Abstract
Purpose
To quantitate and mathematically characterize the whole-body pharmacokinetics (PK) of different ADC analytes following administration of an MMAE-conjugated ADC in tumor-bearing mice.
Methods
The PK of different ADC analytes (total antibody, total drug, unconjugated drug) was measured following administration of an MMAE-conjugated ADC in tumor-bearing mice. The PK of ADC analytes was compared with the whole-body PK of the antibody and drug obtained following administration of these molecules alone. An ADC PBPK model was developed by linking antibody PBPK model with small-molecule PBPK model, where the drug was assumed to deconjugate in DAR-dependent manner.
Results
Comparison of antibody biodistribution coefficient (ABC) values for total antibody suggests that conjugation of drug did not significantly affect the PK of antibody. Comparison of tissue:plasma AUC ratio (T/P) for the conjugated drug and total antibody suggests that in certain tissues (e.g., spleen) ADC may demonstrate higher deconjugation. It was observed that the tissue distribution profile of the drug can be altered following its conjugation to antibody. For example, MMAE distribution to the liver was found to increase while its distribution to the heart was found to decrease upon conjugation to antibody. MMAE exposure in the tumor was found to increase by ~20-fold following administration as conjugate (i.e., ADC). The PBPK model was able to a priori predict the PK of all three ADC analytes in plasma, tissues, and tumor reasonably well.
Conclusions
The ADC PBPK model developed here serves as a platform for translational and clinical investigations of MMAE containing ADCs.
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References
Leung D, Wurst JM, Liu T, Martinez RM, Datta-Mannan A, Feng Y. Antibody Conjugates-Recent Advances and Future Innovations. Antibodies (Basel). 2020;9(1):2.
Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019;394(10200):793–804.
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.
Kaur S, Xu K, Saad OM, Dere RC, Carrasco-Triguero M. Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics. Bioanalysis. 2013;5(2):201–26.
Shah DK, Barletta F, Betts A, Hansel S. Key bioanalytical measurements for antibody-drug conjugate development: PK/PD modelers' perspective. Bioanalysis. 2013;5(9):989–92.
Gorovits B, Alley SC, Bilic S, Booth B, Kaur S, Oldfield P, Purushothama S, Rao C, Shord S, Siguenza P. Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists antibody-drug conjugate working group position paper. Bioanalysis. 2013;5(9):997–1006.
Kraynov E, Kamath AV, Walles M, Tarcsa E, Deslandes A, Iyer RA, Datta-Mannan A, Sriraman P, Bairlein M, Yang JJ, Barfield M, Xiao G, Escandon E, Wang W, Rock DA, Chemuturi NV, Moore DJ. Current approaches for absorption, distribution, metabolism, and excretion characterization of antibody-drug conjugates: An industry white paper. Drug Metab Dispos. 2016;44(5):617–23.
Shah DK, King LE, Han X, Wentland JA, Zhang Y, Lucas J, Haddish-Berhane N, Betts A, Leal M. 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.
Boswell CA, Mundo EE, Firestein R, Zhang C, Mao W, Gill H, Young C, Ljumanovic N, Stainton S, Ulufatu S, Fourie A, Kozak KR, Fuji R, Polakis P, Khawli LA, Lin K. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2. Br J Pharmacol. 2013;168(2):445–57.
Herbertson RA, Tebbutt NC, Lee FT, MacFarlane DJ, Chappell B, Micallef N, et al. Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers. Clin Cancer Res. 2009;15(21):6709–15.
Yip V, Lee MV, Saad OM, Ma S, Khojasteh SC, Shen B-Q. Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats. J Clin Med. 2021;10(6):1323.
Zuo P. Capturing the magic bullet: pharmacokinetic principles and modeling of antibody-drug conjugates. AAPS J. 2020;22(5):105.
Li C, Chen SC, Chen Y, Girish S, Kaagedal M, Lu D, et al. Impact of Physiologically Based Pharmacokinetics, Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics in the Development of Antibody-Drug Conjugates. J Clin Pharmacol. 2020;60(Suppl 1):S105–s19.
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.
Singh AP, Maass KF, Betts AM, Wittrup KD, Kulkarni C, King LE, Khot A, Shah DK. 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.
Bender B, Leipold DD, Xu K, Shen BQ, Tibbitts J, Friberg LE. A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for treatment of metastatic breast cancer. AAPS J. 2014;16(5):994–1008.
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.
Sukumaran S, Gadkar K, Zhang C, Bhakta S, Liu L, Xu K, Raab H, Yu SF, Mai E, Fourie-O’Donohue A, Kozak KR, Ramanujan S, Junutula JR, Lin K. Mechanism-based pharmacokinetic/Pharmacodynamic model for THIOMAB™ drug conjugates. Pharm Res. 2015;32(6):1884–93.
Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE. Structural basis of microtubule destabilization by potent Auristatin anti-Mitotics. PLoS One. 2016;11(8):e0160890.
Zhao B, Zheng S, Alley SC. Physiologically-based pharmacokinetic modeling of an anti-CD70 auristatin antibody-drug conjugate in tumor bearing mice. Conference of Pharmacometrics (ACoP) San Diego, California. 2011.
Khot A, Tibbitts J, Rock D, Shah DK. Development of a translational physiologically based pharmacokinetic model for antibody-drug conjugates: a case study with T-DM1. AAPS J. 2017;19(6):1715–34.
Li L, Chen S-C, Stader F, Rose R, Rao I, Gardner I, et al. Whole Body Physiologically Based Pharmacokinetic Model for Antibody Drug Conjugates - Model Development and Verification in Rats. Presented at: Population Approach Group in Europe (PAGE); June 6-9, 2017, Budapest, Hungary.
Chen Y, Samineni D, Mukadam S, Wong H, Shen BQ, Lu D, Girish S, Hop C, Jin JY, Li C. Physiologically based pharmacokinetic modeling as a tool to predict drug interactions for antibody-drug conjugates. Clin Pharmacokinet. 2015;54(1):81–93.
Samineni D, Ding H, Ma F, Shi R, Lu D, Miles D, Mao J, Li C, Jin J, Wright M, Girish S, Chen Y. Physiologically based pharmacokinetic model-informed drug development for Polatuzumab Vedotin: label for drug-drug interactions without dedicated clinical trials. J Clin Pharmacol. 2020;60(Suppl 1):S120–s31.
Shah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39(1):67–86.
Chang HP, Cheung YK, Shah DK. Whole-body pharmacokinetics and physiologically based pharmacokinetic model for monomethyl Auristatin E (MMAE). J Clin Med. 2021;10(6):1332.
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.
Chang HP, Kim SJ, Shah DK. Whole-body pharmacokinetics of antibody in mice determined using enzyme-linked immunosorbent assay and derivation of tissue interstitial concentrations. J Pharm Sci. 2020;110:446–57.
Meyer DW, Bou LB, Shum S, Jonas M, Anderson ME, Hamilton JZ, Hunter JH, Wo SW, Wong AO, Okeley NM, Lyon RP. An in vitro assay using cultured Kupffer cells can predict the impact of drug conjugation on in vivo antibody pharmacokinetics. Mol Pharm. 2020;17(3):802–9.
Kamath AV, Iyer S. Preclinical pharmacokinetic considerations for the development of antibody drug conjugates. Pharm Res. 2015;32(11):3470–9.
Ponte JF, Sun X, Yoder NC, Fishkin N, Laleau R, Coccia J, Lanieri L, Bogalhas M, Wang L, Wilhelm S, Widdison W, Pinkas J, Keating TA, Chari R, Erickson HK, Lambert JM. Understanding how the stability of the thiol-Maleimide linkage impacts the pharmacokinetics of lysine-linked antibody-Maytansinoid conjugates. Bioconjug Chem. 2016;27(7):1588–98.
Shen BQ, Bumbaca D, Yue Q, Saad O, Tibbitts J, Khojasteh SC, Girish S. Non-clinical disposition and metabolism of DM1, a component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley rats. Drug Metab Lett. 2015;9(2):119–31.
Wagh A, Song H, Zeng M, Tao L, Das TK. Challenges and new frontiers in analytical characterization of antibody-drug conjugates. MAbs. 2018;10(2):222–43.
Mills BJ, Kruger T, Bruncko M, Zhang X, Jameel F. Effect of linker-drug properties and conjugation site on the physical stability of ADCs. J Pharm Sci. 2020;109(5):1662–72.
Wei C, Zhang G, Clark T, Barletta F, Tumey LN, Rago B, Hansel S, Han X. Where did the linker-payload go? A quantitative investigation on the destination of the released linker-payload from an antibody-drug conjugate with a Maleimide linker in plasma. Anal Chem. 2016;88(9):4979–86.
Shen B-Q, 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, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30(2):184–9.
Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, Tsai SP, Schutten M, Xu K, Hristopoulos M, Polakis P. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21(22):5139–50.
Fedoroff S, Doerr J. Effect of human blood serum on tissue cultures. III. A natural cytotoxic system in human blood serum. J Natl Cancer Inst. 1962;29:331–53.
Sorkin MR, Walker JA, Kabaria SR, Torosian NP, Alabi CA. Responsive Antibody Conjugates Enable Quantitative Determination of Intracellular Bond Degradation Rate. Cell Chem Biol. 2019;26(12):1643–51.e4.
Kopp A, Thurber GM. Severing ties: quantifying the payload release from antibody drug conjugates. Cell Chem Biol. 2019;26(12):1631–3.
Bargh JD, Isidro-Llobet A, Parker JS, Spring DR. Cleavable linkers in antibody-drug conjugates. Chem Soc Rev. 2019;48(16):4361–74.
Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol. 2015;33(7):733–5.
Anami Y, Yamazaki CM, Xiong W, Gui X, Zhang N, An Z, Tsuchikama K. Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice. Nat Commun. 2018;9(1):2512.
Jones RD, Taylor AM, Tong EY, Repa JJ. Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse. Drug Metab Dispos. 2013;41(1):40–9.
Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet. 2015;30(1):30–51.
Dorywalska M, Dushin R, Moine L, Farias SE, Zhou D, Navaratnam T, Lui V, Hasa-Moreno A, Casas MG, Tran TT, Delaria K, Liu SH, Foletti D, O'Donnell CJ, Pons J, Shelton DL, Rajpal A, Strop P. Molecular basis of valine-Citrulline-PABC linker instability in site-specific ADCs and its mitigation by linker design. Mol Cancer Ther. 2016;15(5):958–70.
Shah DK, Betts AM. Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. MAbs. 2013;5(2):297–305.
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. Clin Cancer Res. 2004;10(20):7063–70.
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(10):1994–2004.
Vezina HE, Cotreau M, Han TH, Gupta M. Antibody-drug conjugates as Cancer therapeutics: past, present, and future. J Clin Pharmacol. 2017;57(Suppl 10):S11–s25.
Stagg NJ, Shen B-Q, Brunstein F, Li C, Kamath AV, Zhong F, Schutten M, Fine BM. Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: challenges and perspectives in translatability from nonclinical toxicology studies to the clinic. Regul Toxicol Pharmacol. 2016;82:1–13.
Christoffersson G, Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas? Cell Tissue Res. 2018;371(3):415–23.
Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Investig New Drugs. 2018;36(1):121–35.
Zajączkowska R, Kocot-Kępska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci. 2019;20(6):1451.
Areti A, Yerra VG, Naidu VGM, Kumar A. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol. 2014;2:289–95.
Han TH, Zhao B. Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos. 2014;42(11):1914–20.
Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–9.
Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6.
Mandikian D, Figueroa I, Oldendorp A, Rafidi H, Ulufatu S, Schweiger MG, Couch JA, Dybdal N, Joseph SB, Prabhu S, Ferl GZ, Boswell CA. Tissue physiology of Cynomolgus monkeys: cross-species comparison and implications for translational pharmacology. AAPS J. 2018;20(6):107.
Eigenmann MJ, Karlsen TV, Krippendorff BF, Tenstad O, Fronton L, Otteneder MB, Wiig H. Interstitial IgG antibody pharmacokinetics assessed by combined in vivo- and physiologically-based pharmacokinetic modelling approaches. J Physiol. 2017;595(24):7311–30.
Li C, Zhang C, Li Z, Samineni D, Lu D, Wang B, Chen SC, Zhang R, Agarwal P, Fine BM, Girish S. Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human phase 1 studies. MAbs. 2020;12(1):1699768.
CDER FDA. ADCETRIS (brentuximab vedotin) drug approval package, pharmacology review(s). 2011. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125399Orig1s000PharmR.pdf.
Erickson HK, Lambert JM. ADME of antibody–Maytansinoid conjugates. AAPS J. 2012;14(4):799–805.
Sauveur J, Conilh L, Beaumel S, Chettab K, Jordheim LP, Matera EL, Dumontet C. Characterization of T-DM1-resistant breast cancer cells. Pharmacol Res Perspect. 2020;8(4):e00617.
Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117(12):1736–42.
Acknowledgments
We thank Se Jin Kim for editing the manuscript.
Funding
This research was funded by National Institute of General Medical Sciences grant [GM114179] and the Center of Protein Therapeutics at the University at Buffalo. D.K.S is also supported by National Institute of Allergy and Infectious Diseases grant [AI138195] and National Cancer Institute grants [R01CA246785 and R01CA256928].
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Chang, HP., Li, Z. & Shah, D.K. Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice. Pharm Res 39, 1–24 (2022). https://doi.org/10.1007/s11095-021-03162-1
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DOI: https://doi.org/10.1007/s11095-021-03162-1