Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate

Protein Science

Volumn 24, Issue 8, 2015, Pages 1210-1223

  Marcoux, Julien ^a,b,d   Champion, Thierry ^c   Colas, Olivier ^c   Wagner Rousset, Elsa ^c   Corvaïa, Nathalie ^c   Van Dorsselaer, Alain ^a,b   Beck, Alain ^c   Cianférani, Sarah ^a,b  

^a UNIVERSITÉ DE STRASBOURG   (France)

^b CNRS   (France)

^c INSTITUT DE RECHERCHE PIERRE FABRE   (France)

^d INSTITUT DE PHARMACOLOGIE ET DE BIOLOGIE STRUCTURALE   (France)

Author keywords

Antibody drug conjugate (ADCs); Drug to antibody ratio (DAR); Ion mobility mass spectrometry; Kadcyla ; Monoclonal antibody; Native mass spectrometry; T DM1

Indexed keywords

CYSTEINE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; IMIDAZOLE; LYSINE; TRASTUZUMAB; TRASTUZUMAB EMTANSINE; ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; MAYTANSINE; MONOCLONAL ANTIBODY;

ARTICLE; DEGLYCOSYLATION; ION MOBILITY SPECTROMETRY; ISOMER; MASS SPECTROMETRY; MICROTUBULE; MOLECULAR MODEL; PRIORITY JOURNAL; ANALOGS AND DERIVATIVES; CHEMICAL STRUCTURE; CHEMISTRY; HUMAN; ISOMERISM;

ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; HUMANS; IMMUNOCONJUGATES; ISOMERISM; LYSINE; MASS SPECTROMETRY; MAYTANSINE; MODELS, MOLECULAR;

EID: 84938333766     PISSN: 09618368     EISSN: 1469896X     Source Type: Journal    
DOI: 10.1002/pro.2666     Document Type: Article

References (45)

1. Chari RV (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41:98-107.
2. Ornes S (2013) Antibody-drug conjugates. Proc Natl Acad Sci USA 110:13695.
3. Klinguer-Hamour C, Strop P, Shah DK, Ducry L, Xu A, Beck A (2014) World antibody-drug conjugate summit, October 15-16, 2013, San Francisco, CA. MAbs 6:18-29.
4. Beck A (2014) Review of antibody-drug conjugates, methods in molecular biology series: a book edited by Laurent Ducry. MAbs 6:30-33.
5. Beck A, Haeuw JF, Wurch T, Goetsch L, Bailly C, Corvaia N (2010) The next generation of antibody-drug conjugates comes of age. Discov Med 10:329-339.
6. Panowksi S, Bhakta S, Raab H, Polakis P, Junutula JR (2014) Site-specific antibody drug conjugates for cancer therapy. MAbs 6:34-45.
7. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, DeBlanc RL, Gearing RP, Bovee TD, Siegall CB, Francisco JA, Wahl AF, Meyer DL, Senter PD (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21:778-784.
8. Senter PD, 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.
9. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280-9290.
10. Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM (2011) SAR3419: an anti-CD19-maytansinoid immunoconjugate for the treatment of Bcell malignancies. Clin Cancer Res 17:6448-6458.
11. Wang L, Amphlett G, Blattler WA, Lambert JM, Zhang W (2005) Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci 14: 2436-2446.
12. Wakankar A, Chen Y, Gokarn Y, Jacobson FS (2011) Analytical methods for physicochemical characterization of antibody drug conjugates. MAbs 3:161-172.
13. McDonagh CF, Turcott E, Westendorf L, Webster JB, Alley SC, Kim K, Andreyka J, Stone I, Hamblett KJ, Francisco JA, Carter P (2006) Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng Des Sel 19:299-307.
14. Hartley JA, Hamaguchi A, Coffils M, Martin CR, Suggitt M, Chen Z, Gregson SJ, Masterson LA, Tiberghien AC, Hartley JM, Pepper C, Lin TT, Fegan C, Thurston DE, Howard PW (2010) SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity. Cancer Res 70:6849-6858.
15. Hartley JA, Spanswick VJ, Brooks N, Clingen PH, McHugh PJ, Hochhauser D, Pedley RB, Kelland LR, Alley MC, Schultz R, Hollingshead MG, Schweikart KM, Tomaszewski JE, Sausville EA, Gregson SJ, Howard PW, Thurston DE (2004) SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity. Cancer Res 64:6693-6699.
16. Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, French D, Go MA, Jack A, Junutula JR, Koeppen H, Lau J, McBride J, Rawstron A, Shi X, Yu N, Yu SF, Yue P, Zheng B, Ebens A, Polson AG (2009) Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 114:2721-2729.
17. Jeffrey SC, Burke PJ, Lyon RP, Meyer DW, Sussman D, Anderson M, Hunter JH, Leiske CI, Miyamoto JB, Nicholas ND, Okeley NM, Sanderson RJ, Stone IJ, Zeng W, Gregson SJ, Masterson L, Tiberghien AC, Howard PW, Thurston DE, Law CL, Senter PD (2013) A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology. Bioconjug Chem 24:1256-1263.
18. Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS, Lu Y, Meng YG, Ng C, Yang J, Lee CC, Duenas E, Gorrell J, Katta V, Kim A, McDorman K, Flagella K, Venook R, Ross S, Spencer SD, Lee Wong W, Lowman HB, Vandlen R, Sliwkowski MX, Scheller RH, Polakis P, Mallet W (2008) Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 26:925-932.
19. Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP, Zeng W, Harrington KH, Klussman K, Westendorf L, Meyer D, Bernstein ID, Senter PD, Benjamin DR, Drachman JG, McEarchern JA (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.
20. Dennler P, Chiotellis A, Fischer E, Bregeon D, Belmant C, Gauthier L, Lhospice F, Romagne F, Schibli R (2014) Transglutaminase-based chemo-enzymatic conjugation approach yields homogeneous antibody-drug conjugates. Bioconjug Chem 25:569-578.
21. Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim CH, Kazane SA, Halder R, Forsyth JS, Santidrian AF, Stafin K, Lu Y, Tran H, Seller AJ, Biroc SL, Szydlik A, Pinkstaff JK, Tian F, Sinha SC, Felding-Habermann B, Smider VV, Schultz PG (2012) Synthesis of site-specific antibody-drug conjugates using unnatural amino acids. Proc Natl Acad Sci USA 109:16101-16106.
22. Smith EL, Giddens JP, Iavarone AT, Godula K, Wang LX, Bertozzi CR (2014) Chemoenzymatic Fc glycosylation via engineered aldehyde tags. Bioconjug Chem 25: 788-795.
23. Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianferani S (2013) Characterization of therapeutic antibodies and related products. Anal Chem 85:715-736.
24. Debaene F, Boeuf A, Wagner-Rousset E, Colas O, Ayoub D, Corvaia N, Van Dorsselaer A, Beck A, Cianferani S (2014) Innovative native MS methodologies for antibody drug conjugate characterization: high resolution native MS and IM-MS for average DAR and DAR distribution assessment. Anal Chem 86:10674-10683.
25. Wagner-Rousset E, Janin-Bussat MC, Colas O, Excoffier M, Ayoub D, Haeuw JF, Rilatt I, Perez M, Corvaia N, Beck A (2014) Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. MAbs 6:173-184.
26. Janin-Bussat MC, Dillenbourg M, Corvaia N, Beck A, Klinguer-Hamour C. Characterization of antibody drug conjugate positional isomers at cysteine residues by peptide mapping LC-MS analysis. J Chromatogr B, 981-982:9-13.
27. Ouyang J (2013) Drug-to-antibody ratio (DAR) and drug load distribution by hydrophobic interaction chromatography and reversed phase high-performance liquid chromatography. Methods Mol Biol 1045:275-283.
28. Chen Y (2013) Drug-to-antibody ratio (DAR) by UV/Vis spectroscopy. Methods Mol Biol 1045:267-273.
29. Basa L (2013) Drug-to-antibody ratio (DAR) and drug load distribution by LC-ESI-MS. Methods Mol Biol 1045:285-293.
30. Lin J, Lazar AC (2013) Determination of charge heterogeneity and level of unconjugated antibody by imaged cIEF. Methods Mol Biol 1045:295-302.
31. Lu SX, Takach EJ, Solomon M, Zhu Q, Law SJ, Hsieh FY (2005) Mass spectral analyses of labile DOTA-NHS and heterogeneity determination of DOTA or DM1 conjugated anti-PSMA antibody for prostate cancer therapy. J Pharm Sci 94:788-797.
32. Siegel MM, Tabei K, Kunz A, Hollander IJ, Hamann RR, Bell DH, Berkenkamp S, Hillenkamp F (1997) Calicheamicin derivatives conjugated to monoclonal antibodies: determination of loading values and distributions by infrared and UV matrix-assisted laser desorption/ionization mass spectrometry and electrospray ionization mass spectrometry. Anal Chem 69: 2716-2726.
33. Boylan NJ, Zhou W, Proos RJ, Tolbert TJ, Wolfe JL, Laurence JS (2013) Conjugation site heterogeneity causes variable electrostatic properties in Fc conjugates. Bioconjug Chem 24:1008-1016.
34. Kim MT, Chen Y, Marhoul J, Jacobson F (2014) Statistical modeling of the drug load distribution on trastuzumab emtansine (Kadcyla), a lysine-linked antibody drug conjugate. Bioconjug Chem 25:1223-1232.
35. Lazar AC, Wang L, Blattler WA, Amphlett G, Lambert JM, Zhang W (2005) Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometry. Rapid Commun Mass Spectrom 19:1806-1814.
36. Valliere-Douglass JF, Hengel SM, Pan LY. Approaches to interchain cysteine-linked ADC characterization by mass spectrometry. Mol Pharm, in press. DOI: 10.1021/ mp500614p.
37. Thompson NJ, Rosati S, Heck AJ (2014) Performing native mass spectrometry analysis on therapeutic antibodies. Methods 65:11-17.
38. Rose RJ, Damoc E, Denisov E, Makarov A, Heck AJ (2012) High-sensitivity Orbitrap mass analysis of intact macromolecular assemblies. Nat Methods 9: 1084-1086.
39. Hall Z, Politis A, Bush MF, Smith LJ, Robinson CV (2012) Charge-state dependent compaction and dissociation of protein complexes: insights from ion mobility and molecular dynamics. J Am Chem Soc 134:3429-3438.
40. Mehmood S, Marcoux J, Hopper JT, Allison TM, Liko I, Borysik AJ, Robinson CV (2014) Charge reduction stabilizes intact membrane protein complexes for mass spectrometry. J Am Chem Soc 136:17010-17012.
41. Ruotolo BT, Benesch JL, Sandercock AM, Hyung SJ, Robinson CV (2008) Ion mobility-mass spectrometry analysis of large protein complexes. Nat Protoc 3:1139-5211.
42. Pacholarz KJ, Porrini M, Garlish RA, Burnley RJ, Taylor RJ, Henry AJ, Barran PE (2014) Dynamics of intact immunoglobulin G explored by drift-tube ionmobility mass spectrometry and molecular modeling. Angew Chem Int Ed Engl 53:7765-7769.
43. Dere R, Yi JH, Lei C, Saad OM, Huang C, Li Y, Baudys J, Kaur S (2013) PK assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine. Bioanalysis 5:1025-1040.
44. Mesleh MF, Hunter JM, Shvartsburg AA, Schatz GC, Jarrold MF (1996) Structural information from ion mobility measurements: effects of the long-range potential. J Phys Chem 100:16082-16086.
45. Shvartsburg AA, Jarrold MF (1996) An exact hardspheres scattering model for the mobilities of polyatomic ions. Chem Phys Lett 261:86-91.