Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies
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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.
KeywordsMelittin peptides Monoclonal antibody targeted therapy Prostate cancer DU-145 cells LNCaP-LN3 cells
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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