Comprehensive Analysis of the Therapeutic IgG4 Antibody Pembrolizumab: Hinge Modification Blocks Half Molecule Exchange in Vitro and in Vivo

Journal of Pharmaceutical Sciences

Volumn 104, Issue 12, 2015, Pages 4002-4014

  Yang, Xiaoyu ^a   Wang, Fengqiang ^a   Zhang, Ying ^a   Wang, Larry ^a   Antonenko, Svetlana ^a   Zhang, Shuli ^a   Zhang, Yi Wei ^a   Tabrizifard, Mohammad ^a   Ermakov, Grigori ^a   Wiswell, Derek ^a   Beaumont, Maribel ^a   Liu, Liming ^a   Richardson, Daisy ^a   Shameem, Mohammed ^a   Ambrogelly, Alexandre ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

analytical biochemistry; bioanalysis; biotechnology; bispecific antibody; cancer immunotherapy; glycoprotein; half molecule (Fab arm) exchange analysis; IgG4; immunology; pembrolizumab

Indexed keywords

BISPECIFIC ANTIBODY; IMMUNOGLOBULIN FC FRAGMENT; MONOCLONAL ANTIBODY; NATALIZUMAB; PEMBROLIZUMAB; PROGRAMMED DEATH 1 RECEPTOR; IMMUNOGLOBULIN F(AB) FRAGMENT; IMMUNOGLOBULIN G;

AMINO ACID SUBSTITUTION; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBODY DETECTION; ARTICLE; CONTROLLED STUDY; FEMALE; FLUORESCENCE RESONANCE ENERGY TRANSFER; HINGE REGION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MOUSE; NONHUMAN; PROTEIN MODIFICATION; SCID MOUSE; ANIMAL; CHROMATOGRAPHY; IMMUNOASSAY; IMMUNOLOGY; PROCEDURES;

ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; CHROMATOGRAPHY; FEMALE; HUMANS; IMMUNOASSAY; IMMUNOGLOBULIN FAB FRAGMENTS; IMMUNOGLOBULIN FC FRAGMENTS; IMMUNOGLOBULIN G; MICE; MICE, SCID; PROGRAMMED CELL DEATH 1 RECEPTOR;

EID: 84954390191     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.24620     Document Type: Article

References (37)

1. Reichert JM,. 2014. Antibodies to watch in 2014. mAbs 6 (1): 5-14.
2. Reichert JM,. 2012. Which are the antibodies to watch in 2012 ? mAbs 4 (1): 1-3.
3. Reichert JM,. 2013. Which are the antibodies to watch in 2013 ? mAbs 5 (1): 1-4.
4. Brekke OH, Sandlie I,. 2003. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov 2 (1): 52-62.
5. Carter P,. 2001. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1 (2): 118-129.
6. Schuurman J, Graus YF, Labrijn AF, Ruuls S, Parren PW,. 2014. Opening the door to innovation. mAbs 6 (4): 812-819.
7. An Z,. 2010. Monoclonal antibodies-A proven and rapidly expanding therapeutic modality for human diseases. Protein Cell 1 (4): 319-330.
8. Ecker DM, Jones SD, Levine HL,. 2015. The therapeutic monoclonal antibody market. mAbs 7 (1): 9-14.
9. Vidarsson G, Dekkers G, Rispens T,. 2014. IgG subclasses and allotypes: From structure to effector functions. Front Immunol 5: 520.
10. Burton DR, Wilson IA,. 2007. Immunology. Square-dancing antibodies. Science 317 (5844): 1507-1508.
11. Mullard A,. 2015. 2014 FDA drug approvals. Nat Rev Drug Discov 14 (2): 77-81.
12. Wypych J, Li M, Guo A, Zhang Z, Martinez T, Allen MJ, Fodor S, Kelner DN, Flynn GC, Liu YD, Bondarenko PV, Ricci MS, Dillon TM, Balland A,. 2008. Human IgG2 antibodies display disulfide-mediated structural isoforms. J Biol Chem 283 (23): 16194-16205.
13. Yang X, Ambrogelly A,. 2014. Enlarging the repertoire of therapeutic monoclonal antibodies platforms: Domesticating half molecule exchange to produce stable IgG4 and IgG1 bispecific antibodies. Curr Opin Biotechnol 30: 225-229.
14. Bloom JW, Madanat MS, Marriott D, Wong T, Chan SY,. 1997. Intrachain disulfide bond in the core hinge region of human IgG4. Protein Sci 6 (2): 407-415.
15. Schuurman J, Perdok GJ, Gorter AD, Aalberse RC,. 2001. The inter-heavy chain disulfide bonds of IgG4 are in equilibrium with intra-chain disulfide bonds. Mol Immunol 38 (1): 1-8.
16. Aalberse RC, Schuurman J,. 2002. IgG4 breaking the rules. Immunology 105 (1): 9-19.
17. Aalberse RC, Stapel SO, Schuurman J, Rispens T,. 2009. Immunoglobulin G4: An odd antibody. Clin Exp Allergy 39 (4): 469-477.
18. Rispens T, Ooievaar-De Heer P, Vermeulen E, Schuurman J, van der Neut Kolfschoten M, Aalberse RC,. 2009. Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc-Fc interactions. J Immunol 182 (7): 4275-4281.
19. Rispens T, Leeuwen A, Vennegoor A, Killestein J, Aalberse RC, Wolbink GJ, Aarden LA,. 2011. Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody. Anal Biochem 411 (2): 271-276.
20. Labrijn AF, Rispens T, Meesters J, Rose RJ, den Bleker TH, Loverix S, van den Bremer ET, Neijssen J, Vink T, Lasters I, Aalberse RC, Heck AJ, van de Winkel JG, Schuurman J, Parren PW,. 2011. Species-specific determinants in the IgG CH3 domain enable Fab-arm exchange by affecting the noncovalent CH3-CH3 interaction strength. J Immunol 187 (6): 3238-3246.
21. Saphire EO, Stanfield RL, Crispin MD, Parren PW, Rudd PM, Dwek RA, Burton DR, Wilson IA,. 2002. Contrasting IgG structures reveal extreme asymmetry and flexibility. J Mol Biol 319 (1): 9-18.
22. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, De Baets MH, van de Winkel JG, Aalberse RC, Parren PW,. 2007. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317 (5844): 1554-1557.
23. Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, Killestein J, Polman CH, Aalberse RC, Schuurman J, van de Winkel JG, Parren PW,. 2009. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol 27 (8): 767-771.
24. Angal S, King DJ, Bodmer MW, Turner A, Lawson AD, Roberts G, Pedley B, Adair JR,. 1993. A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol Immunol 30 (1): 105-108.
25. Gramer MJ, van den Bremer ET, van Kampen MD, Kundu A, Kopfmann P, Etter E, Stinehelfer D, Long J, Lannom T, Noordergraaf EH, Gerritsen J, Labrijn AF, Schuurman J, van Berkel PH, Parren PW,. 2013. Production of stable bispecific IgG1 by controlled Fab-arm exchange: Scalability from bench to large-scale manufacturing by application of standard approaches. mAbs 5 (6): 962-973.
26. Labrijn AF, Meesters JI, de Goeij BE, van den Bremer ET, Neijssen J, van Kampen MD, Strumane K, Verploegen S, Kundu A, Gramer MJ, van Berkel PH, van de Winkel JG, Schuurman J, Parren PW,. 2013. Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc Natl Acad Sci USA 110 (13): 5145-5150.
27. Schuurman J, Van Ree R, Perdok GJ, Van Doorn HR, Tan KY, Aalberse RC,. 1999. Normal human immunoglobulin G4 is bispecific: It has two different antigen-combining sites. Immunology 97 (4): 693-698.
28. Shapiro MA,. 2010. Regulatory perspectives and expectations of Fc effector function assessment. AAPS NBC. http://mediaserver.aaps.org/meetings/2010NBC/Tuesday/Regulatory-and-Industry-Perspecitves-on-Fc-Effector-Functions/Shapiro.pdf
29. Jin HT, Ahmed R, Okazaki T,. 2011. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol 350: 17-37.
30. Swaika A, Hammond WA, Joseph RW,. 2015. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol 67 (2 Pt A): 4-17.
31. Yang X, Zhang Y, Wang F, Wang L, Richardson D, Shameem M, Ambrogelly A,. 2015. Analysis and purification of IgG4 bispecific hybrid molecules by a mixed-mode chromatography. Anal Biochem 484: 173-179.
32. Rispens T, Ooijevaar-de Heer P, Bende O, Aalberse RC,. 2011. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc 133 (26): 10302-10311.
33. Deng L, Wylie D, Tsao YS, Larkin B, Voloch M, Ling WL,. 2004. Detection and quantification of the human IgG4 half-molecule, HL, from unpurified cell-culture supernatants. Biotechnol Appl Biochem 40 (Pt 3): 261-269.
34. Silva JP, Vetterlein O, Jose J, Peters S, Kirby H,. 2015. The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation. J Biol Chem 290 (9): 5462-5469.
35. Rispens T, den Bleker TH, Aalberse RC,. 2010. Hybrid IgG4/IgG4 Fc antibodies form upon 'Fab-arm' exchange as demonstrated by SDS-PAGE or size-exclusion chromatography. Mol Immunol 47 (7-8): 1592-1594.
36. Stubenrauch K, Wessels U, Regula JT, Kettenberger H, Schleypen J, Kohnert U,. 2010. Impact of molecular processing in the hinge region of therapeutic IgG4 antibodies on disposition profiles in cynomolgus monkeys. Drug Metab Dispos 38 (1): 84-91.
37. Lewis KB, Meengs B, Bondensgaard K, Chin L, Hughes SD, Kjaer B, Lund S, Wang L,. 2009. Comparison of the ability of wild type and stabilized human IgG(4) to undergo Fab arm exchange with endogenous IgG(4)in vitro and in vivo. Mol Immunol 46 (16): 3488-3494.