMAN RJ, et al.: Malignantprogenitors from patients with acute myelogenous leukaemia are sensitive to a diphtheria toxin-granulocyte-macrophage colony- stimulating factor fusion protein. Blood (1998) 92:589–595.
   PubMed Web of Science ®Google Scholar
• •Out of 53 AML patients, 44 had malignant cells with at least 35 GM-CSFR sites/cell. When tested ex vivo with DT388-GM-CSF, 27 out of 28 samples were sensitive as assessed by inhibition of colony forming units with IC50 values 1 pM in 8 patients. This and other preclinical studies led to the Phase I trial now ongoing in patients with relapsed AML.
   Google Scholar
• BENDEL AE, SHAO Y, DAVIES SM, et al.: A recombinant fusion toxin targeted to the granulocyte-macrophage colony-stimulating factor receptor. Leuk Lymphoma (1997) 25:257.
   PubMed Web of Science ®Google Scholar
• TERPSTRA W, ROZEMULLER H, BREEMS DA, et al.: Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor eliminates acute myeloid leukaemia cells with the potential to initiate leukaemia in immunodeflcient mice, but spares normal haemato-poietic stem cells. Blood (1997) 90:3735–3742.
   PubMed Web of Science ®Google Scholar
• HOTCHKISS CE, HALL PD, CLINE JM, et al.: Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys. Toxicol. Appl. Pharmacol. (1999) 158:152–160.
   PubMed Web of Science ®Google Scholar
• DeVita JVT, Hellman S, Rosenberg SA (Eds.), Lippincott-Raven Publishers, Philadelphia, USA (2000). (In Press).
   Google Scholar
• SIEGALL CB, CHACE D, MIXAN B, et al.: In vitro and in vivo characterisation of BR96 sFv-PE40. A single-chain immunotoxin fusion protein that cures human breast carcinoma xenografts in athymic mice and rats. J. Immunol. (1994) 152:2377–2384.
   PubMed Web of Science ®Google Scholar
• LASKE DW, YOULE RJ, OLDFIELD EH: Tumour regres-sion with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumours. Nature Med. (1997) 3:1362–1368.
   PubMed Web of Science ®Google Scholar
• ••A chimeric toxin conjugate containing human transferrinand mutated DT was administered intratumourally to patients with brain tumours, resulting in 2 CRs and 7 PRs out of 18 patients. Although peritumoural injury was observed at concentrations of at least 1 1.1g/ml, the well-tolerated concentration of 0.66 1.1g/m1 was also effective and is currently under Phase II testing.
   Google Scholar
• PURI RK, HOON DS, LELAND P, et al.: Preclinical develop-ment of a recombinant toxin containing circularly permuted interleukin 4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. Cancer Res. (1996) 56:5631–5637.
   PubMed Web of Science ®Google Scholar
• •The IL-4-toxin IL-4 (38–37)-PE38KDEL, containing a circularly permuted ligand to enhance binding of the ligand portion of the fusion toxin, was developed preclinically for the intratumoural therapy of recurrent high grade gliomas. By RT-PCR, most brain tumours were found to be IL-4R+ and normal brain was negative. At least 100 1.1g/m1 could be instilled intracerebrally in animal models withoutnon-specific necrosis of normal neighbouring brain. IL-4(38–37)-PE38KDEL is currently undergoing multicentre Phase I/II testing in the US and Europe.
   Google Scholar
• KREITMAN RJ, PURI RK, PASTAN I: Increased antitumouractivity of a circularly permuted interleukin 4-toxin in mice with interleukin 4 receptor-bearing human carcinoma. Cancer Res. (1995) 55: 3357–3363.
   PubMed Web of Science ®Google Scholar
• SIEGALL CB, HAGGERTY HG, WARNER GL, et al: Preven-tion of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumour efficacy. J. Immunol. (1997) 159:5168–5173.
   PubMed Web of Science ®Google Scholar
• SIEGALL CB, LIGGITT D, CHACE D, et al.: Characterisa-tion of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. Clin. Cancer Res. (1997) 3:339–345.
   PubMed Web of Science ®Google Scholar
• •Despite the lack of cytotoxicity of truncated PE to human endothelial cells [21], this study showed PE40 to cause VLS in rats. This is consistent with the next study [49] where IL6-PE4E cause VLS in rats. Dr Siegall showed that VLS was mediated by cytokines and was blocked by non-steroidal anti-inflammatory agents.
   Google Scholar
• ROZEMULLER H, ROMBOUTS WJC, TOUW IP, et al.: Treatment of acute myelocytic leukaemia with interleukin-6 Pseudomonas exotoxin fusion protein in a rat leukaemia model. Leukaemia (1996) 10:1796–1803.
   PubMed Web of Science ®Google Scholar
• BALUNA R, RIZO J, GORDON BE, GHETIE V, VITETTA ES: Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc. Natl. Acad. ScL USA (1999) 96:3957–3962.
   PubMed Web of Science ®Google Scholar
• ••This study identifies peptide motifs which are present inboth plant and bacterial toxins and even in IL-2 which appear to be responsible for increasing the vascular permeability which leads to VLS. This study is proactive in suggesting that the potency of the catalytic toxin is unneces-sary for the development of VLS. This finding makes it theoretically possible to change or block residues mediating VLS without destroying the toxin.
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