Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies.
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.
Russell
Pamela J
PJ
Oncology Research Centre, Department of Clinical Medicine, Prince of Wales Hospital, University of New South Wales, NSW 2031 Randwick, Australia. p.Russell@unsw.edu.au
Hewish
Dean
D
Carter
Teresa
T
Sterling-Levis
Katy
K
Ow
Kim
K
Hattarki
Meghan
M
Doughty
Larissa
L
Guthrie
Robin
R
Shapira
Deborah
D
Molloy
Peter L
PL
Werkmeister
Jerome A
JA
Kortt
Alexander A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D002455:Cell Division; D003432:Cross-Linking Reagents; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D008555:Melitten / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013388:Succinimides; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D003432:Cross-Linking Reagents; D018796:Immunoconjugates; C478680:J591 monoclonal antibody; D010446:Peptide Fragments; D013388:Succinimides; D008555:Melitten; C018151:N-succinimidyl 3-(2-pyridyldithio)propionate