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Factors Involved in the Design of Cytotoxic Payloads for Antibody–Drug Conjugates

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Antibody-Drug Conjugates and Immunotoxins

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

Abstract

Selective targeting of cancer can be accomplished by the use of monoclonal antibodies (mAbs) that bind to tumor-associated antigens expressed preferentially on the surface of cancer cells. Several of these non-derivatized antibodies, or naked antibodies, have been approved for the treatment of various cancer types. However, compelling single agent activity has only been demonstrated in the treatment of hematological malignancies. For example, the anti-CD20 mAb rituximab (Rituxan) is widely used in the treatment of B-cell lymphomas. Also, the anti-CD52 antibody alemtuzumab (Campath) is used in the treatment of some leukemias. However, antibodies targeting solid tumors, such as trastuzumab (Herceptin) for breast cancer, anti-EGF receptor antibodies cetuximab (Erbitux) and panitumumab (Vectibix) for head and neck and colon cancers, and the anti-angiogenic agent bevacizumab (Avastin), display only modest antitumor activity as single agents. Thus, these antibodies are most often used in combination with conventional anticancer drugs, thus retaining the high systemic toxicity of standard chemotherapy. In an alternative approach, the efficacy of a naked antibody can be greatly enhanced by attachment of a cytotoxic molecule to give an antibody–drug conjugate (ADC). The selection of the optimal cytotoxic effector, linker, and antibody component of the ADC can be facilitated by an understanding of the environments to which the ADC will be exposed to once it is administered to a patient and also through the knowledge gained from the development of previous ADCs. Most of the current ADCs under development are for the treatment of cancer; however, ADCs are also being investigated for the treatment of autoimmune diseases [1]. This chapter will deal with the selection of an appropriate cytotoxic effector for the preparation of anticancer ADCs, but much of the discussion is relevant to ADCs for the treatment of autoimmune diseases as well.

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Notes

  1. 1.

    Because each ADC is itself a drug or drug candidate, the attached cytotoxic effector will not be referred to as a “drug” in this chapter unless it is, on its own, an FDA-approved therapeutic agent (e.g., doxorubicin).

References

  1. Zheng B, Fuji RN, Elkins K, Yu SF, Fuh FK, Chuh J et al (2009) In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates. Mol Cancer Ther 8:2937–2946

    Article  PubMed  CAS  Google Scholar 

  2. Kraus M, Severin T, Wolf B (1994) Relevance of microenvironmental pH for self-organized tumor growth and invasion. Anticancer Res 14:1573–1583

    PubMed  CAS  Google Scholar 

  3. Kraus M, Wolf B (1996) Implications of acidic tumor microenvironment for neoplastic growth and cancer treatment: a computer analysis. Tumour Biol 17:133–154

    Article  PubMed  CAS  Google Scholar 

  4. Madri JA (2003) The evolving roles of cell surface proteases in health and disease: implications for developmental, adaptive, inflammatory, and neoplastic processes. Curr Top Dev Biol 54:391–410

    Article  PubMed  CAS  Google Scholar 

  5. Saito G, Swanson JA, Lee KD (2003) Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. Adv Drug Deliv Rev 55:199–215

    Article  PubMed  CAS  Google Scholar 

  6. Stephan JP, Chan P, Lee C, Nelson C, Elliott JM, Bechtel C et al (2008) Anti-CD22-MCC-DM1 and MC-MMAF conjugates: impact of assay format on pharmacokinetic parameters determination. Bioconjug Chem 19:1673–1683

    Article  PubMed  CAS  Google Scholar 

  7. Junutula JR, Flagella KM, Graham RA, Parsons KL, Ha E, Raab H et al (2010) Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clin Cancer Res 16:4769–4778

    Article  PubMed  CAS  Google Scholar 

  8. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG et al (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063–7070

    Article  PubMed  CAS  Google Scholar 

  9. Chari Ravi VJ (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41:98–107

    Article  PubMed  CAS  Google Scholar 

  10. Le PU, Nabi IR (2003) Distinct caveolae-mediated endocytic pathways target the Golgi apparatus and the endoplasmic reticulum. J Cell Sci 116:1059–1071

    Article  PubMed  CAS  Google Scholar 

  11. Katz J, Janik JE, Younes A (2011) Brentuximab Vedotin (SGN-35). Clin Cancer Res 17:6428–6436

    Article  PubMed  CAS  Google Scholar 

  12. Sedlacek HH et al (1992) Antibodies as carriers of cytotoxicity in contributions to oncology 43, 1–145, H. Huber, W. Queisser eds, Karger, Basel

    Google Scholar 

  13. Uadia P, Blair AH, Ghose T (1984) Tumor and tissue distribution of a methotrexate-anti-EL4 immunoglobulin conjugate in EL4 lymphoma-bearing mice. Cancer Res 44:4263–4266

    PubMed  CAS  Google Scholar 

  14. Tabrizi MA, Tseng CM, Roskos LK (2006) Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 11:81–88

    Article  PubMed  CAS  Google Scholar 

  15. Shen H, Kauvar L, Tew KD (1997) Importance of glutathione and associated enzymes in drug response. Oncol Res 9:295–302

    PubMed  CAS  Google Scholar 

  16. Ishikawa T, Kuo MT, Furuta K, Suzuki M (2000) The human multidrug resistance-associated protein (MRP) gene family: from biological function to drug molecular design. Clin Chem Lab Med 38:893–897

    Article  PubMed  CAS  Google Scholar 

  17. Nooter K, Stoter G (1996) Molecular mechanisms of multidrug resistance in cancer chemotherapy. Pathol Res Pract 192:768–780

    Article  PubMed  CAS  Google Scholar 

  18. Kovtun YV, Audette CA, Mayo MF, Jones GE, Doherty H, Maloney EK et al (2010) Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res 70:2528–2537

    Article  PubMed  CAS  Google Scholar 

  19. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239

    Article  PubMed  CAS  Google Scholar 

  20. Sullivan R, Paré GC, Frederiksen LJ, Semenza GL, Graham CH (2008) Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 7:1961–1973

    Article  PubMed  CAS  Google Scholar 

  21. Teicher BA (1994) Hypoxia and drug resistance. Cancer Metastasis Rev 13:139–168

    Article  PubMed  CAS  Google Scholar 

  22. Caglic D, Kosec G, Bojic L, Reinheckel T, Turk V, Turk B (2009) Murine and human cathepsin B exhibit similar properties: possible implications for drug discovery. Biol Chem 390:175–179

    PubMed  CAS  Google Scholar 

  23. Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (2003) Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4:544–558

    Article  PubMed  CAS  Google Scholar 

  24. Bai R, Edler MC, Bonate PL, Copeland TD, Pettit GR, Luduena RF et al (2009) Intracellular activation and deactivation of tasidotin, an analog of dolastatin 15: correlation with cytotoxicity. Mol Pharmacol 75:218–226

    Article  PubMed  CAS  Google Scholar 

  25. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K et al (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433

    Article  PubMed  CAS  Google Scholar 

  26. 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 17:114–124

    Article  PubMed  CAS  Google Scholar 

  27. Dubowchik GM, Firestone RA, Padilla L, Willner D, Hofstead SJ, Mosure K et al (2002) Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity. Bioconjug Chem 13:855–869

    Article  PubMed  CAS  Google Scholar 

  28. Zhao RY, Wilhelm SD, Audette C, Jones G, Leece BA, Lazar AC et al (2011) Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates. J Med Chem 54:3606–3623

    Article  PubMed  CAS  Google Scholar 

  29. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004) Glutathione metabolism and its implications for health. J Nutr 134:489–492

    PubMed  CAS  Google Scholar 

  30. Mills BJ, Lang CA (1996) Differential distribution of free and bound glutathione and cyst(e)ine in human blood. Biochem Pharmacol 52:401–406

    Article  PubMed  CAS  Google Scholar 

  31. Kupchan SM, Komoda Y, Court WA, Thomas GJ, Smith RM, Karim A et al (1972) Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J Am Chem Soc 94:1354–1356

    Article  PubMed  CAS  Google Scholar 

  32. Remillard S, Rebhun LI, Howie GA, Kupchan SM (1975) Antimitotic activity of the potent tumor inhibitor maytansine. Science 189:1002–1005

    Article  PubMed  CAS  Google Scholar 

  33. Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R et al (2009) Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. Blood 113:4352–4361

    Article  PubMed  CAS  Google Scholar 

  34. Thorson JS, Sievers EL, Ahlert J, Shepard E, Whitwam RE, Onwueme KC et al (2000) Understanding and exploiting nature’s chemical arsenal: the past, present and future of calicheamicin research. Curr Pharm Des 6:1841–1879

    Article  PubMed  CAS  Google Scholar 

  35. Boger D (1994) Design, synthesis, and evaluation of DNA minor groove binding agents: the duocarmycins. Pure Appl Chem 66:837–844

    Article  CAS  Google Scholar 

  36. Gascoigne KE, Taylor SS (2009) How do anti-mitotic drugs kill cancer cells? J Cell Sci 122:2579–2585

    Article  PubMed  CAS  Google Scholar 

  37. Jordan MA, Himes RH, Wilson L (1985) Comparison of the effects of vinblastine, vincristine, vindesine, and vinepidine on microtubule dynamics and cell proliferation in vitro. Cancer Res 45:2741–2747

    PubMed  CAS  Google Scholar 

  38. Hadfield JA, Ducki S, Hirst N, McGown AT (2003) Tubulin and microtubules as targets for anticancer drugs. Prog Cell Cycle Res 5:309–325

    PubMed  Google Scholar 

  39. Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R et al (2010) Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther 9:2689–2699

    Article  PubMed  CAS  Google Scholar 

  40. Cassady JM, Chan KK, Floss HG, Leistner E (2004) Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52:1–26

    Article  CAS  Google Scholar 

  41. Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y et al (2006) Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem 49:4392–4408

    Article  PubMed  CAS  Google Scholar 

  42. Kellogg BA, Garrett L, Kovtun Y, Lai KC, Leece B, Miller M et al (2011) Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage. Bioconjug Chem 22:717–727

    Article  PubMed  CAS  Google Scholar 

  43. Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ et al (2006) Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 66:3214–3221

    Article  PubMed  CAS  Google Scholar 

  44. Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H et al (2010) Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther 9:2700–2713

    Article  PubMed  CAS  Google Scholar 

  45. Pettit RK, Pettit GR, Hazen KC (1998) Specific activities of dolastatin 10 and peptide derivatives against Cryptococcus neoformans. Antimicrob Agents Chemother 42:2961–2965

    PubMed  CAS  Google Scholar 

  46. Pettit GR, Srirangam JK, Barkoczy J, Williams MD, Boyd MR, Hamel E et al (1998) Antineoplastic agents 365. Dolastatin 10 SAR probes. Anticancer Drug Des 13:243–277

    PubMed  CAS  Google Scholar 

  47. Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL et al (2010) Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res 16:888–897

    Article  PubMed  CAS  Google Scholar 

  48. Silverman RB (2004) The organic chemistry of drug design and drug action, 2nd edn. Elsevier Academic Press, Amsterdam/Boston

    Google Scholar 

  49. Reich Z, Ghirlando R, Arad T, Weinberger S, Minsky A (1990) Extensive interference of DNA packaging processes affected by chemotherapeutic drugs. J Biol Chem 265:16004–16006

    PubMed  CAS  Google Scholar 

  50. Leijen S, Beijnen JH, Schellens JH (2010) Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin Pharmacol 5:186–191

    Article  PubMed  CAS  Google Scholar 

  51. Burden DA, Osheroff N (1998) Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1400:139–154

    Article  PubMed  CAS  Google Scholar 

  52. Sapra P, Stein R, Pickett J, Qu Z, Govindan SV, Cardillo TM et al (2005) Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys. Clin Cancer Res 11:5257–5264

    Article  PubMed  CAS  Google Scholar 

  53. Mitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC (2006) The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42:1564–1573

    Article  PubMed  CAS  Google Scholar 

  54. Lee MD, Dunne TS, Chang CC, Ellestad GA, Siegel MM, Morton GO, McGahren WJ, Borders DB (1987) Calichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin gamma 1. J Am Chem Soc 109:3466–3468

    Article  CAS  Google Scholar 

  55. Hamann PR, Hinman LM, Beyer CF, Greenberger LM, Lin C, Lindh D et al (2005) An anti-MUC1 antibody-calicheamicin conjugate for treatment of solid tumors. Choice of linker and overcoming drug resistance. Bioconjug Chem 16:346–353

    Article  PubMed  CAS  Google Scholar 

  56. Rajvanshi P, Shulman HM, Sievers EL, McDonald GB (2002) Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood 99:2310–2314

    Article  PubMed  CAS  Google Scholar 

  57. Advani A, Coiffier B, Czuczman MS, Dreyling M, Foran J, Gine E et al (2010) Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol 28:2085–2093

    Article  PubMed  CAS  Google Scholar 

  58. Fuerst M (2011) NHL: Inotuzumab ozogamicin shows activity both alone & combined with rituximab. Oncol Times 33:52–53

    Google Scholar 

  59. Ichimura M, Ogawa T, Katsumata S, Takahashi K, Takahashi I, Nakano H (1991) Duocarmycins, new antitumor antibiotics produced by Streptomyces; producing organisms and improved production. J Antibiot (Tokyo) 44:1045–1053

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. ImmunoGen, Inc., 830 Winter St., Waltham, MA, 02451, USA

    Wayne C. Widdison & Ravi V. J. Chari

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  1. Wayne C. Widdison
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  2. Ravi V. J. Chari
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Correspondence to Wayne C. Widdison .

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    Gail Lewis Phillips

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Widdison, W.C., Chari, R.V.J. (2013). Factors Involved in the Design of Cytotoxic Payloads for Antibody–Drug Conjugates. In: Phillips, G. (eds) Antibody-Drug Conjugates and Immunotoxins. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5456-4_6

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  • DOI: https://doi.org/10.1007/978-1-4614-5456-4_6

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