title: Stability of IgG isotypes in serum.
abstract: Drug development from early discovery to late stage commercialization is a long arduous process where a number of factors are taken into consideration when deciding on a particular immunoglobulin isotype for a therapeutic purpose. There are no general rules for which isotype is selected; however, prior experiences, effector function and the specific therapy targeted, as well as extensive testing early in development help in pairing the number of candidates. Over 20 monoclonal antibodies are FDA-approved, and most are IgG1 isotype, although a number of non-IgG1 molecules have been approved recently and the number in development is on the rise. Analytical techniques that examine the physicochemical properties of a molecule provide vital information on the stability and efficacy of candidate antibody therapeutics, but most of these studies are conducted using standard buffers and under well defined storage conditions. It has recently become apparent that analysis of antibody therapeutics recovered after circulation in blood show altered physicochemical characteristics, and in many instances therapeutic molecules recovered from serum show lower potency. This review examines some of these studies, with a focus on the physicochemical changes observed in the molecules. Technologies that can facilitate rapid screening of candidate antibody therapeutics directly from blood are highlighted. The facts indicate that antibody therapeutic development programs must incorporate understanding of the basic biology of the isotype and its stability in serum, which is the intended environment of the therapeutic.
authors.affiliation: Abbott Bioresearch Center, Worcester, MA, USA. Ivan.Correia@Abbott.com
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Correia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000737:chemistry* / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000097:blood* / Q000737:chemistry* / Q000378:metabolism; D055550:Protein Stability
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes
references.citation: Ann Med. 2009;41(5):322-31
references.pmid: 19234897
references.citation: Anal Biochem. 2006 Feb 15;349(2):197-207
references.pmid: 16360109
references.citation: Pharm Res. 2004 Jun;21(6):897-903
references.pmid: 15212151
references.citation: Anal Chem. 2005 Mar 1;77(5):1432-9
references.pmid: 15732928
references.citation: J Pharm Sci. 1997 Nov;86(11):1250-5
references.pmid: 9383735
references.citation: Immunology. 1999 Aug;97(4):693-8
references.pmid: 10457225
references.citation: Pharm Res. 2005 Aug;22(8):1338-49
references.pmid: 16078144
references.citation: Nat Rev Immunol. 2006 May;6(5):343-57
references.pmid: 16622479
references.citation: Mol Cell Proteomics. 2002 Nov;1(11):845-67
references.pmid: 12488461
references.citation: Biotechnol Prog. 2005 Jan-Feb;21(1):11-6
references.pmid: 15903235
references.citation: Mol Cell. 2001 Apr;7(4):867-77
references.pmid: 11336709
references.citation: J Biol Chem. 2008 Jun 6;283(23):16194-205
references.pmid: 18339624
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 1;850(1-2):285-94
references.pmid: 17182291
references.citation: Clin Exp Immunol. 1996 Nov;106(2):259-64
references.pmid: 8918571
references.citation: Prog Biophys Mol Biol. 1970;21:209-63
references.pmid: 4194548
references.citation: J Chromatogr B Biomed Sci Appl. 2001 Mar 10;752(2):233-45
references.pmid: 11270864
references.citation: Glycobiology. 2009 Mar;19(3):240-9
references.pmid: 18974198
references.citation: Anal Chem. 2005 Sep 15;77(18):6004-11
references.pmid: 16159134
references.citation: Proc Natl Acad Sci U S A. 1982 Jan;79(2):350-4
references.pmid: 6281767
references.citation: Immunology. 2002 Jan;105(1):9-19
references.pmid: 11849310
references.citation: Mol Immunol. 1993 Jan;30(1):105-8
references.pmid: 8417368
references.citation: Biochem J. 1968 Jan;106(1):15-21
references.pmid: 4889360
references.citation: Proc Natl Acad Sci U S A. 1961 Nov 15;47:1751-8
references.pmid: 13889151
references.citation: Nat Biotechnol. 2005 Sep;23(9):1073-8
references.pmid: 16151394
references.citation: J Biol Chem. 2006 Oct 27;281(43):32676-83
references.pmid: 16950786
references.citation: J Pharm Sci. 2008 Jul;97(7):2426-47
references.pmid: 17828757
references.citation: Nat Biotechnol. 2007 Dec;25(12):1369-72
references.pmid: 18066027
references.citation: Biochem J. 1971 Jan;121(2):217-25
references.pmid: 4940472
references.citation: Clin Chem. 1993 Aug;39(8):1590-7
references.pmid: 8353942
references.citation: Nature. 1970 Dec 5;228(5275):930-2
references.pmid: 5482103
references.citation: J Exp Med. 1994 Sep 1;180(3):1087-96
references.pmid: 8064227
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12409-13
references.pmid: 11606750
references.citation: Nature. 1969 Jan 11;221(5176):145-8
references.pmid: 5782707
references.citation: Chem Rev. 2007 Aug;107(8):3601-20
references.pmid: 17636887
references.citation: Nat Rev Drug Discov. 2004 Aug;3(8):711-5
references.pmid: 15286737
references.citation: Biologicals. 2008 Jan;36(1):41-7
references.pmid: 17890101
references.citation: J Pharm Biomed Anal. 2007 Feb 19;43(3):963-72
references.pmid: 17045770
references.citation: Glycobiology. 2007 Jan;17(1):104-18
references.pmid: 17012310
references.citation: Arch Biochem Biophys. 1994 Jul;312(1):180-8
references.pmid: 8031126
references.citation: Eur J Immunol. 1994 Oct;24(10):2429-34
references.pmid: 7925571
references.citation: Nat Rev Immunol. 2004 Feb;4(2):89-99
references.pmid: 15040582
references.citation: Annu Rev Biochem. 1982;51:531-54
references.pmid: 6287920
references.citation: Immunol Today. 1997 Dec;18(12):592-8
references.pmid: 9425738
references.citation: J Pharm Sci. 2008 Feb;97(2):775-90
references.pmid: 17786988
references.citation: Anal Chem. 2009 Sep 1;81(17):7454-9
references.pmid: 19630420
references.citation: Semin Immunol. 2003 Aug;15(4):215-23
references.pmid: 14690046
references.citation: Science. 2007 Sep 14;317(5844):1554-7
references.pmid: 17872445
references.citation: Anal Biochem. 2009 May 15;388(2):279-87
references.pmid: 19289095
references.citation: Anal Biochem. 2010 Feb 1;397(1):37-47
references.pmid: 19766583
references.citation: Nat Biotechnol. 2005 Mar;23(3):291-2
references.pmid: 15765078
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jun 6;837(1-2):35-43
references.pmid: 16644295
references.citation: Cancer Sci. 2009 Sep;100(9):1566-72
references.pmid: 19538497
references.citation: Biotechnol Bioeng. 2008 Feb 15;99(3):652-65
references.pmid: 17680659
references.citation: Mol Cell Proteomics. 2004 Apr;3(4):311-26
references.pmid: 14718574
references.citation: J Pharm Sci. 2009 Oct;98(10):3509-21
references.pmid: 19475547
references.citation: Clin Chem. 1993 Feb;39(2):263-71
references.pmid: 8432015
references.citation: Int Rev Cytol. 1992;137B:221-44
references.pmid: 1478821
references.citation: Anal Biochem. 2009 Jul 1;390(1):1-13
references.pmid: 19103145
references.citation: Biologicals. 2009 Oct;37(5):313-22
references.pmid: 19608432
references.citation: J Immunol. 1997 Mar 1;158(5):2211-7
references.pmid: 9036967
references.citation: Biologicals. 2008 Jan;36(1):49-60
references.pmid: 17728143
references.citation: MAbs. 2010 Jan-Feb;2(1):84-100
references.pmid: 20065640
references.citation: J Lab Clin Med. 2003 Jul;142(1):21-8
references.pmid: 12878982
references.citation: Physiol Rev. 1995 Jul;75(3):591-609
references.pmid: 7624395
references.citation: Mech Ageing Dev. 2002 May;123(9):1269-81
references.pmid: 12020948
references.citation: J Exp Med. 1961 May 1;113:861-84
references.pmid: 13725659
references.citation: Curr Opin Chem Biol. 2006 Oct;10(5):430-6
references.pmid: 16935549
references.citation: J Biol Chem. 2001 Mar 2;276(9):6591-604
references.pmid: 11096108
references.citation: J Biol Chem. 1987 May 15;262(14):6472-7
references.pmid: 3571265
references.citation: Biotechnol Prog. 2005 Mar-Apr;21(2):550-3
references.pmid: 15801797
references.citation: Adv Exp Med Biol. 2005;564:143-8
references.pmid: 16400822
references.citation: Dev Biol (Basel). 2005;122:117-27
references.pmid: 16375256
references.citation: Glycobiology. 2007 May;17(5):529-40
references.pmid: 17331977
references.citation: Protein Sci. 1997 Feb;6(2):407-15
references.pmid: 9041643
references.citation: Nat Biotechnol. 2005 Sep;23(9):1037-9
references.pmid: 16151384
references.citation: Electrophoresis. 2006 Mar;27(5-6):1169-81
references.pmid: 16470776
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):944-9
references.pmid: 11158575
references.citation: J Immunol. 1986 Dec 1;137(11):3566-71
references.pmid: 3782791
references.citation: Mech Ageing Dev. 2004 Apr;125(4):255-7
references.pmid: 15063100
references.citation: Pharm Res. 1992 Nov;9(11):1386-93
references.pmid: 1475223
references.citation: Mol Immunol. 1992 Feb;29(2):213-20
references.pmid: 1542298
references.citation: J Mol Biol. 1968 May 14;33(3):893-906
references.pmid: 4178186
references.citation: MAbs. 2009 Jul-Aug;1(4):332-8
references.pmid: 20073133
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5283-8
references.pmid: 11959979
references.citation: Curr Opin Immunol. 1992 Feb;4(1):49-52
references.pmid: 1317711
references.citation: Methods Cell Biol. 2008;84:143-79
references.pmid: 17964931
references.citation: Proteins. 2007 Nov 1;69(2):369-78
references.pmid: 17607746
references.citation: Nature. 1967 Apr 1;214(5083):92-4
references.pmid: 4166384
references.citation: Nature. 1969 Jan 11;221(5176):149-51
references.pmid: 4882223
references.citation: J Immunol. 2003 Mar 15;170(6):3134-8
references.pmid: 12626570
references.citation: Mol Immunol. 2009 May;46(8-9):1878-82
references.pmid: 19269032
references.citation: J Lab Clin Med. 2000 May;135(5):396-401
references.pmid: 10811054
references.citation: Protein Sci. 2009 Feb;18(2):424-33
references.pmid: 19165723
references.citation: Eur J Pharm Biopharm. 2005 Apr;59(3):389-96
references.pmid: 15760719
references.citation: Mol Immunol. 2001 Jan;38(1):1-8
references.pmid: 11483205
references.citation: Proc Natl Acad Sci U S A. 1970 Jul;66(3):753-7
references.pmid: 5269237
references.citation: Nature. 1988 Apr 7;332(6164):563-4
references.pmid: 2965792
references.citation: Autoimmunity. 2007 Mar;40(2):131-7
references.pmid: 17453712
references.citation: Curr Opin Biotechnol. 2009 Dec;20(6):708-14
references.pmid: 19880308
references.citation: J Biol Chem. 2008 Jun 6;283(23):16206-15
references.pmid: 18339626
references.citation: Br Med Bull. 1963 Sep;19:197-201
references.pmid: 14062509
references.citation: J Biol Chem. 2008 Oct 24;283(43):29266-72
references.pmid: 18713741
references.citation: Proteomics. 2003 Jul;3(7):1345-64
references.pmid: 12872236
references.citation: Biochemistry. 2008 May 6;47(18):5088-100
references.pmid: 18407665
references.citation: Nat Biotechnol. 2009 Aug;27(8):767-71
references.pmid: 19620983
references.citation: Science. 2002 Mar 8;295(5561):1898-901
references.pmid: 11884756