Advertisement

Outlook on Next Generation Technologies and Strategy Considerations for ADC Process Development and Manufacturing

  • Olivier Marcq
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

In the chapter, we review new conjugation technologies from the standpoints of process development and manufacturability and identify potential process hotspots. We briefly review recent progress in conventional conjugation methods and assess, for instance, how new linkers impact process. We also consider antibody modeling and its untapped potential to help design ADCs. We address outsourcing options and trends and provide an overview of single use technologies. Finally, strategies for efficient early process development to ensure CMC consistency across clinical phases and manufacturing scales and ensure readiness for accelerated regulatory approval paths are discussed.

Keywords

ADC Process development Analytical development Scale-up Manufacturing GMP Drug substance Drug product Bulk drug substance DS DP BDS Conjugation technologies Site specific Bridging Thiobridge Conventional cysteine Engineered cysteine Lysine Serine Unnatural amino acid Non-natural amino acid Maleimide Valine-citruline Maleimidocaproyl Thiosuccinimide Haloacetamide Click chemistry Azide Cyclooctyne Glycan Enzyme Enzymatic ligation Transglutaminase Seleno mAb AmbrX Eucode Xpress THIOMAB Glycoconnect Fleximer Hydraspace Auristatin Ozogamicin Talirine Maystantin Quaternary amine Glucuronide Linker Payload Aggregate Aggregation Stability Hydrophobicity DAR Drug antibody ratio Modeling Antibody Probody Extracellular Bispecific TFF HIC Chromatography Tangential flow filtration Regulatory approval CMC Accelerated approval Single use Outsourcing CMO CQA Critical quality attribute Toxicity Cytotoxicity MTD MED Therapeutic index PK PD 

Abbreviations

ADC

Antibody Drug Conjugate

ADC

Antibody Drug Conjugate

BDS

Bulk Drug Subtance

BDS

Bulk Drug Subtance

BLA

Biologics License Application

BLA

Biologics License Application

Cit

Citruline

CMO

Contract Manufacturing Organization

CQA

Critical Quality Attribute

Cys

Cysteine

DAR

Drug Antibody Ratio

DL

Drug Linker

DoE

Design of Experiments

DP

Drug Product

DS

Drug Substance

DSI

Drug Substance Intermediate

FIP

First In Patient

HIPS

Hydrazino-Pictet-Spengler

MED

Minimum Effective Dose

MFG

Manufacturing

MTD

Maximum Tolerated Dose

NNAA

Non-Natural Amino Acid

PBD

Pyrrolobenzodiazepine

PEG

Polyethylene Glycol

PK

Pharmacokinetics

POC

Proof Of Concept

PPE

Personal Protection Equipment

QA

Quality Attribute

QbD

Quality by Design

SME

Subject Matter Expert

SPAAC

Strain promoted azide–alkyne cycloaddition

SUT

Single Use Technology

TFF

Tangential Flow Filtration

TI

Therapeutic Index

UAA

Un-natural Amino Acid

UF/DF

Ultrafiltration/Diafiltration

References

  1. 1.
    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):315–337PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Lehar SM, Pillow T, Xu M, Staben L, Kajihara KK, Vandlen R, DePalatis L, Raab H, Hazenbos WL, Hiroshi Morisaki J, Kim J, Park S, Darwish M, Lee B-C, Hernandez H, Loyet KM, Lupardus P, Fong R, Yan D, Chalouni C, Luis E, Khalfin Y, Plise E, Cheong J, Lyssikatos JP, Strandh M, Koefoed K, Andersen PS, Flygare JA, Wah Tan M, Brown EJ, Mariathasan S (2015) Novel antibody–antibiotic conjugate eliminates intracellular S. aureus. Nature 527:323PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Lim RK, Yu S, Cheng B, Li S, Kim N-J, Cao Y, Chi V, Kim JY, Chatterjee AK, Schultz PG, Tremblay MS, Kazane SA (2015) Targeted delivery of LXR agonist using a site-specific antibody–drug conjugate. Bioconjug Chem 26(11):2211–2222CrossRefGoogle Scholar
  4. 4.
    Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianferani S (2013) Characterization of therapeutic antibodies and related products. Anal Chem 85(2):715–736PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Wakankar A, Chen Y, Gokarn Y, Jacobson FS (2011) Analytical methods for physicochemical characterization of antibody drug conjugates. MAbs 3(2):161–172PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Agarwal P, Bertozzi CR (2015) Site-specific antibody–drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development. Bioconjug Chem 26(2):176–192PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Deonarain MP, Yahioglu G, Stamati I, Marklew J (2015) Emerging formats for next-generation antibody drug conjugates. Expert Opin Drug Discovery 10(5):463–481CrossRefGoogle Scholar
  8. 8.
    Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, Hallett W, Tsou H-R, Upeslacis J, Shochat D, Mountain A, Flowers DA, Bernstein I (2002) Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody−calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem 13(1):47–58PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Chari RVJ (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41(1):98–107PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Hu X, Bortell E, Kotch FW, Xu A, Arve B, Freese S (2017) Development of commercial-ready processes for antibody drug conjugates. Org Process Res Dev 21(4):601–610CrossRefGoogle Scholar
  11. 11.
    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(7):1223PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Lyon RP, Meyer D, Setter JR, Senter PD (2012) Conjugation of anticancer drugs through endogenous monoclonal antibody cysteine residues. Methods Enzymol 502:123PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Wiggins B, Liu-Shin L, Yamaguchi H, Ratnaswamy G (2015) Characterization of cysteine-linked conjugation profiles of immunoglobulin g1 and immunoglobulin G2 antibody–drug conjugates. J Pharm Sci 104(4):1362–1372PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Marcq O (2015) Impact on new linker payloads on drug substance quality attributes and process solutions. BPD Week, Huntington Beach, IBC Life ScienceGoogle Scholar
  15. 15.
    Adem YT, Schwarz KA, Duenas E, Patapoff TW, Galush WJ, Esue O (2014) Auristatin antibody drug conjugate physical instability and the role of drug payload. Bioconjug Chem 25(4):656–664PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Guo J, Kumar S, Chipley M, Marcq O, Gupta D, Jin Z, Tomar DS, Swabowski C, Smith J, Starkey JA, Singh SK (2016) Characterization and higher-order structure assessment of an interchain cysteine-based ADC: impact of drug loading and distribution on the mechanism of aggregation. Bioconjug Chem 27(3):604–615PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Prashad AS, Nolting B, Patel V, Xu A, Arve B, Letendre L (2017) From R&D to clinical supplies. Org Process Res Dev 21(4):590–600CrossRefGoogle Scholar
  18. 18.
    Cumnock K, Tully T, Cornell C, Hutchinson M, Gorrell J, Skidmore K, Chen Y, Jacobson F (2013) Trisulfide modification impacts the reduction step in antibody–drug conjugation process. Bioconjug Chem 24(7):1154–1160PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Liu R, Chen X, Dushime J, Bogalhas M, Lazar AC, Ryll T, Wang L (2017) The impact of trisulfide modification of antibodies on the properties of antibody-drug conjugates manufactured using thiol chemistry. MAbs 9(3):490–497PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Badescu G, Bryant P, Bird M, Henseleit K, Swierkosz J, Parekh V, Tommasi R, Pawlisz E, Jurlewicz K, Farys M, Camper N, Sheng X, Fisher M, Grygorash R, Kyle A, Abhilash A, Frigerio M, Edwards J, Godwin A (2014) Bridging disulfides for stable and defined antibody drug conjugates. Bioconjug Chem 25(6):1124PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Morais M, Nunes JPM, Karu K, Forte N, Benni I, Smith MEB, Caddick S, Chudasama V, Baker JR (2017) Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis. Org Biomol Chem 15(14):2947–2952PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Behrens CR, Ha EH, Chinn LL, Bowers S, Probst G, Fitch-Bruhns M, Monteon J, Valdiosera A, Bermudez A, Liao-Chan S, Wong T, Melnick J, Theunissen J-W, Flory MR, Houser D, Venstrom K, Levashova Z, Sauer P, Migone T-S, van der Horst EH, Halcomb RL, Jackson DY (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):3986–3998PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Hamann PR (2005) Monoclonal antibody-drug conjugates. Expert Opin Ther Pat 15(9):1087CrossRefGoogle Scholar
  24. 24.
    Hinman LM, Hamann PR, Wallace R, Menendez AT, Durr FE, Upeslacis J (1993) Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res 53(14):3336–3342PubMedPubMedCentralGoogle Scholar
  25. 25.
    Rodwell JD, McKearn TJ (1987) Antibody conjugates for the delivery of compounds to target sites. Patent Number US4671958 AGoogle Scholar
  26. 26.
    Zuberbuhler K, Casi G, Bernardes GJL, Neri D (2012) Fucose-specific conjugation of hydrazide derivatives to a vascular-targeting monoclonal antibody in IgG format. Chem Commun 48(56):7100–7102CrossRefGoogle Scholar
  27. 27.
    van Geel R, Wijdeven MA, Heesbeen R, Verkade JMM, Wasiel AA, van Berkel SS, van Delft FL (2015) Chemoenzymatic conjugation of toxic payloads to the globally conserved N-glycan of native mAbs provides homogeneous and highly efficacious antibody–drug conjugates. Bioconjug Chem 26(11):2233–2242PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zhu Z, Ramakrishnan B, Li J, Wang Y, Feng Y, Prabakaran P, Colantonio S, Dyba MA, Qasba PK, Dimitrov DS (2014) Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. MAbs 6(5):1190–1200PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Zeglis BM, Davis CB, Aggeler R, Kang HC, Chen A, Agnew B, Lewis JS (2013) An enzyme-mediated methodology for the site-specific radiolabeling of antibodies based on catalyst-free click chemistry. Bioconjug Chem 24:1057PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Li X, Fang T, Boons G-J (2014) Preparation of well-defined antibody–drug conjugates through glycan remodeling and strain-promoted azide–alkyne cycloadditions. Angew Chem Int Ed 53(28):7179–7182CrossRefGoogle Scholar
  31. 31.
    Zhou Q, Stefano JE, Manning C, Kyazike J, Chen B, Gianolio DA, Park A, Busch M, Bird J, Zheng X, Simonds-Mannes H, Kim J, Gregory RC, Miller RJ, Brondyk WH, Dhal PK, Pan CQ (2014) Site-specific antibody–drug conjugation through glycoengineering. Bioconjug Chem 25(3):510–520PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Stan AC, Radu DL, Casares S, Bona CA, Brumeanu T-D (1999) Antineoplastic efficacy of doxorubicin enzymatically assembled on galactose residues of a monoclonal antibody specific for the carcinoembryonic antigen. Cancer Res 59(1):115–121PubMedPubMedCentralGoogle Scholar
  33. 33.
    Zhong X, Prashad AS, Kriz RW, He T, Somers W, Wang W, Letendre LJ (2017) Capped and uncapped antibody cysteines, and their use in antibody-drug conjugation. Patent Number WO2017025897 A2Google Scholar
  34. 34.
    Dimasi N, Fleming R, Zhong H, Bezabeh B, Kinneer K, Christie RJ, Fazenbaker C, Wu H, Gao C (2017) Efficient preparation of site-specific antibody–drug conjugates using cysteine insertion. Mol Pharm 14(5):1501–1516PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Shinmi D, Nakano R, Mitamura K, Suzuki-Imaizumi M, Iwano J, Isoda Y, Enokizono J, Shiraishi Y, Arakawa E, Tomizuka K, Masuda K (2017) Novel anticarcinoembryonic antigen antibody–drug conjugate has antitumor activity in the existence of soluble antigen. Cancer Med 6(4):798–808PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Shinmi D, Taguchi E, Iwano J, Yamaguchi T, Masuda K, Enokizono J, Shiraishi Y (2016) One step conjugation method for site-specific antibody-drug conjugates through reactive cysteine-engineered antibodies. Bioconjug Chem 27:1324PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Thompson P, Bezabeh B, Fleming R, Pruitt M, Mao S, Strout P, Chen C, Cho S, Zhong H, Wu H, Gao C, Dimasi N (2015) Hydrolytically stable site-specific conjugation at the N-terminus of an engineered antibody. Bioconjug Chem 26(10):2085–2096PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Harris L, Tavares D, Rui L, Maloney E, Wilhelm A, Costoplus J, Archer K, Bogalhas M, Harvey L, Wu R, Chen X, Xu X, Connaughton S, Wang L, Whiteman K, Ab O, Hong E, Widdison W, Shizuka M, Miller M, Pinkas J, Keating T, Chari R, Fishkin N (2015) Abstract 647: SeriMabs: N-terminal serine modification enables modular, site-specific payload incorporation into antibody-drug conjugates (ADCs). Cancer Res 75(15 Supplement):647–647CrossRefGoogle Scholar
  39. 39.
    Jeger S, Zimmermann K, Blanc A, Grünberg J, Honer M, Hunziker P, Struthers H, Schibli R (2010) Site-specific and stoichiometric modification of antibodies by bacterial transglutaminase. Angew Chem Int Ed 49(51):9995–9997CrossRefGoogle Scholar
  40. 40.
    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(3):569PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Lhospice F, Brégeon D, Belmant C, Dennler P, Chiotellis A, Fischer E, Gauthier L, Boëdec A, Rispaud H, Savard-Chambard S, Represa A, Schneider N, Paturel C, Sapet M, Delcambre C, Ingoure S, Viaud N, Bonnafous C, Schibli R, Romagné F (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):1863–1871PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Strop P, Dorywalska MG, Rajpal A, Shelton D, Liu SH, Pons J, Dushin R (2012) Engineered polypeptide conjugates and methods for making thereof using transglutaminase. Patent Number 2,012,059,882Google Scholar
  43. 43.
    Strop P, Liu SH, Dorywalska M, Delaria K, Dushin RG, Tran TT, Ho WH, Farias S, Casas MG, Abdiche Y, Zhou D, Chandrasekaran R, Samain C, Loo C, Rossi A, Rickert M, Krimm S, Wong T, Chin SM, Yu J, Dilley J, Chaparro-Riggers J, Filzen GF, O’Donnell CJ, Wang F, Myers JS, Pons J, Shelton DL, Rajpal A (2013) Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 20(2):161PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Beerli RR, Hell T, Merkel AS, Grawunder U (2015) Sortase enzyme-mediated generation of site-specifically conjugated antibody drug conjugates with high in vitro and in vivo potency. PLoS One 10(7):e0131177PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bellucci JJ, Bhattacharyya J, Chilkoti A (2015) A noncanonical function of sortase enables site-specific conjugation of small molecules to lysine residues in proteins. Angew Chem Int Ed 54(2):441–445Google Scholar
  46. 46.
    Stefan N, Gébleux R, Waldmeier L, Hell T, Escher M, Wolter FI, Grawunder U, Beerli RR (2017) Highly potent, anthracycline-based antibody drug conjugates generated by enzymatic, site-specific conjugation. Mol Cancer Ther 16(5):879–892PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Bruins JJ, Westphal AH, Albada B, Wagner K, Bartels L, Spits H, van Berkel WJH, van Delft FL (2017) Inducible, site-specific protein labeling by tyrosine oxidation–strain-promoted (4 + 2) cycloaddition. Bioconjug Chem 28(4):1189–1193PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Drake PM, Albers AE, Baker J, Banas S, Barfield RM, Bhat AS, de Hart GW, Garofalo AW, Holder P, Jones LC, Kudirka R, McFarland J, Zmolek W, Rabuka D (2014) Aldehyde tag coupled with HIPS chemistry enables the production of ADCs conjugated site-specifically to different antibody regions with distinct in vivo efficacy and PK outcomes. Bioconjug Chem 25(7):1331PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Rabuka D, Rush JS, deHart GW, Wu P, Bertozzi CR (2012) Site-specific chemical protein conjugation using genetically encoded aldehyde tags. Nat Protoc 7(6):1052PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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 109(40):16101–16106PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Yin G, Stephenson HT, Yang J, Li X, Armstrong SM, Heibeck TH, Tran C, Masikat MR, Zhou S, Stafford RL, Yam AY, Lee J, Steiner AR, Gill A, Penta K, Pollitt S, Baliga R, Murray CJ, Thanos CD, McEvoy LM, Sato AK, Hallam TJ (2017) RF1 attenuation enables efficient non-natural amino acid incorporation for production of homogeneous antibody drug conjugates. Sci Rep 7(1):3026PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    VanBrunt MP, Shanebeck K, Caldwell Z, Johnson J, Thompson P, Martin T, Dong H, Li G, Xu H, D’Hooge F, Masterson L, Bariola P, Tiberghien A, Ezeadi E, Williams DG, Hartley JA, Howard PW, Grabstein KH, Bowen MA, Marelli M (2015) Genetically encoded azide containing amino acid in mammalian cells enables site-specific antibody-drug conjugates using click cycloaddition chemistry. Bioconjug Chem 26:2249PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Li X, Nelson CG, Nair RR, Hazlehurst L, Moroni T, Martinez-Acedo P, Nanna AR, Hymel D, Burke TR, Rader C (2017) Stable and potent selenomab-drug conjugates. Cell Chem Biol 24(4):433–442. e436PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Li X, Yang J, Rader C (2014) Antibody conjugation via one and two C-terminal selenocysteines. Methods 65(1):133–138PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Okeley NM, Toki BE, Zhang X, Jeffrey SC, Burke PJ, Alley SC, Senter PD (2013) Metabolic engineering of monoclonal antibody carbohydrates for antibody–drug conjugation. Bioconjug Chem 24(10):1650–1655PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    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 Biotech 26(8):925–932CrossRefGoogle Scholar
  57. 57.
    Dorywalska M, Strop P, Melton-Witt JA, Hasa-Moreno A, Farias SE, Galindo Casas M, Delaria K, Lui V, Poulsen K, Loo C, Krimm S, Bolton G, Moine L, Dushin R, Tran TT, Liu SH, Rickert M, Foletti D, Shelton DL, Pons J, Rajpal A (2015) Effect of attachment site on stability of cleavable antibody drug conjugates. Bioconjug Chem 26(4):650–659PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Jackson D, Atkinson J, Guevara CI, Zhang C, Kery V, Moon S-J, Virata C, Yang P, Lowe C, Pinkstaff J, Cho H, Knudsen N, Manibusan A, Tian F, Sun Y, Lu Y, Sellers A, Jia X-C, Joseph I, Anand B, Morrison K, Pereira DS, Stover D (2014) In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates. PLoS One 9(1):e83865PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Strop P, Delaria K, Foletti D, Witt JM, Hasa-Moreno A, Poulsen K, Casas MG, Dorywalska M, Farias S, Pios A, Lui V, Dushin R, Zhou D, Navaratnam T, Tran T-T, Sutton J, Lindquist KC, Han B, Liu S-H, Shelton DL, Pons J, Rajpal A (2015) Site-specific conjugation improves therapeutic index of antibody drug conjugates with high drug loading. Nat Biotech 33(7):694–696CrossRefGoogle Scholar
  60. 60.
    Müller-Späth T, Ulmer N, Aumann L, Kennedy C, Bavand M (2015) Twin-column cation-exchange chromatography for the purification of biomolecules. BioPharm Int 28(4):32–36Google Scholar
  61. 61.
    Lyons A, King DJ, Owens RJ, Yarranton GT, Millican A, Whittle NR, Adair JR (1990) Site-specific attachment to recombinant antibodies via introduced surface cysteine residues. Protein Eng Des Sel 3:703CrossRefGoogle Scholar
  62. 62.
    Stimmel JB, Merrill BM, Kuyper LF, Moxham CP, Hutchins JT, Fling ME, Kull FC (2000) Site-specific conjugation on serine right-arrow cysteine variant monoclonal antibodies. J Biol Chem 275:30445PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Zhong X, He T, Prashad AS, Wang W, Cohen J, Ferguson D, Tam AS, Sousa E, Lin L, Tchistiakova L, Gatto S, D’Antona A, Luan Y-T, Ma W, Zollner R, Zhou J, Arve B, Somers W, Kriz R (2017) Mechanistic understanding of the cysteine capping modifications of antibodies enables selective chemical engineering in live mammalian cells. J Biotechnol 248(Supplement C):48–58PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Rudra-Ganguly N, Lowe C, Virata C, Leavitt M, Jin L, Mendelsohn B, Snyder J, Aviña H, Zhang C, Russell DL, Mattie M, Yang P, Randhawa B, Liu G, Malik F, Vest M, Abad JD, Kemball CC, Hubert R, Karki S, Anand B, An Z, Grant J, Dick JE, Doñate F, Morrison K, Challita-Eid P, Joseph IB, Pereira DS, Stover DR (2015) AGS62P1, a novel anti-FLT3 antibody drug conjugate, employing site specific conjugation, demonstrates preclinical anti-tumor efficacy in AML tumor and patient derived xenografts. Blood 126(23):3806–3806Google Scholar
  65. 65.
    Rickert M, Strop P, Lui V, Melton-Witt J, Farias SE, Foletti D, Shelton D, Pons J, Rajpal A (2016) Production of soluble and active microbial transglutaminase in Escherichia coli for site-specific antibody drug conjugation. Protein Sci 25(2):442–455PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Chen L, Cohen J, Song X, Zhao A, Ye Z, Feulner CJ, Doonan P, Somers W, Lin L, Chen PR (2016) Improved variants of SrtA for site-specific conjugation on antibodies and proteins with high efficiency. Sci Rep 6:31899PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, Jonas M, Anderson ME, Setter JR, Senter PD (2015) Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotech 33(7):733–735CrossRefGoogle Scholar
  68. 68.
    Kalia J, Raines RT (2007) Catalysis of imido group hydrolysis in a maleimide conjugate. Bioorg Med Chem Lett 17(22):6286–6289PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Tumey LN, Charati M, He T, Sousa E, Ma D, Han X, Clark T, Casavant J, Loganzo F, Barletta F, Lucas J, Graziani EI (2014) Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy. Bioconjug Chem 25:1871PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Fontaine SD, Reid R, Robinson L, Ashley GW, Santi DV (2015) Long-term stabilization of maleimide-thiol conjugates. Bioconjug Chem 26:145PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Lyon RP, Setter JR, Bovee TD, Doronina SO, Hunter JH, Anderson ME, Balasubramanian CL, Duniho SM, Leiske CI, Li F, Senter PD (2014) Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates. Nat Biotechnol 32:1059PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Shen BQ, 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, Solis WA, Fuji RN, Flagella KM, Patel D, Spencer SD, Khawli LA, Ebens A, Wong WL, Vandlen R, Kaur S, Sliwkowski MX, Scheller RH, Polakis P, Junutula JR (2012) Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol 30:184PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Alley SC, Benjamin DR, Jeffrey SC, Okeley NM, Meyer DL, Sanderson RJ, Senter PD (2008) Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem 19(3):759–765PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Badescu G, Bryant P, Swierkosz J, Khayrzad F, Pawlisz E, Farys M, Cong Y, Muroni M, Rumpf N, Brocchini S, Godwin A (2014) A new reagent for stable thiol-specific conjugation. Bioconjug Chem 25(3):460–469PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Toda N, Asano S, Barbas CF (2013) Rapid, stable, chemoselective labeling of thiols with Julia–Kocieński-like reagents: a serum-stable alternative to maleimide-based protein conjugation. Angew Chem Int Ed 52(48):12592–12596CrossRefGoogle Scholar
  76. 76.
    Bernardim B, Cal PMSD, Matos MJ, Oliveira BL, Martínez-Sáez N, Albuquerque IS, Perkins E, Corzana F, Burtoloso ACB, Jiménez-Osés G, Bernardes GJL (2016) Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents. Nat Commun 7:13128PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Chari RVJ, Martell BA, Gross JL, Cook SB, Shah SA, Blättler WA, McKenzie SJ, Goldmacher VS (1992) Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer Res 52(1):127–131PubMedPubMedCentralGoogle Scholar
  78. 78.
    Hamblett KJ, Senter PD, Chace DF, Sun MMC, Lenox J, Cerveny CG, Kissler KM, Bernhardt SX, Kopcha AK, Zabinski RF, Meyer DL, Francisco JA (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10(20):7063–7070PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Maruani A, Richards DA, Chudasama V (2016) Dual modification of biomolecules. Org Biomol Chem 14(26):6165–6178PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Levengood MR, Zhang X, Hunter JH, Emmerton KK, Miyamoto JB, Lewis TS, Senter PD (2017) Orthogonal cysteine protection enables homogeneous multi-drug antibody–drug conjugates. Angew Chem Int Ed 56(3):733–737CrossRefGoogle Scholar
  81. 81.
    Ariyasu S, Hayashi H, Xing B, Chiba S (2017) Site-specific dual functionalization of cysteine residue in peptides and proteins with 2-azidoacrylates. Bioconjug Chem 28(4):897–902PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Maruani A, Smith MEB, Miranda E, Chester KA, Chudasama V, Caddick S (2015) A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy. Nat Commun 6:6645PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Li X, Patterson JT, Sarkar M, Pedzisa L, Kodadek T, Roush WR, Rader C (2015) Site-specific dual antibody conjugation via engineered cysteine and selenocysteine residues. Bioconjug Chem 26(11):2243–2248PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Tang F, Yang Y, Tang Y, Tang S, Yang L, Sun B, Jiang B, Dong J, Liu H, Huang M, Geng M-Y, Huang W (2016) One-pot N-glycosylation remodeling of IgG with non-natural sialylglycopeptides enables glycosite-specific and dual-payload antibody-drug conjugates. Org Biomol Chem 14(40):9501–9518PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Yurkovetskiy AV, Yin M, Bodyak N, Stevenson CA, Thomas JD, Hammond CE, Qin L, Zhu B, Gumerov DR, Ter-Ovanesyan E, Uttard A, Lowinger TB (2015) A polymer-based antibody–vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res 75(16):3365–3372PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Burke PJ, Hamilton JZ, Pires TA, Setter JR, Hunter JH, Cochran JH, Waight AB, Gordon KA, Toki BE, Emmerton KK, Zeng W, Stone IJ, Senter PD, Lyon RP, Jeffrey SC (2016) Development of novel quaternary ammonium linkers for antibody–drug conjugates. Mol Cancer Ther 15:938PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Pillow TH (2017) Novel linkers and connections for antibody–drug conjugates to treat cancer and infectious disease. Pharm Patent Anal 6(1):25–33CrossRefGoogle Scholar
  88. 88.
    Jeffrey SC, Andreyka JB, Bernhardt SX, Kissler KM, Kline T, Lenox JS, Moser RF, Nguyen MT, Okeley NM, Stone IJ, Zhang X, Senter PD (2006) Development and properties of β-glucuronide linkers for monoclonal antibody−drug conjugates. Bioconjug Chem 17(3):831–840PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Zhao RY, Wilhelm SD, Audette C, Jones G, Leece BA, Lazar AC, Goldmacher VS, Singh R, Kovtun Y, Widdison WC, Lambert JM, Chari RVJ (2011) Synthesis and evaluation of hydrophilic linkers for antibody–maytansinoid conjugates. J Med Chem 54(10):3606–3623PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kern JC, Cancilla M, Dooney D, Kwasnjuk K, Zhang R, Beaumont M, Figueroa I, Hsieh S, Liang L, Tomazela D, Zhang J, Brandish PE, Palmieri A, Stivers P, Cheng M, Feng G, Geda P, Shah S, Beck A, Bresson D, Firdos J, Gately D, Knudsen N, Manibusan A, Schultz PG, Sun Y, Garbaccio RM (2016) Discovery of pyrophosphate diesters as tunable, soluble, and bioorthogonal linkers for site-specific antibody–drug conjugates. J Am Chem Soc 138(4):1430–1445PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Mendelsohn BA, Barnscher SD, Snyder JT, An Z, Dodd JM, Dugal-Tessier J (2017) Investigation of hydrophilic auristatin derivatives for use in antibody drug conjugates. Bioconjug Chem 28(2):371–381PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Buck PM, Kumar S, Wang X, Agrawal NJ, Trout BL, Singh SK (2012) Computational methods to predict therapeutic protein aggregation. Methods Mol Biol 899:425PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Jain T, Sun T, Durand S, Hall A, Houston NR, Nett JH, Sharkey B, Bobrowicz B, Caffry I, Yu Y, Cao Y, Lynaugh H, Brown M, Baruah H, Gray LT, Krauland EM, Xu Y, Vásquez M, Wittrup KD (2017) Biophysical properties of the clinical-stage antibody landscape. Proc Natl Acad Sci 114(5):944–949PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lee CC, Perchiacca JM, Tessier PM (2013) Toward aggregation-resistant antibodies by design. Trends Biotechnol 31(11):612–620PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Sharma VK, Patapoff TW, Kabakoff B, Pai S, Hilario E, Zhang B, Li C, Borisov O, Kelley RF, Chorny I, Zhou JZ, Dill KA, Swartz TE (2014) In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability. Proc Natl Acad Sci 111(52):18601–18606PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Tomar DS, Kumar S, Singh SK, Goswami S, Li L (2016) Molecular basis of high viscosity in concentrated antibody solutions: strategies for high concentration drug product development. MAbs 8(2):216–228PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Beckley NS, Lazzareschi KP, Chih H-W, Sharma VK, Flores HL (2013) Investigation into temperature-induced aggregation of an antibody drug conjugate. Bioconjug Chem 24(10):1674–1683PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Guo J, Kumar S, Prashad A, Starkey J, Singh SK (2014) Assessment of physical stability of an antibody drug conjugate by higher order structure analysis: impact of thiol- maleimide chemistry. Pharm Res 31(7):1710–1723PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Li W, Prabakaran P, Chen W, Zhu Z, Feng Y, Dimitrov D (2016) Antibody aggregation: insights from sequence and structure. Antibodies 5(3):19CrossRefGoogle Scholar
  100. 100.
    Voynov V, Chennamsetty N, Kayser V, Wallny HJ, Helk B, Trout BL (2010) Design and application of antibody cysteine variants. Bioconjug Chem 21:385PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Tumey LN, Li F, Rago B, Han X, Loganzo F, Musto S, Graziani EI, Puthenveetil S, Casavant J, Marquette K, Clark T, Bikker J, Bennett EM, Barletta F, Piche-Nicholas N, Tam A, O’Donnell CJ, Gerber HP, Tchistiakova L (2017) Site selection: a case study in the identification of optimal cysteine engineered antibody drug conjugates. AAPS J 19(4):1123–1135PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Tiller KE, Tessier PM (2015) Advances in antibody design. Annu Rev Biomed Eng 17(1):191–216PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14(8):1049–1053PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Marshall DJ, Harried SS, Murphy JL, Hall CA, Shekhani MS, Pain C, Lyons CA, Chillemi A, Malavasi F, Pearce HL, Thorson JS, Prudent JR (2016) Extracellular antibody drug conjugates exploiting the proximity of two proteins. Mol Ther 24(10):1760–1770PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Brinkmann U, Kontermann RE (2017) The making of bispecific antibodies. MAbs 9(2):182–212PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Sheridan C (2016) Despite slow progress, bispecifics generate buzz. Nat Biotechnol 34:1215PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Metz S, Haas AK, Daub K, Croasdale R, Stracke J, Lau W, Georges G, Josel H-P, Dziadek S, Hopfner K-P, Lammens A, Scheuer W, Hoffmann E, Mundigl O, Brinkmann U (2011) Bispecific digoxigenin-binding antibodies for targeted payload delivery. Proc Natl Acad Sci 108(20):8194–8199PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Rossi EA, Goldenberg DM, Chang C-H (2012) The dock-and-lock method combines recombinant engineering with site-specific covalent conjugation to generate multifunctional structures. Bioconjug Chem 23(3):309–323PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, Hinrichs MJ, Bezabeh BZ, Fleming RL, Dimasi N, Feng H, Toader D, Yuan AQ, Xu L, Lin J, Gao C, Wu H, Dixit R, Osbourn JK, Coats SR (2016) A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29:117PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Trail PA, Dubowchik GM, Lowinger TB (2018) Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Therap 181:126–142CrossRefGoogle Scholar
  111. 111.
    de Goeij BECG, Vink T, ten Napel H, Breij ECW, Satijn D, Wubbolts R, Miao D, Parren PWHI (2016) Efficient payload delivery by a bispecific antibody–drug conjugate targeting HER2 and CD63. Mol Cancer Ther 15(11):2688–2697PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    de Goeij BECG, Satijn D, Freitag CM, Wubbolts R, Bleeker WK, Khasanov A, Zhu T, Chen G, Miao D, van Berkel PHC, Parren PWHI (2015) High turnover of tissue factor enables efficient intracellular delivery of antibody–drug conjugates. Mol Cancer Ther 14(5):1130–1140PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Andreev J, Thambi N, Perez Bay AE, Delfino F, Martin J, Kelly MP, Kirshner JR, Rafique A, Kunz A, Nittoli T, MacDonald D, Daly C, Olson W, Thurston G (2017) Bispecific antibodies and antibody–drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther 16(4):681–693PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    DeVay RM, Delaria K, Zhu G, Holz C, Foletti D, Sutton J, Bolton G, Dushin R, Bee C, Pons J, Rajpal A, Liang H, Shelton D, Liu S-H, Strop P (2017) Improved lysosomal trafficking can modulate the potency of antibody drug conjugates. Bioconjug Chem 28(4):1102–1114PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Ducry L (2012) Challenges in the development and manufacturing of antibody–drug conjugates. In: Voynov V, Caravella JA (eds) Therapeutic proteins: methods and protocols. Humana Press, Totowa, pp 489–497CrossRefGoogle Scholar
  116. 116.
    Rohrer T (2012) Consideration for the safe and effective manufacturing of antibody drug conjugates. Chim Oggi 30(5):76Google Scholar
  117. 117.
    Denk R, Flückiger A (2017) ADCs: Anforderungen an GMP und Arbeitsschutz. TechnoPharm 7(1):32–37Google Scholar
  118. 118.
    Ducry L, Suhartono M, Rohrer T (2016) Manufacturing ADCs utilizing full-disposable system. World ADC Summit, Berlin, Hanson WadeGoogle Scholar
  119. 119.
    Stanton D (2014) ADC pipelines drive single-use expansion at Lonza’s clinical facility. 2017Google Scholar
  120. 120.
    Han T (2017) Utilize disposable technologies for ADC manufacture. World ADC Summit, Berlin, Hanson WadeGoogle Scholar
  121. 121.
    Boedeker B, Jones Seymor K (2015) A single-use ADC process: from development to clinical. World ADC Summit, San Diego, Hanson WadeGoogle Scholar
  122. 122.
    Czapkowski B, Steen J, Bortell E, Patel V, Seo YS, Jiang J, Lagliva J, Di Grandi D, Kozlov M (2017) Trial of high efficiency TFF capsule prototype for ADC purification. ADC Rev J Antibody-Drug Conjug.  https://doi.org/10.14229/jadc.2017.11.04.001
  123. 123.
    Dunny E, O’Connor I, Bones J (2017) Containment challenges in HPAPI manufacture for ADC generation. Drug Discov Today 22(6):947–951PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    ISPE Baseline Guide: Volume 7 – Risk-based manufacture of pharmaceutical products (Risk-MaPP). International Society for Pharmaceutical Engineering (2017)Google Scholar
  125. 125.
    Hensgen MI, Stump B (2013) Safe handling of cytotoxic compounds in a biopharmaceutical environment. In: Ducry L (ed) Antibody-drug conjugates. Humana Press, Totowa, pp 133–143CrossRefGoogle Scholar
  126. 126.
    Marcq O (2017) Robustly outsource and transfer ADC technology. World ADC Summit, Berlin, Hanson WadeGoogle Scholar
  127. 127.
    Marcq O (2017) ADC safety and toxicity: technology choices and importance of process development to control safety related CQAs. In: 5th antibody industrial symposium, ToursGoogle Scholar
  128. 128.
    Turula V (2016) Manufacturing support for antibody drug conjugates: clinical and commercial scenarios. World ADC Summit, Berlin, Hanson WadeGoogle Scholar
  129. 129.
    Krummen L (2013) Lessons learned from two case studies in the FDA QbD biotech pilot. CMC Forum Europe, PragueGoogle Scholar
  130. 130.
    Galush WJ, Wakankar AA (2013) Formulation development of antibody–drug conjugates. In: Ducry L (ed) Antibody-drug conjugates. Humana Press, Totowa, pp 217–233CrossRefGoogle Scholar
  131. 131.
    Roberts SA, Andrews PA, Blanset D, Flagella KM, Gorovits B, Lynch CM, Martin PL, Kramer-Stickland K, Thibault S, Warner G (2013) Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology. Regul Toxicol Pharmacol 67(3):382–391PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Hinrichs MJM, Dixit R (2015) Antibody drug conjugates: nonclinical safety considerations. AAPS J 17(5):1055–1064PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Kumar S, King LE, Clark TH, Gorovits B (2015) Antibody–drug conjugates nonclinical support: from early to late nonclinical bioanalysis using ligand-binding assays. Bioanalysis 7(13):1605–1617PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Brachet G, Respaud R, Arnoult C, Henriquet C, Dhommee C, Viaud-Massuard MC, Heuze-Vourc’h N, Joubert N, Pugniere M, Gouilleux-Gruart V (2016) Increment in drug loading on an antibody-drug conjugate increases its binding to the human neonatal Fc receptor in vitro. Mol Pharm 13:1405PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
  136. 136.
    Kelley B, Cromwell M, Jerkins J (2016) Integration of QbD risk assessment tools and overall risk management. Biologicals 44(5):341–351PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Lacoste E (2016) Optimization of ADC process development. World ADC Summit, Berlin, Hanson WadeGoogle Scholar
  138. 138.
    Nilapwar S (2016) Development of robust, scalable site-specific conjugation for monoclonal and bispecific mAbs: a DOE approach. World ADC Summit, San Diego, Hanson WadeGoogle Scholar
  139. 139.
    Agten SM, Dawson PE, Hackeng TM (2016) Oxime conjugation in protein chemistry: from carbonyl incorporation to nucleophilic catalysis. J Pept Sci 22(5):271–279PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Rashidian M, Mahmoodi MM, Shah R, Dozier JK, Wagner CR, Distefano MD (2013) A highly efficient catalyst for oxime ligation and hydrazone–oxime exchange suitable for bioconjugation. Bioconjug Chem 24(3):333–342PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Botzanowski T, Erb S, Hernandez-Alba O, Ehkirch A, Colas O, Wagner-Rousset E, Rabuka D, Beck A, Drake PM, Cianférani S (2017) Insights from native mass spectrometry approaches for top- and middle- level characterization of site-specific antibody-drug conjugates. MAbs 9(5):801–811PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Pan LY, Salas-Solano O, Valliere-Douglass JF (2014) Conformation and dynamics of interchain cysteine-linked antibody-drug conjugates as revealed by hydrogen/deuterium exchange mass spectrometry. Anal Chem 86(5):2657–2664PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Chizkov RR, Million RP (2015) Trends in breakthrough therapy designation. Nat Rev Drug Discov 14(9):597PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Shea M, Ostermann L, Hohman R, Roberts S, Kozak M, Dull R, Allen J, Sigal E (2016) Impact of breakthrough therapy designation on cancer drug development. Nat Rev Drug Discov 15:152PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Dye E, Sturgess A, Maheshwari G, May K, Ruegger C, Ramesh U, Tan H, Cockerill K, Groskoph J, Lacana E, Lee S, Miksinski SP (2016) Examining manufacturing readiness for breakthrough drug development. AAPS PharmSciTech 17(3):529–538PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Dye ES, Groskoph J, Kelley B, Millili G, Nasr M, Potter CJ, Thostesen E, Vermeersch H (2015) CMC considerations when a drug development project is assigned breakthrough therapy status. Pharm Eng 35(1):1–11Google Scholar
  147. 147.
    Jacobson F (2016) Antibody drug conjugates – introduction to a new EBE initiative. CMC Strategy Forum – EBE Satellite Session. ParisGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Agensys, an affiliate of Astellas PharmaSanta MonicaUSA
  2. 2.SutroVaxFoster CityUSA

Personalised recommendations