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Review Article

Approaches to Improve the Translation of Safety, Pharmacokinetics and Therapeutic Index of ADCs

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Received 12 Mar 2024, Accepted 03 May 2024, Accepted author version posted online: 11 May 2024
Accepted author version

Reference

  • Balamkundu S, Liu CF. 2023. Lysosomal-cleavable peptide linkers in antibody-drug conjugates. Biomedicines. 11(11):3080. doi: 10.3390/biomedicines11113080.
  • Beck A, Goetsch L, Dumontet C, Corvaia N. 2017. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 16(5):315–37. doi: 10.1038/nrd.2016.268.
  • Behrens CR, Ha EH, Chinn LL, Bowers S, Probst G, Fitch-Bruhns M, Monteon J, Valdiosera A, Bermudez A, Liao-Chan S et al. 2015. Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs. Mol Pharm. 12(11):3986-98. doi: 10.1021/acs.molpharmaceut.5b00432.
  • Betts A, Clark T, Jasper P, Tolsma J, van der Graaf PH, Graziani EI, Rosfjord E, Sung M, Ma D, Barletta F. 2020. Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1. J Pharmacokinet Pharmacodyn 47 (5): 513-526. doi: 10.1007/s10928-020-09702-3.
  • Bizzaro, D. 2022 Association of Animal Models in the Field of Translational Medicine: Prediction and Validation. Handbook of Animal Models and its Uses in Cancer Research. Singapore: Springer Nature Singapore, 2022. 1-8. doi: 10.1007/978-981-19-1282-5_45-1.
  • Boswell CA, Tesar DB, Mukhyala K, Theil F. P., Fielder P. J., Khawli LA. 2010. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjugate Chemistry. 21(12): 2153–2163. doi: 10.1021/bc100261d.
  • Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O et al. 2012. Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): a randomized, open-label, phase 3 study. Lancet.379(9825):1508-16. doi: 10.1016/S0140-6736(12)60485-1.
  • Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, Raitano A, Nadell R, Liu W, Lortie DR et al. 2016. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 76(10):3003-13. doi: 10.1158/0008-5472.CAN-15-1313.
  • Chuprakov S, Ogunkoya AO, Barfield RM, Bauzon M, Hickle C, Kim YC, Yeo D, Zhang F, Rabuka D, Drake PM. 2021. Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates. Bioconjug Chem. 32(4):746-754. doi: 10.1021/acs.bioconjchem.1c00029.
  • Coats S, Williams M, Kebble B, Dixit R, Tseng L, Yao NS, Tice DA, Soria JC. 2019. Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index. Clin Cancer Res. 25 (18): 5441–5448. doi: 10.1158/1078-0432.ccr-19-0272.
  • Colombo R, Rich JR. 2022. The therapeutic window of antibody drug conjugates: A dogma in need of revision. Cancer Cell. 40(11):1255-1263. doi: 10.1016/j.ccell.2022.09.016.
  • Copeland-Halperin RS, Liu JE, Yu AF. 2019. Cardiotoxicity of HER2-targeted therapies. Curr Opin Cardiol. 34(4):451-458. doi: 10.1097/HCO.0000000000000637.
  • Cote GM, Sawyer DB, Chabner BA. 2012. ERBB2 inhibition and heart failure. N Engl J Med. 367(22):2150-3. doi: 10.1056/NEJMcibr1203156.
  • Dan N, Setua S, Kashyap VK, Khan S, Jaggi M, Yallapu MM, Chauhan SC. 2018. Antibody-drug conjugates for cancer therapy: chemistry to clinical implications. Pharmaceuticals (Basel). 11(2):32-54. doi: 10.3390/ph11020032.
  • Denayer T, Stöhr T, Van Roy M. 2014.Animal models in translational medicine: Validation and prediction. New Horizons in Translational Medicine 2(1): 5-11. doi: 10.1016/j.nhtm.2014.08.001.
  • Dent SF, Morse A, Burnette S, Guha A, Moore H. 2021. Cardiovascular Toxicity of Novel HER2-Targeted Therapies in the Treatment of Breast Cancer. Curr Oncol Rep. 23(11):128. doi: 10.1007/s11912-021-01114-x.
  • Dong S, Nessler I, Kopp A, Rubahamya B, Thurber GM. 2022. Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics. Front Pharmacol. 13:836925. doi: 10.3389/fphar.2022.836925.
  • Dumontet C, Reichert JM., Senter PD, Lambert JM, Beck A. 2023.Antibody–drug conjugates come of age in oncology. Nat Rev Drug Discov 22(8):641-661. doi: 10.1038/s41573-023-00709-2.
  • International Conference on Harmonisation ICH guideline S9 on nonclinical evaluation for anticancer. 2009. S9 step 4 (ich.org).
  • Gerber HP, Gangwar S, Betts A. 2023. Therapeutic index improvement of antibody-drug conjugates. MAbs. 15 (1): 2230618. doi: 10.1080/19420862.2023.2230618.
  • Gogia P, Ashraf H, Bhasin S, Xu Y. 2023. Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers (Basel) 15 (15): 3886. doi: 10.3390/cancers15153886.
  • Gorovits B, Krinos-Fiorotti C. 2013. Proposed mechanism of off-target toxicity for antibody-drug conjugates driven by mannose receptor uptake Cancer Immunology, Immunotherapy. 62 (2): 217-223. doi: 10.1007/s00262-012-1369-3.
  • Griffin RJ, Avery E, Xia CQ. 2022. Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis. Frontiers in Pharmacology 13: 1-7. doi: 10.3389/fphar.2022.830972.
  • Haddish-Berhane N, Shah DK, Ma D, Leal M, Gerber HP, Sapra P, Barton HA, Betts AM. 2013. On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach. Journal of pharmacokinetics and pharmacodynamics 40 (5): 557-571. doi: 10.1007/s10928-013-9329-x.
  • Hamblett, KJ, Le T, Rock BM, Rock DA, Siu S, Huard J N, Conner KP, Milburn RR, O'Neill JW, Tometsko ME, Fanslow WC. 2016. Altering antibody-drug conjugate binding to the neonatal Fc receptor impacts efficacy and tolerability. Molecular Pharmaceutics. 13 (7): 2387–2396. doi: 10.1021/acs.molpharmaceut.6b00153.
  • Heider KH, Mulder JW, Ostermann E, Susani S, Patzelt E, Pals ST, Adolf GR. 1995. Splice variants of the cell surface glycoprotein CD44 associated with metastatic tumour cells are expressed in normal tissues of humans and cynomolgus monkeys. Eur J Cancer. 31A(13-14):2385-91. doi: 10.1016/0959-8049(95)00420-3.
  • Hinrichs MJ, Dixit R. 2015. Antibody Drug Conjugates: Nonclinical Safety Considerations. AAPS J. 17(5):1055-64. doi: 10.1208/s12248-015-9790-0.
  • Hinrichs MJM, Ryan PM, Zheng B, Afif-Rider S, Yu XQ, Gunsior M, Zhong H, Harper J, Bezabeh B, Vashisht K, Rebelatto M, Reed M, Ryan PC, Breen S, Patel N, Chen C, Masterson L, Tiberghien A, Howard PW, Dimasi N, Dixit R. Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates. Clin Cancer Res. 2017 Oct 1;23(19):5858-5868. doi: 10.1158/1078-0432.CCR-17-0219.
  • Jackson D, Stover D. 2015. Using the lessons learned from the clinic to improve the preclinical development of antibody drug conjugates. Pharm Res. 32 (11):3458–3469. doi: 10.1007/s11095-014-1536-7.
  • Junutula JR, Flagella KM, Graham RA, Parsons KL, Ha E, Raab H, Bhakta S, Nguyen T, Dugger DL, Li G, 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(19):4769-78. doi: 10.1158/1078-0432.CCR-10-0987.
  • Kågedal M, Samineni D, Gillespie WR, Lu D, Fine BM, Girish S, Li C, Jin JY. 2019. Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates. CPT Pharmacometrics Syst Pharmacol. 8(8):606-615. doi: 10.1002/psp4.12442.
  • Kesireddy M, Kothapalli SR, Gundepalli SG, Asif S. 2024 A Review of the Current FDA-Approved Antibody-Drug Conjugates: Landmark Clinical Trials and Indications. Pharmaceutical Medicine 38(1):39-54. doi: 10.1007/s40290-023-00505-8.
  • Khera E, Thurber GM. 2018. Pharmacokinetic and immunological considerations for expanding the therapeutic window of next-generation antibody–drug conjugates. BioDrugs 32 (5): 465-480. doi: 10.1007/s40259-018-0302-5.
  • Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. 2020. Antibody-Drug Conjugates: A Comprehensive Review. Mol Cancer Res. 18(1):3-19. doi: 10.1158/1541-7786.MCR-19-0582.
  • Kim SB, Meric-Bernstam F, Kalyan A, Babich A, Liu R, Tanigawa T, Sommer A, Osada M, Reetz F, Laurent D, et al. 2019. First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody-Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer. Target Oncol. 14(5):591-601. doi: 10.1007/s11523-019-00670-4.
  • Kondapalli L. 2016. Cardiotoxicity: An Unexpected Consequence of HER2-Targeted Therapies, Aerucab College of Cardiology. Expert Analysis. American College of Cardiology (acc.org). https://www.acc.org/latest-in-cardiology/articles/2016/06/06/09/32/cardiotoxicity
  • Kong C, Pu J, Zhao Q, Weng W, Ma L, Qian Y, Hu W, Meng X, Meng T. 2023. MTX-13, a novel PTK7-directed antibody-drug conjugate with widened therapeutic index shows sustained tumor regressions for a broader spectrum of PTK7-positive tumors. Molecular Cancer Therapeutics. 22(10): 1128–1143. doi: 10.1158/1535-7163.MCT-23-0164.
  • Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K et al. 2019. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 104(1):113-119. doi: 10.3324/haematol.2018.188888.
  • Lee NK, Su Y, Bidlingmaier S, Liu B. 2019. Manipulation of cell-type selective antibody internalization by a guide-effector bispecific design. Mol Cancer Ther. 18(6): 1092–1103. doi: 10.1158/1535-7163.MCT-18-1313.
  • Lewis GD, Li G, Guo J, Yu SF, Fields CT, Lee G, Zhang D, Dragovich PS, Pillow T, Wei B et al. 2024. The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. Nat Commun 15 (1): 466. doi: 10.1038/s41467-023-44533-z.
  • Lhospice F, Brégeon D, Belmant C, Dennler P, Chiotellis A, Fischer E, Gauthier L, Boëdec A, Rispaud H, Savard-Chambard S et al. 2015. Site-Specific Conjugation of Monomethyl Auristatin E to Anti-CD30 Antibodies Improves Their Pharmacokinetics and Therapeutic Index in Rodent Models. Mol Pharm. 12(6):1863-71. doi: 10.1021/mp500666j.
  • Liao MZ, Lu D, Kågedal M, Miles D, Samineni D, Liu SN, Li C. 2021. Model-Informed Therapeutic Dose Optimization Strategies for Antibody-Drug Conjugates in Oncology: What Can We Learn From US Food and Drug Administration-Approved Antibody-Drug Conjugates? Clin Pharmacol Ther. 110(5):1216-1230. doi: 10.1002/cpt.2278.
  • Lucas AT, Robinson R, Schorzman AN, Piscitelli JA, Razo JF, Zamboni WC. 2019. Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients. Antibodies 8(1): 3. doi: 10.3390/antib8010003.
  • Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, Senter PD. 2015. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nature Biotechnology. 33(7): 733–735. doi: 10.1038/nbt.3212.
  • Mahalingaiah PK, Ciurlionis R, Durbin KR, Yeager RL, Philip BK, Bawa B, Mantena SR, Enright BP, Liguori MJ, Van Vleet TR. 2019. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 200:110-125. doi: 10.1016/j.pharmthera.2019.04.008.
  • Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. 2018. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs. 36(1):121-135. doi: 10.1007/s10637-017-0520-6.Epub 2017 Oct 13.
  • Muller PY, Milton MN. 2012. The determination and interpretation of the therapeutic index in drug development. Nature reviews Drug discovery 11(10): 751-761. doi: 10.1038/nrd3801.
  • Nguyen TD, Bordeau BM, Balthasar JP. 2023. Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability. Cancers (Basel). 15(3):713. doi: 10.3390/cancers15030713.
  • Pillow TH, Schutten M, Yu SF, Ohri R, Sadowsky J, Poon KA, Solis W, Zhong F, Del Rosario G, Go MAT et al. 2017. Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers. Mol Cancer Ther. 16(5):871-878. doi: 10.1158/1535-7163.MCT-16-0641.
  • Prabhu S, Boswell CA, Leipold D, Khawli LA, Li D, Lu D, Theil FP, Joshi A, Lum BL. 2011. Antibody delivery of drugs and radionuclides: factors influencing clinical pharmacology. Ther Deliv. 2(6):769–791. doi: 10.4155/tde.11.41.
  • Saber H, Leighton JK. 2015. An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol. 71(3):444-52. doi: 10.1016/j.yrtph.2015.01.014.
  • Saber H, Simpson N, Ricks TK, Leighton JK. 2019. An FDA oncology analysis of toxicities associated with PBD-containing antibody-drug conjugates. Regul Toxicol Pharmacol. 107:104429. doi: 10.1016/j.yrtph.2019.104429.
  • Sau S, Alsaab HO, Kashaw SK, Tatiparti K, Iyer AK. 2017. Advances in antibody-drug conjugates: A new era of targeted cancer therapy. Drug Discov Today. 22(10):1547-1556. doi: 10.1016/j.drudis.2017.05.011.
  • Schlereth B, Attinger-toller I, Probst P, Bertrand R, Stark R, Santimaria R, Renard E, Fay R, Sharman JP, Grabulovski D, Spycher P. 2022. A CD79b Targeting ADC with Superior Anti-Tumor Activity and Safety Resulting in Significantly Improved Therapeutic Index (TI): Safe and Efficacious CD79b ADC. Blood 140 (Supplement 1): 11568-11569.
  • Schmidt BJ, Pan C, Vezina HE, Sun H, Leipold DD, Gupta M. 2016. Nonclinical pharmacology and mechanistic modeling of antibody-drug conjugates in support of human clinical trials. In: Olivier KJ, Hurvitz SA, editors. Antibody-drug conjugates: fundamentals, drug development, and clinical outcomes to target cancer. Hoboken: Wiley; 2016. p. 207–43. Chapter 9. doi: 10.1002/9781119060727.ch9.
  • Schöffski P, Concin N, Suarez C, Subbiah V, Ando Y, Ruan S, Wagner JP, Mansfield K, Zhu X, Origuchi S et al. 2021. A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events. Oncol Res Treat. 44(10):547-556. doi: 10.1159/000518549.
  • Shah DK, Haddish-Berhane N, Betts A. 2012. Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. Journal of pharmacokinetics and pharmacodynamics 39(6): 643-659. doi: 10.1007/s10928-012-9276-y.
  • Singh AP, Shin YG, Shah DK. 2015. Application of pharmacokinetic/pharmacodynamic modeling and simulation for antibody-drug conjugate development. Pharm Res. 32(11):3508–25. doi: 10.1007/s11095-015-1626-1.
  • Su D, Zhang D. 2021. Linker design impacts antibody-drug conjugate pharmacokinetics and efficacy via modulating the stability and payload release efficiency. Front. Pharmacol., 12: 1-8. doi: 10.3389/fphar.2021.687926.
  • Swaminathan M, Cortes JE. 2023. Update on the role of gemtuzumab-ozogamicin in the treatment of acute myeloid leukemia. Ther Adv Hematol. 14:20406207231154708. doi: 10.1177/20406207231154708.
  • Tijink BM, Buter J, de Bree R, Giaccone G, Lang MS, Staab A, Leemans CR, van Dongen GA. 2006. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res. 12(20 Pt 1):6064-72. doi: 10.1158/1078-0432.CCR-06-0910.
  • Center for Biologics Evaluation and Research (CBER) (2002). Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers: Draft Guidance.
  • Williams M, Spreafico A, Vashisht K, Hinrichs MJ. 2020. Patient Selection Strategies to Maximize Therapeutic Index of Antibody–Drug Conjugates: Prior Approaches and Future Directions. Mol Cancer Ther. 19 (9): 1770–1783. doi: 10.1158/1535-7163.MCT-19-0993.
  • Zhu AZ. 2018. Quantitative translational modeling to facilitate preclinical to clinical efficacy and toxicity translation in oncology. Futur Sci OA. 4(5):306. doi: 10.4155/fsoa-2017-0152.
  • Zhu Y, Liu K, Wang K, Zhu H. Treatment-related adverse events of antibody-drug conjugates in clinical trials: A systematic review and meta-analysis. 2023. Cancer. 129(2):283-295. doi: 10.1002/cncr.34507.

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