Background: Monoclonal antibodies (MAbs) can target therapy to tumours while minimising normal tissue exposure. Efficacy of immunoconjugates containing peptide 101, designed around the first 22 amino acids of bee venom, melittin, to maintain the amphipathic helix, to enhance water solubility, and to increase hemolytic activity, was assessed in nude mice bearing subcutaneous human prostate cancer xenografts. Methods: Mouse MAbs, J591 and BLCA-38, which recognise human prostate cancer cells, were cross-linked to peptide 101 using SPDP. Tumour-bearing mice were used to compare biodistributions of radiolabeled immunoconjugates and MAb, or received multiple sequential injections of immunoconjugates. Therapeutic efficacy was assessed by delay in tumour growth and increased mouse survival. Results: Radiolabeled immunoconjugates and antibodies showed similar xenograft tropism. Systemic or intratumoural injection of immunoconjugates inhibited tumour growth in mice relative to carrier alone, unconjugated antibody and nonspecific antibody-peptide conjugates and improved survival for treated mice. Conclusions: Immunoconjugates deliver beneficial effects; further peptide modifications may increase cytotoxicity.
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Bosslet K, Straub R, Blumrich M, Czech J, Gerken M, Sperker B, Kroemer HK, Gesson JP, Koch M, Monneret C (1998) Elucidation of the mechanism enabling tumour selective prodrug monotherapy. Cancer Res 58:1195
Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP (1998) Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer 82:2256
Brown JL, Russell PJ, Philips J, Wotherspoon J, Raghavan D (1990) Clonal analysis of bladder cancer cell line: an experimental model of tumour heterogeneity. Br J Cancer 61:369
DeNardo S, Kroger LA, DeNardo G (1999) A new era for radiolabeled antibodies in cancer? Curr Opin Immunol 11:563
Denmeade SR, Nagy A, Gao J, Lilja H, Schally AV, Isaacs JT (1998) Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res 58:2537
Dunn RD, Weston KM, Longhurst TJ, Lilley GG, Rivett DE, Hudson PJ, Raison RL (1996) Antigen binding and cytotoxic properties of a recombinant immunotoxin incorporating the lytic peptide, melittin. Immunotechnology 2:229
Elgamal AA, Troychak MJ, Murphy GP (1998) ProstaScint scan may enhance identification of prostate cancer recurrences after prostatectomy, radiation or hormone therapy: an analysis of 136 scans of 100 patients. Prostate 37:261
Fletcher JE, Ming-Shu J (1993) Possible mechanisms of action of cobra snake venom cardiotoxins and bee venom melittin. Toxicon 31:669
Grauer LS, Lawler KD, Marignac JL, Kumar A, Goel AS, Wolfert RL (1998) Identification, purification and subcellular localization of prostate specific membrane antigen PSM protein in the LNCaP prostate carcinoma cell line. Cancer Res 58:4787
Habermann E, Jentsch J (1967) Sequence analysis of melittin from tryptic and peptic degradation products. Hoppe-Seylers Z Physiol Chem 348:37
Heston WD (1997) Characterization and glutaymyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 49[Suppl 3A]:104
Hewish D, Werkmeister J, Kirkpartick A, Curtain C, Pantela G, Rivett DE (1996) Peptide inhibitors of melittin action. J Protein Chem 15:395
Li Y, Tian Z, Rizvi SMA, Bander NH, Allen BJ (2002) In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. Prostate Cancer Prostatic Dis 5:36
Lightfoot DV, Walker KZ, Boniface GR, Hetherington EL, Izard ME, Russell PJ (1991) Dosimetric and therapeutic studies in nude mice xenograft models with153Samarium-labelled monoclonal antibody, BLCA-38. Antibody Immunoconj Radiopharm 4:319
Liu H, Rajasekaran AK, Moy P, Xia Y, Kim S, Navarro V, Rahmati R, Bander NH (1998) Constitutive and antibody-induced internalization of prostate-specific membrane antigen. Cancer Res 58:4055
Neurath AR, Strick N (1981) Enzyme-linked fluorescence immunoassays using β-galactosidase and antibodies covalently bound to polystyrene plates. J Virol Meth 3:155
Panchal RG, Cusack E, Cheley S, Bayley H (1996) Tumour protease-activated, pore-forming toxins from a combinatorial library. Nat Biotechnol 14: 852
Pettaway CA, Pathak S, Greene G, Tamirez E, Wilson MR, Killion JJ, Fidler IJ (1996) Selection of highly metastatic varients of different human prostate carcinomas using orthotopic implantation in nude mice. Clin Cancer Res 2:1627
Rivett DE, Kirkpatrick A, Hewish DR, Reilly W, Werkmeister JA (1996) Dimerization of truncated melittin analogues results in cytolytic peptides. Biochem J 316: 525
Rosenthal SA, Haseman MK, Polascik TJ (2001) Utility of capromab pendetide (ProstaScint) imaging in the management of prostate cancer. Tech Urol 7:27
Russell PJ, Raghavan D, Gregory P, Philips J, Wills EG, Jelbart M, Wass J, Zbroja R, Vincent PC (1986) Bladder cancer xenografts: a model of tumour cell heterogeneity. Cancer Res 46:2035
Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81
Tosteson MT, Tosteson DC (1981) The sting: melittin forms channels in lipid bilayers. Biophys J 36:109
Walker KZ, Russell PJ, Kingsley EA, Philips J, Raghavan D (1989) Detection of malignant cells in voided urine from patients with bladder cancer, a novel monoclonal assay. J Urol 142:1578
Werkmeister JA, Kirkpatrick A, McKenzie JA, Rivett DE (1993) The effect of sequence variations and structure on the cytolytic activity of melittin peptides. Biochim Biophys Acta 1157:50
Werkmeister JA, Hewish DR, Kirkpatrick A, Rivett DE (2002) Sequence requirements for the activity of membrane-active peptides. J. Peptide Res 60(4): 232
Wright GL Jr, Grob BM, Haley C, Grossman K, Newhall K, Petrylak D, Troyer J, Konchuba A, Schellhammer PF, Moriarty R (1996) Upregulation of prostate-specific membrane antigen after androgen deprivation therapy. Urol 48:326
This work was supported by a grant from AusIndustry, and by CSL Limited. We wish to thank Dr Lindsay Sparrow for preparation of 14C-labeled peptide 101, Dr Neil Bander for making available the J591 hybridoma, Drs Simon Green and Robyn McLachlan from CSL Limited for helpful discussions and expert advice, and Ms Mila Sajinovic, Oncology Research Centre, Prince of Wales Hospital, for excellent animal husbandry. Dr Warick Delprado from Douglass Hanly Moir Pathology kindly assessed our slides for pathologic effects.
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Russell, P.J., Hewish, D., Carter, T. et al. Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies. Cancer Immunol Immunother 53, 411–421 (2004). https://doi.org/10.1007/s00262-003-0457-9