Different Adaptations of IgG Effector Function in Human and Nonhuman Primates and Implications for Therapeutic Antibody Treatment

被引:80
作者
Warncke, Max [1 ]
Calzascia, Thomas [1 ]
Coulot, Michele [1 ]
Balke, Nicole [1 ]
Touil, Ratiba [1 ]
Kolbinger, Frank [1 ]
Heusser, Christoph [1 ]
机构
[1] Novartis Pharma AG, Novartis Inst Biomed Res, CH-4002 Basel, Switzerland
关键词
FC-GAMMA-RIII; MONOCLONAL-ANTIBODY; BINDING-SITE; IN-VIVO; B-CELLS; RECEPTORS; EXPRESSION; VARIANTS; HETEROGENEITY; SPECIFICITY;
D O I
10.4049/jimmunol.1200090
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Safety of human therapeutic Abs is generally assessed in nonhuman primates. Whereas IgG1 shows identical Fe gamma R interaction and effector function profile in both species, fundamental differences in the IgG2 and IgG4 Ab subclasses were found between the two species. Granulocytes, the main effector cells against IgG2- and IgG4-opsonized bacteria and parasites, do not express Fc gamma RIIIb, but show higher levels of Fc gamma RII in cynomolgus monkey. In humans, IgG2 and IgG4 adapted a silent Fc region with weak binding to Fc gamma R and effector functions, whereas, in contrast, cynomolgus monkey IgG2 and IgG4 display strong effector function as well as differences in IgG4 Fab arm exchange. To balance this shift toward activation, the cynomolgus inhibitory Fc gamma RIIb shows strongly increased affinity for IgG2. In view of these findings, in vitro and in vivo results for human IgG2 and IgG4 obtained in the cynomolgus monkey have to be cautiously interpreted, whereas effector function-related effects of human IgG1 Abs are expected to be predictable for humans. The Journal of Immunology, 2012, 188: 4405-4411.
引用
收藏
页码:4405 / 4411
页数:7
相关论文
共 45 条
[1]   IgG4 breaking the rules [J].
Aalberse, RC ;
Schuurman, J .
IMMUNOLOGY, 2002, 105 (01) :9-19
[2]  
Agrawal A, 2009, ADV EXP MED BIOL, V653, P98
[3]  
Aldrich T., 2005, Amgen, Patent No. [WO 20051047325, 20051047325]
[4]  
BARRETT DJ, 1986, CLIN EXP IMMUNOL, V63, P127
[5]   Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses [J].
Bruhns, Pierre ;
Iannascoli, Bruno ;
England, Patrick ;
Mancardi, David A. ;
Fernandez, Nadine ;
Jorieux, Sylvie ;
Daeron, Marc .
BLOOD, 2009, 113 (16) :3716-3725
[6]   REGULATION OF IGE AND IGG(4) RESPONSES BY ALLERGEN-SPECIFIC T-CELL CLONES TO BEE VENOM PHOSPHOLIPASE A(2) IN-VITRO [J].
CARBALLIDO, JM ;
CARBALLIDOPERRIG, N ;
OBERLISCHRAMMLI, A ;
HEUSSER, CH ;
BLASER, K .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1994, 93 (04) :758-767
[7]   Opinion - Preclinical safety testing of monoclonal antibodies: the significance of species relevance [J].
Chapman, Kathryn ;
Pullen, Nick ;
Graham, Mark ;
Ragan, Ian .
NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (02) :120-126
[8]   IDENTIFICATION OF THE FC-GAMMA RECEPTOR CLASS-I BINDING-SITE IN HUMAN-IGG THROUGH THE USE OF RECOMBINANT IGG1/IGG2 HYBRID AND POINT-MUTATED ANTIBODIES [J].
CHAPPEL, MS ;
ISENMAN, DE ;
EVERETT, M ;
XU, YY ;
DORRINGTON, KJ ;
KLEIN, MH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (20) :9036-9040
[9]  
Chu S., 2008, Xencor, Patent No. [WO 2008 1150494, 20081150494]
[10]   FcγRIII mediates neutrophil recruitment to immune complexes:: A mechanism for neutrophil accumulation in immune-mediated inflammation [J].
Coxon, A ;
Cullere, X ;
Knight, S ;
Sethi, S ;
Wakelin, MW ;
Stavrakis, G ;
Luscinskas, FW ;
Mayadas, TN .
IMMUNITY, 2001, 14 (06) :693-704