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EphA2 Immunoconjugate

Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Antibody–drug conjugates (ADCs) have the potential to increase the therapeutic index of small molecules by minimizing systemic toxicity and improving tumor targeting. The discovery of new cell surface cancer targets is an important component for the development of new cancer therapies utilizing the ADC approach. The cell surface receptor EphA2 provides just such a new targeted therapeutic opportunity in multiple cancers, notably ovarian, breast, cervical, renal, and prostate, among others. Antibodies that bind to EphA2 on tumor cells can induce rapid internalization and degradation of the protein and antibody complex. The development of MEDI-547, an anti-EphA2 ADC that is composed of a fully human IgG1 monoclonal antibody (known as 1C1) conjugated to monomethyl auristatin phenylalanine through a maleimidocaproyl linker, is discussed.

Keywords

Primitive Streak Drug Efflux Pump Solid Tumor Type EphA2 Expression EphrinA Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Kullander K, Klein R (2002) Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3:475–486PubMedCrossRefGoogle Scholar
  2. 2.
    Murai KK, Pasquale EB (2003) ‘Eph’ective signaling: forward, reverse and crosstalk. J Cell Sci 116:2823–2832PubMedCrossRefGoogle Scholar
  3. 3.
    Beckmann MP, Cerretti DP, Baum P et al (1994) Molecular characterization of a family of ligands for eph-related tyrosine kinase receptors. EMBO J 13:3757–3762PubMedGoogle Scholar
  4. 4.
    Davis S, Gale NW, Aldrich TH et al (1994) Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266:816–819PubMedCrossRefGoogle Scholar
  5. 5.
    Egea J, Nissen UV, Dufour A et al (2005) Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function. Neuron 47:515–528PubMedCrossRefGoogle Scholar
  6. 6.
    Vearing CJ, Lackmann M (2005) Eph receptor signalling: dimerisation just isn’t enough. Growth Factors 23:67–76PubMedCrossRefGoogle Scholar
  7. 7.
    Himanen JP, Chumley MJ, Lackmann M et al (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7:501–509PubMedCrossRefGoogle Scholar
  8. 8.
    Gale NW, Yancopoulos GD (1997) Ephrins and their receptors: a repulsive topic? Cell Tissue Res 290:227–241PubMedCrossRefGoogle Scholar
  9. 9.
    Flanagan JG, Vanderhaeghen P (1998) The ephrins and Eph receptors in neural development. Annu Rev Neurosci 21:309–345PubMedCrossRefGoogle Scholar
  10. 10.
    Hafner C, Schmitz G, Meyer S et al (2004) Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem 50:490–499PubMedCrossRefGoogle Scholar
  11. 11.
    Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52PubMedCrossRefGoogle Scholar
  12. 12.
    Zisch AH, Pasquale EB (1997) The Eph family: a multitude of receptors that mediate cell recognition signals. Cell Tissue Res 290:217–226PubMedCrossRefGoogle Scholar
  13. 13.
    Huusko P, Ponciano-Jackson D, Wolf M et al (2004) Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat Genet 36:979–983PubMedCrossRefGoogle Scholar
  14. 14.
    Kittles RA, Baffoe-Bonnie AB, Moses TY et al (2006) A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. J Med Genet 43:507–511PubMedCrossRefGoogle Scholar
  15. 15.
    Alazzouzi H, Davalos V, Kokko A et al (2005) Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Res 65:10170–10173PubMedCrossRefGoogle Scholar
  16. 16.
    Guo DL, Zhang J, Yuen ST et al (2006) Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours. Carcinogenesis 27:454–464PubMedCrossRefGoogle Scholar
  17. 17.
    Guo H, Miao H, Gerber L, Singh J, Denning MF, Gilliam AC, Wang B (2006) Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res 66(14):7050–7058PubMedCrossRefGoogle Scholar
  18. 18.
    Elowe S, Holland SJ, Kulkarni S, Pawson T (2001) Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol Cell Biol 21(21):7429–7441PubMedCrossRefGoogle Scholar
  19. 19.
    Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E (1999) An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci USA 96:13813–13818PubMedCrossRefGoogle Scholar
  20. 20.
    Nakada M, Niska JA, Tran NL, McDonough WS, Berens ME (2005) EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. Am J Pathol 167:565–576PubMedCrossRefGoogle Scholar
  21. 21.
    Kumar SR, Masood R, Spannuth WA et al (2007) The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome. Br J Cancer 96:1083–1091PubMedCrossRefGoogle Scholar
  22. 22.
    Kumar SR, Scehnet JS, Ley EJ, Singh J et al (2009) Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res 69(9):3736–3745PubMedCrossRefGoogle Scholar
  23. 23.
    Noren NK, Foos G, Hauser CA, Pasquale EB (2006) The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol 8:815–825PubMedCrossRefGoogle Scholar
  24. 24.
    Lindberg RA, Hunter T (1990) cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases. Mol Cell Biol 10:6316–6324PubMedGoogle Scholar
  25. 25.
    Ruiz JC, Robertson EJ (1994) The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development. Mech Dev 46:87–100PubMedCrossRefGoogle Scholar
  26. 26.
    Chen J, Nachabah A, Scherer C et al (1996) Germ-line inactivation of the murine Eck receptor tyrosine kinase by gene trap retroviral insertion. Oncogene 12:979–988PubMedGoogle Scholar
  27. 27.
    Ireton RC, Chen J (2005) EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets 5(3):149–157PubMedCrossRefGoogle Scholar
  28. 28.
    Wykosky J, Debinski W (2008) The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol Cancer Res 6(12):1795–1806PubMedCrossRefGoogle Scholar
  29. 29.
    Zeng G, Hu Z, Kinch MS et al (2003) High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol 163:2271–2276PubMedCrossRefGoogle Scholar
  30. 30.
    Thaker PH, Deavers M, Celestino J et al (2004) EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res 10:5145–5150PubMedCrossRefGoogle Scholar
  31. 31.
    Mudali SV, Fu B, Lakkur SS, Luo M, Embuscado EE, Iacobuzio-Donahue CA (2006) Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. Clin Exp Metastasis 23:357–365PubMedCrossRefGoogle Scholar
  32. 32.
    Wykosky J, Gibo DM, Stanton C, Debinski W (2005) EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res 3:541–551PubMedCrossRefGoogle Scholar
  33. 33.
    Walker-Daniels J, Coffman K, Azimi M et al (1999) Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate 41:275–280PubMedCrossRefGoogle Scholar
  34. 34.
    Fox BP, Kandpal RP (2004) Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun 318:882–892PubMedCrossRefGoogle Scholar
  35. 35.
    Kinch MS, Moore MB, Harpole DH (2003) Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res 9:613–618PubMedGoogle Scholar
  36. 36.
    Miyazaki T, Kato H, Fukuchi M, Nakajima M, Kuwano H (2003) EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int J Cancer 103:657–663PubMedCrossRefGoogle Scholar
  37. 37.
    Han L, Dong Z, Qiao Y (2005) The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas. Gynecol Oncol 99:278–286PubMedCrossRefGoogle Scholar
  38. 38.
    Hess AR, Seftor EA, Gardner LM et al (2001) Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: role of epithelial cell kinase (Eck/EphA2). Cancer Res 61:3250–3255PubMedGoogle Scholar
  39. 39.
    Wang LF, Fokas E, Bieker M et al (2008) Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. Oncol Rep 19:151–156PubMedGoogle Scholar
  40. 40.
    Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS (2001) EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 61:2301–2316PubMedGoogle Scholar
  41. 41.
    Fang WB, Brantley-Sieders DM, Parker MA, Reith AD, Chen J (2005) A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene 24:7859PubMedCrossRefGoogle Scholar
  42. 42.
    Huang F, Reeves K, Han X (2007) Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res 67:2226–2238PubMedCrossRefGoogle Scholar
  43. 43.
    Mitra S, Duggineni S, Koolpe M, Zhu X, Huang Z, Pasquale EB (2010) Structure-activity relationship analysis of peptides targeting the EphA2 receptor. Biochemistry 49(31):6687–6695PubMedCrossRefGoogle Scholar
  44. 44.
    Carles-Kinch K, Kilpatrick KE, Stewart JC, Kinch MS (2002) Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer Res 62(10):2840–2847PubMedGoogle Scholar
  45. 45.
    Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S et al (2010) Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 70(1):299–308PubMedCrossRefGoogle Scholar
  46. 46.
    Kiewlich D, Zhang J, Gross C et al (2006) Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do not inhibit tumor growth. Neoplasia 8:18–30PubMedCrossRefGoogle Scholar
  47. 47.
    Hammond SA, Lutterbuese R, Roff S et al (2007) Selective targeting and potent control of tumor growth using an EphA2/CD3-Bispecific single-chain antibody construct. Cancer Res 67(8):3927–35PubMedCrossRefGoogle Scholar
  48. 48.
    Zhuang G, Hunter S, Hwang Y, Chen J (2007) Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation. J Biol Chem 282(4):2683–2694PubMedCrossRefGoogle Scholar
  49. 49.
    Jackson D, Gooya J, Mao S, Kinneer K, Xu L, Camara M et al (2008) A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res 68(22):9367–9374PubMedCrossRefGoogle Scholar
  50. 50.
    Wykosky J, Palma E, Gibo DM, Ringler S, Turner CP, Debinski W (2008) Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene 27(58):7260–75273PubMedCrossRefGoogle Scholar
  51. 51.
    Lee JW, Han HD, Shahzad MM, Kim SW, Mangala LS, Nick AM et al (2009) EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma. J Natl Cancer Inst 101(17):1193–1205PubMedCrossRefGoogle Scholar
  52. 52.
    Lee JW, Stone RL, Lee SJ, Nam EJ, Roh JW, Nick AM et al (2010) EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin Cancer Res 16(9):2562–2570PubMedCrossRefGoogle Scholar
  53. 53.
    Coffman KT, Hu M, Carles-Kinch K et al (2003) Differential EphA2 epitope display on normal versus malignant cells. Cancer Res 63:7907–7912PubMedGoogle Scholar
  54. 54.
    Dall’Acqua WF, Damschroder MM, Zhang J et al (2005) Antibody humanization by framework shuffling. Methods 36(1):43–60PubMedCrossRefGoogle Scholar
  55. 55.
    Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF et al (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21(7):778–84PubMedCrossRefGoogle Scholar
  56. 56.
    Mirsalis JC, Schindler-Horvat J, Hill JR, Tomaszewski JE, Donohue SJ, Tyson CA (1999) Toxicity of dolastatin 10 in mice, rats and dogs and its clinical relevance. Cancer Chemother Pharmacol 44(5):395–402PubMedCrossRefGoogle Scholar
  57. 57.
    Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL et al (2006) Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem 17(1):114–124PubMedCrossRefGoogle Scholar
  58. 58.
    Mansouri A, Henle KJ, Nagle WA (1992) Multidrug resistance: prospects for clinical management. SAAS Bull Biochem Biotechnol 5:48–52PubMedGoogle Scholar
  59. 59.
    Patwardhan G, Gupta V, Huang J, Gu X, Liu YY et al (2010) Direct assessment of P-glycoprotein efflux to determine tumor response to chemotherapy. Biochem Pharmacol 80(1):72–79PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.MedImmuneGaithersburgUSA
  2. 2.Agensys, Inc.Santa MonicaUSA

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