Chemical structure and concentration of intratumor catabolites determine efficacy of antibody drug conjugates

Drug Metabolism and Disposition

Volumn 44, Issue 9, 2016, Pages 1517-1523

  Zhang, Donglu ^a   Yu, Shang Fan ^a   Ma, Yong ^a   Xu, Keyang ^a   Dragovich, Peter S ^a   Pillow, Thomas H ^a   Liu, Luna ^a   Del Rosario, Geoffrey ^a   He, Jintang ^a   Pei, Zhonghua ^a   Sadowsky, Jack D ^a   Erickson, Hans K ^a   Hop, Cornelis E C A ^a   Khojasteh, S Cyrus ^a  

^a GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY CD22 CYCLOBUTYL PYRROLO[2,1 C][1,4]BENZODIAZEPINE DIMER; ANTIBODY CD22 CYCLOPROPYL PYRROLO[2,1 C][1,4]BENZODIAZEPINE DIMER; ANTIBODY CD22 DISULFIDE PYRROLO[2,1 C][1,4]BENZODIAZEPINE DIMER; ANTIBODY CONJUGATE; UNCLASSIFIED DRUG; BENZODIAZEPINE DERIVATIVE; MONOCLONAL ANTIBODY; PYRROLE DERIVATIVE; PYRROLO(2,1-C)(1,4)BENZODIAZEPINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG CONJUGATION; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG STRUCTURE; DRUG TISSUE LEVEL; FEMALE; HUMAN; HUMAN CELL; IN VIVO STUDY; LIMIT OF QUANTITATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; SINGLE DRUG DOSE; ANIMAL; CHEMISTRY; DRUG SCREENING; METABOLISM; NEOPLASM; SCID MOUSE;

ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; BENZODIAZEPINES; FEMALE; IMMUNOCONJUGATES; MICE; MICE, SCID; NEOPLASMS; PYRROLES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84982179580     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.116.070631     Document Type: Article

References (29)

1. Alley SC and Anderson KE (2013) Analytical and bioanalytical technologies for characterizing antibody-drug conjugates.
2. Bhakta S, Raab H, and Junutula JR (2013) Engineering THIOMABs for site-specific conjugation of thiol-reactive linkers. Methods Mol Biol 1045:189-203.
3. Carter PJ and Senter PD (2008) Antibody-drug conjugates for cancer therapy. Cancer J 14: 154-169.
4. Chari RVJ, Miller ML, and Widdison WC (2014) Antibody-drug conjugates: An emerging concept in cancer therapy.
5. Erickson HK and Lambert JM (2012) ADME of antibody-maytansinoid conjugates. AAPS J 14: 799-805.
6. Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, Gunter B, Audette CA, Gupta M, Pinkas J, and Tibbitts J (2012) The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther 11:1133-112.
7. Hartley JA (2011) The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin Investig Drugs 20:733-744.
8. Jeffrey SC, Burke PJ, Lyon RP, Meyer DW, Sussman D, Anderson M, Hunter JH, Leiske CI, Miyamoto JB, Nicholas ND, et al. (2013) A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology. Bioconjug Chem 24:1256-1263.
9. Jenkins TC, Hurley LH, Neidle S, and Thurston DE (1994) Structure of a covalent DNA minor groove adduct with a pyrrolobenzodiazepine dimer: evidence for sequence-specific interstrand cross-linking. J Med Chem 37:4529-4537.
10. Junutula JR, Flagella KM, Graham RA, Parsons KL, Raab H, Bhakta S, Nguyen T, Dugger DL, Li G, Lewis Phillips GD, 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 16:4769-4778.
11. Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS, et al. (2008) Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 26:925-932.
12. Kamath AV and Iyer S (2015) Preclinical pharmacokinetic considerations for the development of antibody drug conjugates. Pharm Res 32:3470-3479.
13. Khot A, Sharma S, and Shah DK (2015) Integration of bioanalytical measurements using PK-PD modeling and simulation: implications for antibody-drug conjugate development. Bioanalysis 7: 1633-1648.
14. Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP, et al. (2013) SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122:1455-1463.
15. Leal M, Wentland J, Han X, Zhang Y, Rago B, Duriga N, Spriggs F, Kadar E, Song W, McNally J, et al. (2015) Preclinical development of an anti-5T4 antibody-drug conjugate: pharmacokinetics in mice, rats, and NHP and tumor/tissue distribution in mice. Bioconjug Chem 26:2223-2232.
16. Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, Tsai SP, Schutten M, Xu K, Hristopoulos M, et al. (2015) Preclinical development of an anti-NaPi2b (SLC34A2) antibodydrug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res 21: 5139-5150.
17. Pillow TH, Sadowsky JD, Zhang D, Yu SF, Del Rosario G, Xu K, He J, Bhakta S, Ohri R, Kozak KR, et al. (2016) Decoupling stability and release in disulfide bonds with antibody-small molecule conjugates. Chem Sci (Camb), in press.
18. Polakis P (2016) Antibody drug conjugates for cancer therapy. Pharmacol Rev 68:3-19.
19. Polson AG, Williams M, Gray AM, Fuji RN, Poon KA, McBride J, Raab H, Januario T, Go M, Lau J, et al. (2010) Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma. Leukemia 24:1566-1573.
20. Rahman KM, Thompson AS, James CH, Narayanaswamy M, and Thurston DE (2009) The pyrrolobenzodiazepine dimer SJG-136 forms sequence-dependent intrastrand DNA cross-links and monoalkylated adducts in addition to interstrand cross-links. J Am Chem Soc 131: 13756-13766.
21. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, Escarpe PA, Hampl J, Laysang A, et al. (2015) A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136.
22. Senter PD and Sievers EL (2012) The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 30: 631-637.
23. Shah DK, King LE, Han X, Wentland J-A, Zhang Y, Lucas J, Haddish-Berhane N, Betts A, and Leal M (2014) A priori prediction of tumor payload concentrations: preclinical case study with an auristatin-based anti-5T4 antibody-drug conjugate. AAPS J 16:452-463.
24. Shen B-Q, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, Parsons-Reponte KL, Tien J, Yu S-F, Mai E, et al. (2012) Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol 30:184-189.
25. Singh AP, Shin YG, and Shah DK (2015) Application of pharmacokinetic-pharmacodynamic modeling and simulation for antibody-drug conjugate development. Pharm Res 32:3508-3525.
26. Wang J, Gu H, Liu A, Kozhich A, Rangan V, Myler H, Luo L, Wong R, Sun H, Wang B, et al. (2016) Antibody-drug conjugate bioanalysis using LB-LC-MS/MS hybrid assays: strategies, methodology and correlation to ligand-binding assays. Bioanalysis 8:1383-1401.
27. Xu K, Liu L, Maia M, Li J, Lowe J, Song A, and Kaur S (2014) A multiplexed hybrid LC-MS/MS pharmacokinetic assay to measure two co-administered monoclonal antibodies in a clinical study. Bioanalysis 6:1781-1794.
28. Xu K, Liu L, Saad OM, Baudys J, Williams L, Leipold D, Shen B, Raab H, Junutula JR, Kim A, et al. (2011) Characterization of intact antibody-drug conjugates from plasma/serum in vivo by affinity capture capillary liquid chromatography-mass spectrometry. Anal Biochem 412:56-66.
29. Zhang D, Pillow T, Ma Y, Cruz-Chuh J, Kozak KR, Sadowsky JD, Lewis Phillips GD, Guo J, Darwish M, Fan P, et al. (2016) Linker immolation determines cell killing activity of disulfidelinked pyrrolobenzodiazepine antibody drug conjugates. ACS Med Chem Lett, submitted.