Preclinical pharmacokinetics, distribution, metabolism and excretion of disitamab vedotin: Original scientific article

Ling Wang; Limeng Zhu; Fengzhu Wang; Lihou Dong; Zhihao Liu; Fang Chen; Jing Jiang

doi:10.5599/admet.2582

Authors

Ling Wang RemeGen Co., Ltd, Yantai 264000, Shandong, China and Rongchang Industry College, 264003, Shandong, China https://orcid.org/0009-0000-9665-2991
Limeng Zhu RemeGen Co., Ltd, Yantai 264000, Shandong, China and Rongchang Industry College, 264003, Shandong, China https://orcid.org/0009-0003-2259-7469
Fengzhu Wang New York University, Grossman School of Medicine, New York, NY, USA https://orcid.org/0009-0002-3758-6263
Lihou Dong United-Power Pharma Tech Co. Ltd, Beijing 102206, China https://orcid.org/0000-0002-4297-7368
Zhihao Liu RemeGen Co., Ltd, Yantai 264000, Shandong, China and Rongchang Industry College, 264003, Shandong, China https://orcid.org/0009-0004-4452-1286
Fang Chen United-Power Pharma Tech Co. Ltd, Beijing 102206, China https://orcid.org/0009-0003-0672-0690
Jing Jiang Department of Pharmacology, Binzhou Medical University, Yantai 264003, Shandong, China and Rongchang Industry College, 264003, Shandong, China https://orcid.org/0009-0000-4246-0644

DOI:

https://doi.org/10.5599/admet.2582

Keywords:

Antibody-drug conjugate, physiological disposition, monomethyl auristatin E (MMAE), mass balance

Abstract

Background and purpose: Disitamab vedotin is an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody (mAb) targeting HER2 conjugated to monomethyl auristatin E(MMAE) via a cleavable dipeptide linker. Experimental approach: The pharmacokinetics, distribution, catabolism/meta-bolism and elimination properties of disitamab vedotin and its payload MMAE were characterized in rats and tumour-bearing mice. Key results: The configured mAb and total antibody showed linear dynamic characteristics. Moreover, the molecular structure of disitamab vedotin effectively reduces the exposure of MMAE, which has a fast clearance. Two radiolabeled probes were developed to track the fate of different components of the disitamab vedotin, including ¹²⁵I labelled antibody and 3H labelled MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes to the tumour-bearing mice and rats, blood, various tissues, and excreta samples were collected and analyzed for radioactivity and to characterize the metabolites/catabolites. Disitamab vedotin and free MMAE (FM) were majorly distributed in tissues and organs with rich blood flow. Moreover, both disitamab vedotin and MMAE have higher and longer exposure in tumour tissue. Disitamab vedotin was mainly eliminated through renal excretion, while the FM was mainly eliminated through the biliary faecal route (>70 %) and a small fraction (<10 %) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with 10 other minor species. Conclusion: These studies provided significant insight into disitamab vedotin pharmacokinetics, distribution, metabolism and elimination properties, which supports the clinical development of disitamab vedotin.

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References

U. Hafeez, S. Parakh, H.K. Gan, A.M. Scott. Antibody-Drug Conjugates for Cancer Therapy. Molecules 25 (2020) 4764. https://doi.org/10.3390/molecules25204764

C. do Pazo, K. Nawaz, R.M. Webster. The oncology market for antibody-drug conjugates. Nat. Rev. Drug Discovery 20 (2021) 583-584. https://doi.org/10.1038/d41573-021-00054-2

J. Jiang, L. Dong, L. Wang, L. Wang, J. Zhang, F. Chen, X. Zhang, M. Huang, S. Li, W. Ma, Q. Xu, C. Huang, J. Fang, C. Wang. HER2-targeted antibody drug conjugates for ovarian cancer therapy. European Journal of Pharmaceutical Sciences 93 (2016) 274-286. https://doi.org/10.1016/j.ejps.2016.08.015

X. Sheng, X. Yan, L. Wang, Y. Shi, X. Yao, H. Luo, B. Shi, J. Liu, Z. He, G. Yu, J. Ying, W. Han, C. Hu, Y. Ling, Z. Chi, C. Cui, L. Si, J. Fang, A. Zhou, J. Guo. Open-label, Multicenter, Phase II Study of RC48-ADC, a HER2-Targeting Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma. Clinical Cancer Research 27 (2021) 43-51. https://doi.org/10.1158/1078-0432.CCR-20-2488

Z. Peng, T. Liu, J. Wei, A. Wang, Y. He, L. Yang, X. Zhang, N. Fan, S. Luo, Z. Li, K. Gu, J. Lu, J. Xu, Q. Fan, R. Xu, L. Zhang, E. Li, Y. Sun, G. Yu, C. Bai, Y. Liu, J. Zeng, J. Ying, X. Liang, N. Xu, C. Gao, Y. Shu, D. Ma, G. Dai, S. Li, T. Deng, Y. Cui, J. Fang, Y. Ba, L. Shen. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Communications 41 (2021) 1173-1182. https://doi.org/10.1002/cac2.12214

Y. Xu, Y. Wang, J. Gong, X. Zhang, Z. Peng, X. Sheng, C. Mao, Q. Fan, Y. Bai, Y. Ba, D. Jiang, F. Yang, C. Qi, J. Li, X. Wang, J. Zhou, M. Lu, Y. Cao, J. Yuan, D. Liu, Z. Wang, J. Fang, L. Shen. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer 24 (2021) 913-925. https://doi.org/10.1007/s10120-021-01168-7

J. Kalmuk, D. Rinder, C. Heltzel, A.C. Lockhart. An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic. Expert Opinion on Drug Discovery 17 (2022) 427-436. https://doi.org/10.1080/17460441.2022.2050692

C. Li, C. Zhang, R. Deng, D. Leipold, D. Li, B. Latifi, Y. Gao, C. Zhang, Z. Li, D. Miles, S.C. Chen, D. Samineni, B. Wang, P. Agarwal, D. Lu, S. Prabhu, S. Girish, A.V. Kamath. Prediction of Human Pharmacokinetics of Antibody-Drug Conjugates from Nonclinical Data. Clinical and Translational Science 12 (2019) 534-544. https://doi.org/10.1111/cts.12649

S.N. Liu, C. Li. Clinical pharmacology strategies in supporting drug development and approval of antibody-drug conjugates in oncology. Cancer Chemotherapy and Pharmacology 87 (2021) 743-765. https://doi.org/10.1007/s00280-021-04250-0

`P.M. Drake, D. Rabuka. Recent Developments in ADC Technology: Preclinical Studies Signal Future Clinical Trends. BioDrugs 31 (2017) 521-531. https://doi.org/10.1007/s40259-017-0254-1

A.V. Kamath, S. Iyer. Challenges and advances in the assessment of the disposition of antibody-drug conjugates. Biopharm. Drug Dispos. 37 (2016) 66-74. https://doi.org/10.1002/bdd.1957

J. Bolleddula, K. Brady, G. Bruin, A. Lee, J.A. Martin, M. Walles, K. Xu, T.Y. Yang, X. Zhu, H. Yu. Absorption, Distribution, Metabolism, and Excretion of Therapeutic Proteins: Current Industry Practices and Future Perspectives. Drug Metabolism and Disposition 50 (2022) 837-845. https://doi.org/10.1124/dmd.121.000461

The U.S. Food and drug administration. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125388Orig1s000PharmR.pdf

V. Yip, M.V. Lee, O.M. Saad, S. Ma, S.C. Khojasteh, B.Q. Shen. Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody-Drug Conjugate in Sprague Dawley Rats. Journal of Clinical Medicine 10 (2021) 1323. https://doi.org/10.3390/jcm10061323

T.H. Han, A.K. Gopal, R. Ramchandren, A. Goy, R. Chen, J.V. Matous, M. Cooper, L.E. Grove, S.C. Alley, C.M. Lynch, O.A. O'Connor. CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies. The Journal of Clinical Pharmacology 53 (2013) 866-877. https://doi.org/10.1002/jcph.116