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. 1997;75(6):837–844. doi: 10.1038/bjc.1997.149

Biodistribution of charged F(ab')2 photoimmunoconjugates in a xenograft model of ovarian cancer.

L R Duska 1, M R Hamblin 1, M P Bamberg 1, T Hasan 1
PMCID: PMC2063388  PMID: 9062404

Abstract

The effect of charge modification of photoimmunoconjugates (PICs) on their biodistribution in a xenograft model of ovarian cancer was investigated. Chlorin(e6)c(e6) was attached site specifically to the F(ab')2 fragment of the murine monoclonal antibody OC125, directed against human ovarian cancer cells, via poly-1-lysine linkers carrying cationic or anionic charges. Preservation of immunoreactivity was checked by enzyme-linked immunosorbent assay (ELISA). PICs were radiolabelled with 125I and compared with non-specific rabbit IgG PICs after intraperitoneal (i.p.) injection into nude mice. Samples were taken from normal organs and tumour at 3 h and 24 h. Tumour to normal 125I ratios showed that the cationic OC125F(ab')2 PIC had the highest tumour selectivity. Ratios for c(e6) were uniformly higher than for 125I, indicating that c(e6) became separated from 125I. OC125F(ab')2 gave highest tissue values of 125I, followed by cationic OC125F(ab')2 PIC; other species were much lower. The amounts of c(e6) delivered per gram of tumour were much higher for cationic OC125F(ab')2 PIC than for other species. The results indicate that cationic charge stimulates the endocytosis and lysosomal degradation of the OC125F(ab')2-pl-c(e6) that has bound to the i.p. tumour. Positively charged PICs may have applications in the i.p. photoimmunotherapy of minimal residual ovarian cancer.

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Selected References

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  1. Beck E., Hofmann M., Bernhardt G., Jäger W., Wildt L., Lang N. In vitro activity of immunoconjugates between cisplatin and an anti-CA125 monoclonal antibody on ovarian cancer cell lines. Cell Biophys. 1994;24-25:163–173. doi: 10.1007/BF02789227. [DOI] [PubMed] [Google Scholar]
  2. Buchegger F., Pèlegrin A., Delaloye B., Bischof-Delaloye A., Mach J. P. Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice. J Nucl Med. 1990 Jun;31(6):1035–1044. [PubMed] [Google Scholar]
  3. Carroll S. F., Bernhard S. L., Goff D. A., Bauer R. J., Leach W., Kung A. H. Enhanced stability in vitro and in vivo of immunoconjugates prepared with 5-methyl-2-iminothiolane. Bioconjug Chem. 1994 May-Jun;5(3):248–256. doi: 10.1021/bc00027a010. [DOI] [PubMed] [Google Scholar]
  4. DeLaney T. F., Sindelar W. F., Tochner Z., Smith P. D., Friauf W. S., Thomas G., Dachowski L., Cole J. W., Steinberg S. M., Glatstein E. Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Int J Radiat Oncol Biol Phys. 1993 Feb 15;25(3):445–457. doi: 10.1016/0360-3016(93)90066-5. [DOI] [PubMed] [Google Scholar]
  5. Fisher A. M., Murphree A. L., Gomer C. J. Clinical and preclinical photodynamic therapy. Lasers Surg Med. 1995;17(1):2–31. doi: 10.1002/lsm.1900170103. [DOI] [PubMed] [Google Scholar]
  6. Flessner M. F., Dedrick R. L. Monoclonal antibody delivery to intraperitoneal tumors in rats: effects of route of administration and intraperitoneal solution osmolality. Cancer Res. 1994 Aug 15;54(16):4376–4384. [PubMed] [Google Scholar]
  7. Goff B. A., Bamberg M., Hasan T. Photoimmunotherapy of human ovarian carcinoma cells ex vivo. Cancer Res. 1991 Sep 15;51(18):4762–4767. [PubMed] [Google Scholar]
  8. Goff B. A., Hermanto U., Rumbaugh J., Blake J., Bamberg M., Hasan T. Photoimmunotherapy and biodistribution with an OC125-chlorin immunoconjugate in an in vivo murine ovarian cancer model. Br J Cancer. 1994 Sep;70(3):474–480. doi: 10.1038/bjc.1994.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Haisma H. J., Moseley K. R., Battaile A. I., Griffiths T. C., Zurawski V. R., Knapp R. C. Biodistribution, pharmacokinetics and imaging of 131I-labelled OC125 in ovarian cancer. Int J Cancer Suppl. 1988;2:109–113. doi: 10.1002/ijc.2910410725. [DOI] [PubMed] [Google Scholar]
  10. Hamblin M. R., Miller J. L., Hasan T. Effect of charge on the interaction of site-specific photoimmunoconjugates with human ovarian cancer cells. Cancer Res. 1996 Nov 15;56(22):5205–5210. [PubMed] [Google Scholar]
  11. Hamblin M. R., Newman E. L. Photosensitizer targeting in photodynamic therapy. II. Conjugates of haematoporphyrin with serum lipoproteins. J Photochem Photobiol B. 1994 Nov;26(2):147–157. doi: 10.1016/1011-1344(94)07036-9. [DOI] [PubMed] [Google Scholar]
  12. Hansen S. H., Sandvig K., van Deurs B. Molecules internalized by clathrin-independent endocytosis are delivered to endosomes containing transferrin receptors. J Cell Biol. 1993 Oct;123(1):89–97. doi: 10.1083/jcb.123.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Henderson B. W., Dougherty T. J. How does photodynamic therapy work? Photochem Photobiol. 1992 Jan;55(1):145–157. doi: 10.1111/j.1751-1097.1992.tb04222.x. [DOI] [PubMed] [Google Scholar]
  14. Hosono M. N., Endo K., Sakahara H., Watanabe Y., Saga T., Nakai T., Hosono M., Nakajima T., Onoyama Y., Konishi J. Different antigenic nature in apparently healthy women with high serum CA 125 levels compared with typical patients with ovarian cancer. Cancer. 1992 Dec 15;70(12):2851–2856. doi: 10.1002/1097-0142(19921215)70:12<2851::aid-cncr2820701222>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  15. Karlan B. Y., Amin W., Casper S. E., Littlefield B. A. Hormonal regulation of CA125 tumor marker expression in human ovarian carcinoma cells: inhibition by glucocorticoids. Cancer Res. 1988 Jun 15;48(12):3502–3506. [PubMed] [Google Scholar]
  16. Molpus K. L., Kato D., Hamblin M. R., Lilge L., Bamberg M., Hasan T. Intraperitoneal photodynamic therapy of human epithelial ovarian carcinomatosis in a xenograft murine model. Cancer Res. 1996 Mar 1;56(5):1075–1082. [PubMed] [Google Scholar]
  17. Muto M. G., Finkler N. J., Kassis A. I., Howes A. E., Anderson L. L., Lau C. C., Zurawski V. R., Jr, Weadock K., Tumeh S. S., Lavin P. Intraperitoneal radioimmunotherapy of refractory ovarian carcinoma utilizing iodine-131-labeled monoclonal antibody OC125. Gynecol Oncol. 1992 Jun;45(3):265–272. doi: 10.1016/0090-8258(92)90302-y. [DOI] [PubMed] [Google Scholar]
  18. Ozols R. F. Carboplatin and paclitaxel in ovarian cancer. Semin Oncol. 1995 Jun;22(3 Suppl 6):78–83. [PubMed] [Google Scholar]
  19. Pardridge W. M., Bickel U., Buciak J., Yang J., Diagne A., Aepinus C. Cationization of a monoclonal antibody to the human immunodeficiency virus REV protein enhances cellular uptake but does not impair antigen binding of the antibody. Immunol Lett. 1994 Oct;42(3):191–195. doi: 10.1016/0165-2478(94)90085-x. [DOI] [PubMed] [Google Scholar]
  20. Press O. W., DeSantes K., Anderson S. K., Geissler F. Inhibition of catabolism of radiolabeled antibodies by tumor cells using lysosomotropic amines and carboxylic ionophores. Cancer Res. 1990 Feb 15;50(4):1243–1250. [PubMed] [Google Scholar]
  21. Press O. W., Hansen J. A., Farr A., Martin P. J. Endocytosis and degradation of murine anti-human CD3 monoclonal antibodies by normal and malignant T-lymphocytes. Cancer Res. 1988 Apr 15;48(8):2249–2257. [PubMed] [Google Scholar]
  22. Ryser H. J., Drummond I., Shen W. C. The cellular uptake of horseradish peroxidase and its poly(lysine) conjugate by cultured fibroblasts is qualitatively similar despite a 900-fold difference in rate. J Cell Physiol. 1982 Oct;113(1):167–178. doi: 10.1002/jcp.1041130126. [DOI] [PubMed] [Google Scholar]
  23. Salacinski P. R., McLean C., Sykes J. E., Clement-Jones V. V., Lowry P. J. Iodination of proteins, glycoproteins, and peptides using a solid-phase oxidizing agent, 1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenyl glycoluril (Iodogen). Anal Biochem. 1981 Oct;117(1):136–146. doi: 10.1016/0003-2697(81)90703-x. [DOI] [PubMed] [Google Scholar]
  24. Smith A., Alberto R., Blaeuenstein P., Novak-Hofer I., Maecke H. R., Schubiger P. A. Preclinical evaluation of 67Cu-labeled intact and fragmented anti-colon carcinoma monoclonal antibody MAb35. Cancer Res. 1993 Dec 1;53(23):5727–5733. [PubMed] [Google Scholar]
  25. Smith A., Alberto R., Shubiger P. A. Influence of radiolabel on the in vivo processing of intact and fragmented anti-tumour monoclonal antibody. J Nucl Biol Med. 1994 Dec;38(4 Suppl 1):54–58. [PubMed] [Google Scholar]
  26. Thédrez P., Saccavini J. C., Nolibé D., Simoen J. P., Guerreau D., Gestin J. F., Kremer M., Chatal J. F. Biodistribution of indium-111-labeled OC 125 monoclonal antibody after intraperitoneal injection in nude mice intraperitoneally grafted with ovarian carcinoma. Cancer Res. 1989 Jun 1;49(11):3081–3086. [PubMed] [Google Scholar]
  27. Tochner Z., Mitchell J. B., Smith P., Harrington F., Glatstein E., Russo D., Russo A. Photodynamic therapy of ascites tumours within the peritoneal cavity. Br J Cancer. 1986 Jun;53(6):733–736. doi: 10.1038/bjc.1986.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Triguero D., Buciak J. L., Pardridge W. M. Cationization of immunoglobulin G results in enhanced organ uptake of the protein after intravenous administration in rats and primate. J Pharmacol Exp Ther. 1991 Jul 1;258(1):186–192. [PubMed] [Google Scholar]
  29. Veenhuizen R. B., Ruevekamp-Helmers M. C., Helmerhorst T. J., Kenemans P., Mooi W. J., Marijnissen J. P., Stewart F. A. Intraperitoneal photodynamic therapy in the rat: comparison of toxicity profiles for photofrin and MTHPC. Int J Cancer. 1994 Dec 15;59(6):830–836. doi: 10.1002/ijc.2910590620. [DOI] [PubMed] [Google Scholar]
  30. Weagle G., Paterson P. E., Kennedy J., Pottier R. The nature of the chromophore responsible for naturally occurring fluorescence in mouse skin. J Photochem Photobiol B. 1988 Nov;2(3):313–320. doi: 10.1016/1011-1344(88)85051-6. [DOI] [PubMed] [Google Scholar]
  31. Yarmush M. L., Thorpe W. P., Strong L., Rakestraw S. L., Toner M., Tompkins R. G. Antibody Targeted Photolysis. Crit Rev Ther Drug Carrier Syst. 1993;10(3):197–252. [PubMed] [Google Scholar]

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