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Antibody Coadministration as a Strategy to Overcome Binding-Site Barrier for ADCs: a Quantitative Investigation

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Abstract

It has been proposed that the binding-site barrier (BSB) for antibody-drug conjugates (ADCs) can be overcome with the help of antibody coadministration. However, broad utility of this strategy remains in question. Consequently, here, we have conducted in vivo experiments and pharmacokinetics-pharmacodynamics (PK-PD) modeling and simulation (M&S) to further evaluate the antibody coadministration hypothesis in a quantitative manner. Two different Trastuzumab-based ADCs, T-DM1 (no bystander effect) and T-vc-MMAE (with a bystander effect), were evaluated in high-HER2 (N87) and low-HER2 (MDA-MB-453) expressing tumors, with or without the coadministration of 1, 3, or 8-fold higher Trastuzumab. The tumor growth inhibition (TGI) data was quantitatively characterized using a semi-mechanistic PK-PD model to determine the nature of drug interaction for each coadministration regimen, by estimating the interaction parameter ψ. It was found that the coadministration strategy improved ADC efficacy under certain conditions and had no impact on ADC efficacy in others. The benefit was more pronounced for N87 tumors with very high antigen expression levels where the effect on treatment was synergistic (a synergistic drug interaction, ψ = 2.86 [2.6–3.12]). The benefit was diminished in tumor with lower antigen expression (MDA-MB-453) and payload with bystander effect. Under these conditions, the coadministration regimens resulted in an additive or even less than additive benefit (ψ ≤ 1). As such, our results suggest that while antibody coadministration may be helpful for ADCs in certain circumstances, one should not broadly apply this strategy to all the scenarios without first identifying the costs and benefits of this approach.

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References

  1. 1.

    Singh AP, Maass KF, Betts AM, Wittrup KD, Kulkarni C, King LE, et al. Evolution of antibody- drug conjugate tumor disposition model to predict preclinical tumor pharmacokinetics of Trastuzumab-emtansine (T-DM1). AAPS J. 2016;18(4):861–75.

  2. 2.

    Teicher BA. Antibody drug conjugates. Curr Opin Oncol. 2014;26(5):476–83.

  3. 3.

    Teicher BA, Chari RV. Antibody conjugate therapeutics: challenges and potential. Clin Cancer Res. 2011;17(20):6389–97.

  4. 4.

    Schumacher D, Hackenberger CP, Leonhardt H, Helma J. Current status: site-specific antibody drug conjugates. J Clin Immunol. 2016;36(Suppl 1):100–7.

  5. 5.

    Mistri F. Where do ADCs sit in the clinical landscape? Comparison of ADCs with current standard of care: World ADC 2017, Berlin; 2017.

  6. 6.

    Cilliers C, Guo H, Liao J, Christodolu N, Thurber GM. Multiscale modeling of antibody-drug conjugates: connecting tissue and cellular distribution to whole animal pharmacokinetics and potential implications for efficacy. AAPS J. 2016;18(5):1117–30.

  7. 7.

    Pak Y, Pastan I, Kreitman RJ, Lee B. Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model. PLoS One. 2014;9(10):e110716.

  8. 8.

    Pak Y, Zhang Y, Pastan I, Lee B. Antigen shedding may improve efficiencies for delivery of antibody-based anticancer agents in solid tumors. Cancer Res. 2012;72(13):3143–52.

  9. 9.

    Oldham RK, Foon KA, Morgan AC, Woodhouse CS, Schroff RW, Abrams PG, et al. Monoclonal antibody therapy of malignant melanoma: in vivo localization in cutaneous metastasis after intravenous administration. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. n. 1984;2(11):1235–44.

  10. 10.

    Schroff RW, Morgan AC Jr, Woodhouse CS, Abrams PG, Farrell MM, Carpenter BE, et al. Monoclonal antibody therapy in malignant melanoma: factors effecting in vivo localization. J Biol Response Mod. 1987;6(4):457–72.

  11. 11.

    Schroff RW, Woodhouse CS, Foon KA, Oldham RK, Farrell MM, Klein RA, et al. Intratumor localization of monoclonal antibody in patients with melanoma treated with antibody to a 250,000-dalton melanoma-associated antigen. J Natl Cancer Inst. 1985;74(2):299–306.

  12. 12.

    Eary JF, Schroff RW, Abrams PG, Fritzberg AR, Morgan AC, Kasina S, et al. Successful imaging of malignant melanoma with technetium-99m-labeled monoclonal antibodies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 1989;30(1):25–32.

  13. 13.

    Del Vecchio S, Reynolds JC, Carrasquillo JA, Blasberg RG, Neumann RD, Lotze MT, et al. Local distribution and concentration of intravenously injected 131I-9.2.27 monoclonal antibody in human malignant melanoma. Cancer Res. 1989;49(10):2783–9.

  14. 14.

    Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, et al. Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma. Proc Natl Acad Sci U S A. 1985;82(4):1242–6.

  15. 15.

    Murray J, Rosenblum M, Zhang H, Podoloff D, Kasi L, Curley S, et al. Comparative tumor localization of whole immunoglobulin G anticarcinoembryonic antigen monoclonal antibodies IMMU-4 and IMMU-4 F(ab′)2 in colorectal cancer patients. Cancer. 1994;73(3):850s-7.

  16. 16.

    Elias DJ, Hirschowitz L, Kline LE, Kroener JF, Dillman RO, Walker LE, et al. Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma. Cancer Res. 1990;50(13):4154–9.

  17. 17.

    Oosterwijk E, Bander NH, Divgi CR, Welt S, Wakka JC, Finn RD, et al. Antibody localization in human renal cell carcinoma: a phase I study of monoclonal antibody G250. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1993;11(4):738–50.

  18. 18.

    Scott AM, Lee FT, Jones R, Hopkins W, MacGregor D, Cebon JS, et al. A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: Biodistribution, pharmacokinetics, and quantitative tumor uptake. Clinical Cancer Research. 2005;11(13):4810–7.

  19. 19.

    Singh AP, Shah DK. Utility of PK-PD Modeling and simulation to improve decision making for antibody-drug conjugate development. In: Damelin M, editor. Innovations for next-generation antibody-drug conjugates. Cham: Humana Press; 2018. p. 73–97.

  20. 20.

    Singh AP, Shin YG, Shah DK. Application of pharmacokinetic-pharmacodynamic modeling and simulation for antibody-drug conjugate development. Pharm Res. 2015;32(11):3508–25.

  21. 21.

    Cilliers C, Menezes B, Nessler I, Linderman J, Thurber GM. Improved tumor penetration and single-cell targeting of antibody-drug conjugates increases anticancer efficacy and host survival. Cancer Res. 2018;78(3):758–68.

  22. 22.

    Singh AP, Sharma S, Shah DK. Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J Pharmacokinet Pharmacodyn. 2016;43(6):567–82.

  23. 23.

    Koch G, Walz A, Lahu G, Schropp J. Modeling of tumor growth and anticancer effects of combination therapy. J Pharmacokinet Pharmacodyn. 2009;36(2):179–97.

  24. 24.

    Barok M, Tanner M, Koninki K, Isola J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res. 2011;13(2):R46.

  25. 25.

    Singh AP, Shah DK. Measurement and mathematical characterization of cell-level pharmacokinetics of antibody-drug conjugates: a case study with Trastuzumab-vc-MMAE. Drug Metab Dispos. 2017;45(11):1120–32.

  26. 26.

    Singh AP, Shah DK. Application of a PK-PD modeling and simulation-based strategy for clinical translation of antibody-drug conjugates: a case study with Trastuzumab emtansine (T-DM1). AAPS J. 2017;19(4):1054–70.

  27. 27.

    Shah DK, Haddish-Berhane N, Betts A. Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. J Pharmacokinet Pharmacodyn. 2012;39(6):643–59.

  28. 28.

    Shah DK, King LE, Han X, Wentland JA, Zhang Y, Lucas J, et al. A priori prediction of tumor payload concentrations: preclinical case study with an auristatin-based anti-5T4 antibody-drug conjugate. AAPS J. 2014;16(3):452–63.

  29. 29.

    Haddish-Berhane N, Shah DK, Ma D, Leal M, Gerber HP, Sapra P, et al. On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach. J Pharmacokinet Pharmacodyn. 2013;40(5):557–71.

  30. 30.

    Yang J, Mager DE, Straubinger RM. Comparison of two pharmacodynamic transduction models for the analysis of tumor therapeutic responses in model systems. AAPS J. 2010;12(1):1–10.

  31. 31.

    Chan PL, Jacqmin P, Lavielle M, McFadyen L, Weatherley B. The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects. J Pharmacokinet Pharmacodyn. 2011;38(1):41–61.

  32. 32.

    Yamashita-Kashima Y, Iijima S, Yorozu K, Furugaki K, Kurasawa M, Ohta M, et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(15):5060–70.

  33. 33.

    Yamashita-Kashima Y, Shu S, Harada N, Fujimoto-Ouchi K. Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncology reports. 2013;30(3):1087–93.

  34. 34.

    Muchekehu R, Liu D, Horn M, Campbell L, Del Rosario J, Bacica M, et al. The effect of molecular weight, PK, and valency on tumor biodistribution and efficacy of antibody-based drugs. Transl Oncol. 2013;6(5):562–72.

  35. 35.

    Adams G, Schier R, McCall A, Simmons H, Horak E, Alpaugh K, et al. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Research. 2001;61:4750–5.

  36. 36.

    Thurber GM, Wittrup KD. Quantitative spatiotemporal analysis of antibody fragment diffusion and endocytic consumption in tumor spheroids. Cancer Research. 2008;68:3334–41.

  37. 37.

    Abuqayyas L. Evaluation of the mechanistic determinants of antibody exposure in tissues. Buffalo: State University of New York at Buffalo; 2012.

  38. 38.

    Baker J, Lindquist K, Huxham L, Kyle A, Sy J, Minchinton A. Direct visualization of heterogeneous extravascular distribution of trastuzumab in human epidermal growth factor receptor type 2 overexpressing xenografts. Clinical Cancer Research. 2008;14(7):2171–9.

  39. 39.

    Baker JHE, Kyle AH, Reinsberg SA, Moosvi F, Patrick HM, Cran J, et al. Heterogeneous distribution of trastuzumab in HER2-positive xenografts and metastases: role of the tumor microenvironment. Clinical & experimental metastasis. 2018.

  40. 40.

    Khera E, Cilliers C, Bhatnagar S, Thurber G. Computational transport analysis of antibody-drug conjugate bystander effects and payload tumoral distribution: implications for therapy. Mol Syst Des Eng. 2018.

  41. 41.

    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(6):351–8.

  42. 42.

    Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008;60(12):1421–34.

  43. 43.

    Kwan BH, Zhu EF, Tzeng A, Sugito HR, Eltahir AA, Ma B, et al. Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses. The Journal of experimental medicine. 2017;214(6):1679–90.

  44. 44.

    Cao Y, Jusko WJ. Incorporating target-mediated drug disposition in a minimal physiologically- based pharmacokinetic model for monoclonal antibodies. J Pharmacokinet Pharmacodyn. 2014;41(4):375–87.

  45. 45.

    Mager DE. Target-mediated drug disposition and dynamics. Biochemical Pharmacology. 2006;72(1):1–10.

  46. 46.

    Boswell CA, Mundo EE, Zhang C, Stainton SL, Yu SF, Lacap JA, et al. Differential effects of predosing on tumor and tissue uptake of an 111In-labeled anti-TENB2 antibody-drug conjugate. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2012;53(9):1454–61.

  47. 47.

    Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004;10(20):7063–70.

  48. 48.

    Sharma SK, Pourat J, Abdel-Atti D, Carlin SD, Piersigilli A, Bankovich AJ, et al. Noninvasive interrogation of DLL3 expression in metastatic small cell lung cancer. Cancer Res. 2017;77(14):3931–41.

  49. 49.

    Maass KF, Kulkarni C, Quadir MA, Hammond PT, Betts AM, Wittrup KD. A flow cytometric clonogenic assay reveals the single-cell potency of doxorubicin. J Pharm Sci. 2015.

  50. 50.

    Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496–512.

  51. 51.

    Leyland-Jones B, Colomer R, Trudeau ME, Wardley A, Latreille J, Cameron D, et al. Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated. J Clin Oncol. 2010;28(6):960–6.

  52. 52.

    Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast cancer research : BCR. 2014;16(2):209.

  53. 53.

    Hamblett KJ, Jacob AP, Gurgel JL, Tometsko ME, Rock BM, Patel SK, et al. SLC46A3 Is required to transport catabolites of noncleavable antibody maytansine conjugates from the lysosome to the cytoplasm. Cancer Res. 2015;75(24):5329–40.

  54. 54.

    Nessler I, Khera E, Thurber GM. Quantitative pharmacology in antibody-drug conjugate development: armed antibodies or targeted small molecules? Oncoscience. 2018;5(5-6):161–3.

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Acknowledgments

Authors would also like to thank Zhe Li and Farah Al Qaraqhuli for their technical help during TGI studies, and Cornelius Cilliers for helpful comments on the manuscript.

Funding Information

This work was financially supported by the Centre for Protein Therapeutics at University at Buffalo. D.K.S is supported by NIH grant GM114179 and AI138195.

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Correspondence to Dhaval K. Shah.

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Singh, A.P., Guo, L., Verma, A. et al. Antibody Coadministration as a Strategy to Overcome Binding-Site Barrier for ADCs: a Quantitative Investigation. AAPS J 22, 28 (2020). https://doi.org/10.1208/s12248-019-0387-x

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KEY WORDS

  • antibody-drug conjugates
  • cellular disposition
  • microtubule inhibitors
  • Trastuzumab-vc-MMAE
  • tumor PK-PD model