Skip to main content
SpringerLink
Log in

Anti-Sp17 monoclonal antibody–doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma

  • Original Research
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Sperm protein 17 (Sp17) is selectively overexpressed in several human malignancies including ovarian carcinoma, but is absent or expressed at low levels in most normal tissues. Previous work from our group characterized an anti-Sp17 monoclonal antibody (clone 3C12) and showed that it specifically targeted tumor cells. In this report, we investigated whether a novel immunoconjugate containing 3C12 linked to the chemotherapeutic agent doxorubicin [(DOX) Adriamycin] had antitumor activity against ovarian cancer cell lines and tumor models. DOX was conjugated to 3C12 using a linker, and the specificity of 3C12-DOX was examined in Sp17-positive SKOV3 and Sp17-negative COC2 ovarian cancer cells using cell-based ELISA and internalization assays. The cytotoxicity of 3C12-DOX was assessed with the MTT assay, and its therapeutic effectiveness was evaluated in immunodeficient mice bearing SKOV3 cells. In vitro, the 3C12-DOX immunoconjugate specifically bound to and was internalized by Sp17-positive SKOV3 cells but did not bind to Sp17-negative cells. Treatment with 3C12-DOX (0.001 to 10 μg/mL) decreased the viability of SKOV3 cells in a Sp17-specific manner. In vivo, 3C12-DOX (3 mg/kg) induced the regression of established SKOV3 xenograft tumors in BALB/c mice compared with control treatment. The antitumor effects of 3C12-DOX were significantly associated with the induction of apoptosis in tumor cells. In addition, 3C12-DOX showed no observable adverse effects or toxicity when compared with DOX alone in mice bearing ovarian tumor xenografts. Our findings suggest that 3C12-DOX may be a potential antibody–drug conjugate for clinical development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

Sp17:

Sperm protein 17

3C12:

Anti-Sp17 monoclonal antibody

DOX:

Doxorubicin

OC:

Ovarian cancer

References

  1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300

    Article  PubMed  Google Scholar 

  2. Herzog TJ (2004) Recurrent ovarian cancer: how important is it to treat to disease progression? Clin Cancer Res 10(22):7439–7449

    Article  CAS  PubMed  Google Scholar 

  3. Baek SJ, Park JY, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH (2008) Stage IIIC epithelial ovarian cancer classified solely by lymph node metastasis has a more favorable prognosis than other types of stage IIIC epithelial ovarian cancer. J Gynecol Oncol 19(4):223–228

    Article  PubMed Central  PubMed  Google Scholar 

  4. Dai F, Zhang Y, Zhu X, Shan N, Chen Y (2012) Anticancer role of MUC1 aptamer-miR-29b chimera in epithelial ovarian carcinoma cells through regulation of PTEN methylation. Target Oncol 7(4):217–225

    Article  PubMed  Google Scholar 

  5. Hortobagyi GN (1997) Anthracyclines in the treatment of cancer. An overview. Drugs 54(Suppl 4):1–7

    Article  CAS  PubMed  Google Scholar 

  6. Safra T, Borgato L, Nicoletto MO, Rolnitzky L, Pelles-Avraham S, Geva R, Donach ME, Curtin J, Novetsky A, Grenader T, Lai WC, Gabizon A, Boyd L, Muggia F (2011) BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10(10):2000–2007

    Article  CAS  PubMed  Google Scholar 

  7. Rivera E (2003) Liposomal anthracyclines in metastatic breast cancer: clinical update. Oncologist 8(Suppl 2):3–9

    Article  CAS  PubMed  Google Scholar 

  8. Shen F, Chu S, Bence AK, Bailey B, Xue X, Erickson PA, Montrose MH, Beck WT, Erickson LC (2008) Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. J Pharmacol Exp Ther 324(1):95–102

    Article  CAS  PubMed  Google Scholar 

  9. Oei AL, Sweep FC, Thomas CM, Boerman OC, Massuger LF (2008) The use of monoclonal antibodies for the treatment of epithelial ovarian cancer (review). Int J Oncol 32(6):1145–1157

    Article  CAS  PubMed  Google Scholar 

  10. Frederick PJ, Straughn JM Jr, Alvarez RD, Buchsbaum DJ (2009) Preclinical studies and clinical utilization of monoclonal antibodies in epithelial ovarian cancer. Gynecol Oncol 113(3):384–390

    Article  CAS  PubMed  Google Scholar 

  11. Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9(3):167–181

    Article  CAS  PubMed  Google Scholar 

  12. Zangemeister-Wittke U (2005) Antibodies for targeted cancer therapy—technical aspects and clinical perspectives. Pathobiology 72(6):279–286

    Article  CAS  PubMed  Google Scholar 

  13. Ricart AD, Tolcher AW (2007) Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol 4(4):245–255

    Article  CAS  PubMed  Google Scholar 

  14. Lim SH, Wang Z, Chiriva-Internati M, Xue Y (2001) Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood 97(5):1508–1510

    Article  CAS  PubMed  Google Scholar 

  15. Straughn JM Jr, Shaw DR, Guerrero A, Bhoola SM, Racelis A, Wang Z, Chiriva-Internati M, Grizzle WE, Alvarez RD, Lim SH, Strong TV (2004) Expression of sperm protein 17 (Sp17) in ovarian cancer. Int J Cancer 108(6):805–811

    Article  CAS  PubMed  Google Scholar 

  16. Grizzi F, Gaetani P, Franceschini B, Di Ieva A, Colombo P, Ceva-Grimaldi G, Bollati A, Frezza EE, Cobos E, Rodriguezy Baena R, Dioguardi N, Chiriva-Internati M (2006) Sperm protein 17 is expressed in human nervous system tumours. BMC Cancer 6:23

    Article  PubMed Central  PubMed  Google Scholar 

  17. Liu Q, Li FQ, Han YL, Wang LK, Hou YY (2008) Aberrant expression of sperm protein 17 enhances migration of ovarian cancer cell line HO-8910. Natl J Androl 14(11):982–986

    CAS  Google Scholar 

  18. Chiriva-Internati M, Weidanz JA, Yu Y, Frezza EE, Jenkins MR, Kennedy RC, Cobos E, Kast WM (2008) Sperm protein 17 is a suitable target for adoptive T-cell-based immunotherapy in human ovarian cancer. J Immunother 31(8):693–703

    Article  CAS  PubMed  Google Scholar 

  19. Chiriva-Internati M, Yu Y, Mirandola L, Jenkins MR, Chapman C, Cannon M, Cobos E, Kast WM (2010) Cancer testis antigen vaccination affords long-term protection in a murine model of ovarian cancer. PLoS One 5(5):e10471

    Article  PubMed Central  PubMed  Google Scholar 

  20. Li FQ, Zhang SX, An LX, Gu YQ (2011) In vivo molecular targeting effects of anti-Sp17- ICG-Der-02 on hepatocellular carcinoma evaluated by an optical imaging system. J Exp Clin Cancer Res 30:25

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Li FQ, Yang AL, Miao JW, Zhang CH, Wu B, Zhang XH (2006) Preparation and characterization of the monoclonal antibody against human sperm protein 17. Chin J Cell Mol Immunol 22(5):638–640

    Google Scholar 

  22. Li FQ, Liu Q, Han YL, Wu B, Yin HL (2010) Sperm protein 17 is highly expressed in endometrial and cervical cancers. BMC Cancer 10:429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Park LS, Friend D, Gillis S, Urdal DL (1986) Characterization of the cell surface receptor for a multi-lineage colony-stimulating factor (CSF-2 alpha). J Biol Chem 261(1):205–210

    CAS  PubMed  Google Scholar 

  24. Farries TC, Atkinson JP (1989) Biosynthesis of properdin. J Immunol 142(3):842–847

    CAS  PubMed  Google Scholar 

  25. Sinkule JA, Rosen ST, Radosevich JA (1991) Monoclonal antibody 44-3A6 doxorubicin immunoconjugates: comparative in vitro anti-tumor efficacy of different conjugation methods. Tumour Biol 12(4):198–206

    Article  CAS  PubMed  Google Scholar 

  26. Sivam GP, Martin PJ, Reisfeld RA, Mueller BM (1995) Therapeutic efficacy of a doxorubicin immunoconjugate in a preclinical model of spontaneous metastatic human melanoma. Cancer Res 55(11):2352–2356

    CAS  PubMed  Google Scholar 

  27. Song JX, Cao WL, Li FQ, Shi LN, Jia X (2012) Anti-Sp17 monoclonal antibody with antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities against human ovarian cancer cells. Med Oncol 29(4):2923–2931

    Article  CAS  PubMed  Google Scholar 

  28. Chircop M, Perera S, Mariana A, Lau H, Ma MP, Gilbert J, Jones NC, Gordon CP, Young KA, Morokoff A, Sakoff J, O'Brien TJ, McCluskey A, Robinson PJ (2011) Inhibition of dynamin by dynole 34-2 induces cell death following cytokinesis failure in cancer cells. Mol Cancer Ther 10(9):1553–1562

    Article  CAS  PubMed  Google Scholar 

  29. Fishel ML, He Y, Smith ML, Kelley MR (2007) Manipulation of base excision repair to sensitize ovarian cancer cells to alkylating agent temozolomide. Clin Cancer Res 13(1):260–267

    Article  CAS  PubMed  Google Scholar 

  30. Wen Y, Richardson RT, Widgren EE, O'Rand MG (2001) Characterization of Sp17: a ubiquitous three domain protein that binds heparin. Biochem J 357(Pt 1):25–31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Chiriva-Internati M, Wang Z, Xue Y, Bumm K, Hahn AB, Lim SH (2001) Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk. Eur J Immunol 31(8):2277–2283

    Article  CAS  PubMed  Google Scholar 

  32. Polakis P (2005) Arming antibodies for cancer therapy. Curr Opin Pharmacol 5(4):382–387

    Article  CAS  PubMed  Google Scholar 

  33. Lacy HM, Sanderson RD (2001) Sperm protein 17 is expressed on normal and malignant lymphocytes and promotes heparan sulfate-mediated cell–cell adhesion. Blood 98(7):2160–2165

    Article  CAS  PubMed  Google Scholar 

  34. Zhang Y, Wang Z, Robinson WR, Lim SH (2004) Combined real time PCR and immunohistochemical evaluation of sperm protein 17 as a cancer-testis antigen. Eur J Haematol 73(4):280–284

    Article  CAS  PubMed  Google Scholar 

  35. McLeskey SB, Dowds C, Carballada R, White RR, Saling PM (1998) Molecules involved in mammalian sperm–egg interaction. Int Rev Cytol 177:57–113

    Article  CAS  PubMed  Google Scholar 

  36. Chiriva-Internati M, Gagliano N, Donetti E, Costa F, Grizzi F, Franceschini B, Albani E, Levi-Setti PE, Gioia M, Jenkins M, Cobos E, Kast WM (2009) Sperm protein 17 is expressed in the sperm fibrous sheath. J Transl Med 7:61

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Prof. Zhang Yu for assistance with preparation of immunoconjugates and Liu Qi for the gift of SKOV3 and COC2 human ovary carcinoma cell lines. This project was supported by a grant from National Nature Science Foundation of China (No.81101978).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Biology, Institute of Medical Laboratory Sciences, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, People’s Republic of China

    Jia-Xi Song, Fang-Qiu Li, Wang-Li Cao, Xuan Jia, Li-Ning Shi, Jing-Fen Lu, Chun-Fang Ma & Qian-Qian Kong

Authors
  1. Jia-Xi Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang-Qiu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wang-Li Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Ning Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing-Fen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chun-Fang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qian-Qian Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fang-Qiu Li.

Additional information

Jia-Xi Song and Fang-Qiu Li contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Song, JX., Li, FQ., Cao, WL. et al. Anti-Sp17 monoclonal antibody–doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma. Targ Oncol 9, 263–272 (2014). https://doi.org/10.1007/s11523-013-0293-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-013-0293-6

Keywords

Search

Navigation