Skip to main content

Advertisement

SpringerLink
Log in

ADME of Antibody–Maytansinoid Conjugates

  • Review Article
  • Theme: ADME of Therapeutic Proteins
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radio-labeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack cross-reactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs—particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

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

Similar content being viewed by others

References

  1. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98–107.

    Article  PubMed  CAS  Google Scholar 

  2. Lambert JM. Antibody-maytansinoid conjugates; a new strategy for the treatment of cancer. Drugs Future 2010; 35(6): 471

    Google Scholar 

  3. Chanan-Khan A, W. J, Gharibo M, Jagannath S, Munshi N, Anderson KC, DePaolo D, Lee K, Miller KC, Guild R, et al. Phase 1 Study of IMGN901, used as a monotherapy, in patients with heavily pre-treated CD56-positive multiple myeloma. A preliminary safety and efficacy analysis. Blood (Ash Annual Meeting Abstracts) abstract 2283. 2009.

  4. Fossella F, W. P, Lorigan P, Tolcher A, O’Brien M, O’Keeffe J, Zildjian S, Qin A, O’Leary J, Villalona-Calero M. Investigation of IMGN901 in CD56+ solid tumors: results from a phase I/II trial (study 001) and a phase I trial (study 002). 13th World Conference on Lung Cancer. 2009.

  5. Lambert JM. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol. 2005;5:543–9.

    Article  PubMed  CAS  Google Scholar 

  6. Younes A, G. L, Kim S, Romaguera J, Copeland AR, deCastro Farial S, Kwak L, Fayad L, Hagemeister F, Fanale M, et al. Phase I multi-dose escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by IV infusion every 3 weeks to patients with relapsed/refractory B-cell NHL. Blood (Ash Annual Meeting Abstracts) abstract 585. 2009.

  7. Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698–704.

    Article  PubMed  CAS  Google Scholar 

  8. Bai R, Friedman SJ, Pettit GR, Hamel E. Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol. 1992;43:2637–45.

    Article  PubMed  CAS  Google Scholar 

  9. Singh R, Erickson HK. Antibody–cytotoxic agent conjugates: preparation and characterization. Methods Mol Biol. 2009;525:445–67. xiv.

    Article  PubMed  CAS  Google Scholar 

  10. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347–56.

    Article  PubMed  CAS  Google Scholar 

  11. Kellogg BA, Garrett L, Kovtun Y, Lai KC, Leece B, Miller M, Payne G, Steeves R, Whiteman KR, Widdison W, Xie H, Singh R, Chari RV, Lambert JM, Lutz RJ. 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. 2011;22:717–27.

    Article  PubMed  CAS  Google Scholar 

  12. Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y, Goldmacher VS, Xie H, Steeves RM, Lutz RJ, Zhao R, Wang L, Blattler WA, Chari RV. Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem. 2006;49:4392–408.

    Article  PubMed  CAS  Google Scholar 

  13. Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris Iii HA, Lorusso PM, Yi JH, Saad O, Tong B, Chu YW, Holden S, Joshi A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol. 2012;69(5):1229–40.

    Article  PubMed  CAS  Google Scholar 

  14. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17:6437–47.

    Article  PubMed  CAS  Google Scholar 

  15. Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, Smith L, de Bono J, Schwartz G, Mays T, Jonak ZL, Johnson R, DeWitte M, Martino H, Audette C, Maes K, Chari RV, Lambert JM, Rowinsky EK. Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol. 2003;21:211–22.

    Article  PubMed  CAS  Google Scholar 

  16. Xie H, Blattler WA. In vivo behaviour of antibody-drug conjugates for the targeted treatment of cancer. Expert Opin Biol Ther. 2006;6:281–91.

    Article  PubMed  CAS  Google Scholar 

  17. Junutula JR, Flagella KM, Graham RA, Parsons KL, Ha E, Raab H, Bhakta S, Nguyen T, Dugger DL, Li G, Mai E, Lewis Phillips GD, Hiraragi H, Fuji RN, Tibbitts J, Vandlen R, Spencer SD, Scheller RH, Polakis P, Sliwkowski MX. Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clin Cancer Res. 2010;16:4769–78.

    Article  PubMed  CAS  Google Scholar 

  18. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.

    Article  PubMed  CAS  Google Scholar 

  19. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blattler WA. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426–33.

    Article  PubMed  CAS  Google Scholar 

  20. Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, Gunter B, Audette CA, Audette CA, Gupta M, Pinkas J, Tibbitts J. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 2012;11(5):1133–42.

    Article  PubMed  CAS  Google Scholar 

  21. Stephan JP, Chan P, Lee C, Nelson C, Elliott JM, Bechtel C, Raab H, Xie D, Akutagawa J, Baudys J, Saad O, Prabhu S, Wong WL, Vandlen R, Jacobson F, Ebens A. Anti-CD22-MCC-DM1 and MC-MMAF conjugates: impact of assay format on pharmacokinetic parameters determination. Bioconjug Chem. 2008;19:1673–83.

    Article  PubMed  CAS  Google Scholar 

  22. Alley SC, Benjamin DR, Jeffrey SC, Okeley NM, Meyer DL, Sanderson RJ, Senter PD. Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem. 2008;19:759–65.

    Article  PubMed  CAS  Google Scholar 

  23. Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, Parsons-Reponte KL, Tien J, Yu SF, Mai E, Li D, Tibbitts J, Baudys J, Saad OM, Scales SJ, McDonald PJ, Hass PE, Eigenbrot C, Nguyen T, Solis WA, Fuji RN, Flagella KM, Patel D, Spencer SD, Khawli LA, Ebens A, Wong WL, Vandlen R, Kaur S, Sliwkowski MX, Scheller RH, Polakis P, Junutula JR. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30:184–9.

    Article  PubMed  CAS  Google Scholar 

  24. Fishkin N, Maloney EK, Chari RV, Singh R. A novel pathway for maytansinoid release from thioether linked antibody-drug conjugates (ADCs) under oxidative conditions. Chem Commun (Camb). 2011;47:10752–4.

    Article  CAS  Google Scholar 

  25. Baldwin AD, Kiick KL. Tunable degradation of maleimide-thiol adducts in reducing environments. Bioconjug Chem. 2011;22:1946–53.

    Article  PubMed  CAS  Google Scholar 

  26. Xie H, Audette C, Hoffee M, Lambert JM, Blattler WA. Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther. 2004;308:1073–82.

    Article  PubMed  CAS  Google Scholar 

  27. Mayo F, X. H, Erickson H, Wunderli P, Garrett L, Whitman K, Leece B, Lutz RJ. Pharmacokinetics and Biodistribution of huC242-DM4, an Antibody-Maytansinoid Conjugate That Tartgets CanAg-Postive Tumors, In AACR Meeting. 2005.

  28. Boswell CA, Mundo EE, Zhang C, Bumbaca D, Valle NR, Kozak KR, Fourie A, Chuh J, Koppada N, Saad O, Gill H, Shen BQ, Rubinfeld B, Tibbitts J, Kaur S, Theil FP, Fielder PJ, Khawli LA, Lin K. Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats. Bioconjug Chem. 2011;22:1994–2004.

    Article  PubMed  CAS  Google Scholar 

  29. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, Kissler KM, Bernhardt SX, Kopcha AK, Zabinski RF, Meyer DL, Francisco JA. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10:7063–70.

    Article  PubMed  CAS  Google Scholar 

  30. Sun X, Widdison W, Mayo M, Wilhelm S, Leece B, Chari R, Singh R, Erickson H. Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. Bioconjug Chem. 2011;22:728–35.

    Article  PubMed  CAS  Google Scholar 

  31. Shen BQ, Bumbaca D, Saad O, Yue Q, Pastuskovas CV, Khojasteh SC, Tibbitts J, Kaur S, Wang B, Chu YW, Lorusso PM, Girish S. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine T-DM1: an emphasis on preclinical and clinical catabolism. Curr Drug Metab. 2012 (in press)

  32. Alley SC, Zhang X, Okeley NM, Anderson M, Law CL, Senter PD, Benjamin DR. The pharmacologic basis for antibody–auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330:932–8.

    Article  PubMed  CAS  Google Scholar 

  33. Wright A, Sato Y, Okada T, Chang K, Endo T, Morrison S. In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology. 2000;10:1347–55.

    Article  PubMed  CAS  Google Scholar 

  34. Issell BF, Crooke ST. Maytansine. Cancer Treat Rev. 1978;5:199–207.

    Article  PubMed  CAS  Google Scholar 

  35. Chanan-Khan A, J. S, Heffner T, Avigan D, Lee K, Lutz RJ, Haeder T, Ruehle M, Uherek C, Wartenberg-Demand A, et al. Phase I Study of BT062 given as repeated single dose once every 3 weeks in patients with relapsed or relapsed/refractory multiple myeloma. Blood (Ash Annual Meeting Abstracts) abstract 1862. 2009.

  36. Smith SV. Technology evaluation: huN901-DM1, ImmunoGen. Curr Opin Mol Ther. 2005;7:394–401.

    PubMed  CAS  Google Scholar 

  37. Younes A, F-T A, Bartlett NL, Leonard JP, Lynch C, Kennedy DA, Sievers EL. Multiple complete responses in a Phase 1 dose-escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or refractory CD30-positive lymphomas. Blood (Ash Annual Meeting Abstracts) abstract 2731. 2008.

  38. Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ, Leece BA, Chittenden T, Blattler WA, Goldmacher VS. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66:3214–21.

    Article  PubMed  CAS  Google Scholar 

  39. Jain RK. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng. 1999;1:241–63.

    Article  PubMed  CAS  Google Scholar 

  40. Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008;60:1421–34.

    Article  PubMed  CAS  Google Scholar 

  41. Christiansen J, Rajasekaran AK. Biological impediments to monoclonal antibody-based cancer immunotherapy. Mol Cancer Ther. 2004;3:1493–501.

    PubMed  CAS  Google Scholar 

  42. Sedlacek H-H, Seeman G, Hoffman D, Czech J, Lorenz P, Kolar C, Bosslet K. Antibodies as carriers of cytotoxicity, vol. 43. Marburg: Karger; 1992.

    Google Scholar 

  43. Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB, Tice DA, Chen X. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging. 2007;34:2024–36.

    Article  PubMed  CAS  Google Scholar 

  44. McLarty K, Cornelissen B, Scollard DA, Done SJ, Chun K, Reilly RM. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging. 2009;36:81–93.

    Article  PubMed  CAS  Google Scholar 

  45. Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255:232–40.

    Article  PubMed  CAS  Google Scholar 

  46. Juweid M, Neumann R, Paik C, Perez-Bacete MJ, Sato J, van Osdol W, Weinstein JN. Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. Cancer Res. 1992;52:5144–53.

    PubMed  CAS  Google Scholar 

  47. Blumenthal RD, Fand I, Sharkey RM, Boerman OC, Kashi R, Goldenberg DM. The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: an autoradiographic study. Cancer Immunol Immunother. 1991;33:351–8.

    Article  PubMed  CAS  Google Scholar 

  48. Baker JH, Lindquist KE, Huxham LA, Kyle AH, Sy JT, Minchinton AI. Direct visualization of heterogeneous extravascular distribution of trastuzumab in human epidermal growth factor receptor type 2 overexpressing xenografts. Clin Cancer Res. 2008;14:2171–9.

    Article  PubMed  CAS  Google Scholar 

  49. Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM. SAR3419: an anti-CD19-maytansinoid immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res. 2011;17:6448–58.

    Article  PubMed  CAS  Google Scholar 

  50. Sun X, C. L, Ellis M, Whiteman KR, Pinkas J, Lazar A, Erickson H. Lorvotuzumab mertansine displays favorable pharmacokinetics and tumor delivery in mouse models. AACR-NCI-EORTC Abstract # B195. 2011.

  51. Erickson HK, P. C, Mayo MF, Widdison WC, Audette C, et al. Target-cell processing of the anti-CD19 antibody maytansinoid conjugate SAR3419 in preclinical models. AACR Abstract 5473. 2009.

  52. Erickson HK, M. M, Widdison W, Audette C, Kovtun Y, Chari R, Lutz RJ, Singh R. Linker selection in antibody-maytansinoid conjugates impacts bystander killing in tumor xenograft mouse models. AACR-NCI-EORTC abstract #A86. 2007.

Download references

Author information

Authors and Affiliations

  1. ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts, 02451, USA

    Hans K. Erickson & John M. Lambert

Authors
  1. Hans K. Erickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John M. Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans K. Erickson.

Additional information

Guest Editors: Craig Svensson, Joseph Balthasar, and Frank-Peter Theil

Rights and permissions

Reprints and permissions

About this article

Cite this article

Erickson, H.K., Lambert, J.M. ADME of Antibody–Maytansinoid Conjugates. AAPS J 14, 799–805 (2012). https://doi.org/10.1208/s12248-012-9386-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-012-9386-x

Key words

Search

Navigation