Journal Article
. 2012 Mar; 188(9):4405-11.
doi: 10.4049/jimmunol.1200090.

Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment

Max Warncke 1 Thomas Calzascia  Michele Coulot  Nicole Balke  Ratiba Touil  Frank Kolbinger  Christoph Heusser  
Affiliations
  • PMID: 22461693
  •     47 citations

Abstract

Safety of human therapeutic Abs is generally assessed in nonhuman primates. Whereas IgG1 shows identical FcγR 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 FcγRIIIb, but show higher levels of FcγRII in cynomolgus monkey. In humans, IgG2 and IgG4 adapted a silent Fc region with weak binding to FcγR 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 FcγRIIb 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.

Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo.
Brian Moldt, Eva G Rakasz, +8 authors, Dennis R Burton.
Proc Natl Acad Sci U S A, 2012 Oct 27; 109(46). PMID: 23100539    Free PMC article.
Highly Cited.
Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.
Aran F Labrijn, Joyce I Meesters, +11 authors, Paul W H I Parren.
Proc Natl Acad Sci U S A, 2013 Mar 13; 110(13). PMID: 23479652    Free PMC article.
Highly Cited.
Challenges and approaches for the development of safer immunomodulatory biologics.
Jean G Sathish, Swaminathan Sethu, +18 authors, B Kevin Park.
Nat Rev Drug Discov, 2013 Mar 29; 12(4). PMID: 23535934    Free PMC article.
Review.
Protective effect of vaginal application of neutralizing and nonneutralizing inhibitory antibodies against vaginal SHIV challenge in macaques.
C Moog, N Dereuddre-Bosquet, +12 authors, R Le Grand.
Mucosal Immunol, 2013 Apr 18; 7(1). PMID: 23591718
Highly Cited.
Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.
Halina M Trist, Peck Szee Tan, +9 authors, P Mark Hogarth.
J Immunol, 2013 Dec 18; 192(2). PMID: 24342805    Free PMC article.
Cynomolgus and pigtail macaque IgG subclasses: characterization of IGHG genes and computational analysis of IgG/Fc receptor binding affinity.
Doan C Nguyen, Rashesh Sanghvi, +3 authors, Roberta Attanasio.
Immunogenetics, 2014 May 09; 66(6). PMID: 24811270
Highly parallel characterization of IgG Fc binding interactions.
Austin W Boesch, Eric P Brown, +5 authors, Margaret E Ackerman.
MAbs, 2014 Jun 14; 6(4). PMID: 24927273    Free PMC article.
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
Roy S Herbst, Jean-Charles Soria, +19 authors, F Stephen Hodi.
Nature, 2014 Nov 28; 515(7528). PMID: 25428504    Free PMC article.
Highly Cited.
The role of Fc receptors in HIV prevention and therapy.
Austin W Boesch, Eric P Brown, Margaret E Ackerman.
Immunol Rev, 2015 Oct 27; 268(1). PMID: 26497529    Free PMC article.
Review.
Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs.
Diane L Bolton, Amarendra Pegu, +13 authors, Richard A Koup.
J Virol, 2015 Nov 20; 90(3). PMID: 26581981    Free PMC article.
IgG4 Characteristics and Functions in Cancer Immunity.
Silvia Crescioli, Isabel Correa, +4 authors, Sophia N Karagiannis.
Curr Allergy Asthma Rep, 2016 Jan 09; 16(1). PMID: 26742760    Free PMC article.
Review.
SEC Based Method for Size Determination of Immune Complexes of Therapeutic Antibodies in Animal Matrix.
Marta Boysen, Laura Schlicksupp, +2 authors, Mario Richter.
J Immunol Res, 2016 Aug 25; 2016. PMID: 27556050    Free PMC article.
IgG Binding Characteristics of Rhesus Macaque FcγR.
Ying N Chan, Austin W Boesch, +13 authors, Margaret E Ackerman.
J Immunol, 2016 Aug 26; 197(7). PMID: 27559046    Free PMC article.
Engineering an IgG Scaffold Lacking Effector Function with Optimized Developability.
Frederick W Jacobsen, Riki Stevenson, +14 authors, Kannan Gunasekaran.
J Biol Chem, 2016 Dec 21; 292(5). PMID: 27994062    Free PMC article.
Biological Characterization of a Stable Effector Functionless (SEFL) Monoclonal Antibody Scaffold in Vitro.
Ling Liu, Frederick W Jacobsen, +12 authors, Jeanine L Bussiere.
J Biol Chem, 2016 Dec 21; 292(5). PMID: 27994063    Free PMC article.
Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses.
Austin W Boesch, Nana Yaw Osei-Owusu, +14 authors, Margaret E Ackerman.
Front Immunol, 2016 Dec 27; 7. PMID: 28018355    Free PMC article.
AllergoOncology - the impact of allergy in oncology: EAACI position paper.
E Jensen-Jarolim, H J Bax, +29 authors, S N Karagiannis.
Allergy, 2016 Dec 30; 72(6). PMID: 28032353    Free PMC article.
Review.
IgG Fc variant cross-reactivity between human and rhesus macaque FcγRs.
Austin W Boesch, Adam R Miles, +2 authors, Margaret E Ackerman.
MAbs, 2017 Jan 06; 9(3). PMID: 28055295    Free PMC article.
Single nucleotide polymorphisms in the FcγR3A and TAP1 genes impact ADCC in cynomolgus monkey PBMCs.
Jonathan C Sanford, Hong Wu, +3 authors, Karissa Adkins.
Immunogenetics, 2017 Feb 06; 69(4). PMID: 28154890
Multiplexed Fc array for evaluation of antigen-specific antibody effector profiles.
Eric P Brown, Karen G Dowell, +7 authors, Margaret E Ackerman.
J Immunol Methods, 2017 Feb 07; 443. PMID: 28163018    Free PMC article.
Antibody Functional Assays as Measures of Fc Receptor-Mediated Immunity to HIV - New Technologies and their Impact on the HIV Vaccine Field.
Bruce D Wines, Hugh Billings, +2 authors, P Mark Hogarth.
Curr HIV Res, 2017 Mar 23; 15(3). PMID: 28322167    Free PMC article.
Review.
B cells and the humoral response in melanoma: The overlooked players of the tumor microenvironment.
Giulia Chiaruttini, Silvia Mele, +4 authors, Sophia N Karagiannis.
Oncoimmunology, 2017 May 17; 6(4). PMID: 28507802    Free PMC article.
Review.
Natural Killer (NK) Cell Education Differentially Influences HIV Antibody-Dependent NK Cell Activation and Antibody-Dependent Cellular Cytotoxicity.
Nicole F Bernard, Zahra Kiani, +3 authors, Franck P Dupuy.
Front Immunol, 2017 Sep 09; 8. PMID: 28883824    Free PMC article.
Review.
Enrichment of high affinity subclasses and glycoforms from serum-derived IgG using FcγRs as affinity ligands.
Austin W Boesch, James H Kappel, +5 authors, Margaret E Ackerman.
Biotechnol Bioeng, 2018 Jan 10; 115(5). PMID: 29315477    Free PMC article.
Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.
Randi B Gombos, Ana Gonzalez, +24 authors, Nicholas S Wilson.
PLoS One, 2018 Apr 05; 13(4). PMID: 29617360    Free PMC article.
Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey.
Tsutomu Oshima, Hideaki Miyashita, +5 authors, Tomofumi Kurokawa.
PLoS One, 2018 May 04; 13(5). PMID: 29723247    Free PMC article.
Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration.
Bryan Smith, Andrea Kiessling, +21 authors, Frank R Brennan.
MAbs, 2018 Aug 22; 10(7). PMID: 30130439    Free PMC article.
Profile of atezolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives.
Francesco Facchinetti, Paola Bordi, +2 authors, Marcello Tiseo.
Drug Des Devel Ther, 2018 Sep 22; 12. PMID: 30237696    Free PMC article.
Review.
Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions.
Tania F Rowley, Shirley J Peters, +17 authors, David P Humphreys.
Commun Biol, 2018 Oct 03; 1. PMID: 30272022    Free PMC article.
Antibody Structure and Function: The Basis for Engineering Therapeutics.
Mark L Chiu, Dennis R Goulet, Alexey Teplyakov, Gary L Gilliland.
Antibodies (Basel), 2019 Dec 11; 8(4). PMID: 31816964    Free PMC article.
Review.
Use of nonhuman primates in obstructive lung disease research - is it required?
Franziska Dahlmann, Katherina Sewald.
Primate Biol, 2017 Jun 30; 4(1). PMID: 32110701    Free PMC article.
Review.
Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV.
Margaret E Ackerman, Jishnu Das, +19 authors, Galit Alter.
Nat Med, 2018 Sep 05; 24(10). PMID: 30177821    Free PMC article.
Highly Cited.
Characterization of Mauritian Cynomolgus Macaque FcγR Alleles Using Long-Read Sequencing.
Amelia K Haj, Jaren M Arbanas, +13 authors, David H O'Connor.
J Immunol, 2018 Dec 12; 202(1). PMID: 30530595    Free PMC article.
Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies.
Thach H Chu, Andrew R Crowley, +11 authors, Margaret E Ackerman.
PLoS Pathog, 2020 Feb 25; 16(2). PMID: 32092122    Free PMC article.
Igh locus structure and evolution in Platyrrhines: new insights from a genomic perspective.
Diego Garzón-Ospina, Sindy P Buitrago.
Immunogenetics, 2019 Dec 16; 72(3). PMID: 31838542
From Rhesus macaque to human: structural evolutionary pathways for immunoglobulin G subclasses.
William David Tolbert, Ganesh Prasad Subedi, +4 authors, Marzena Pazgier.
MAbs, 2019 Apr 04; 11(4). PMID: 30939981    Free PMC article.
The Human FcγRII (CD32) Family of Leukocyte FcR in Health and Disease.
Jessica C Anania, Alicia M Chenoweth, Bruce D Wines, P Mark Hogarth.
Front Immunol, 2019 Apr 04; 10. PMID: 30941127    Free PMC article.
Review.
Mind the Gap: How Interspecies Variability in IgG and Its Receptors May Complicate Comparisons of Human and Non-human Primate Effector Function.
Andrew R Crowley, Margaret E Ackerman.
Front Immunol, 2019 Apr 27; 10. PMID: 31024542    Free PMC article.
Review.
Impact of Th1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques.
Anil Verma, Brian A Schmidt, +19 authors, Smita S Iyer.
J Virol, 2019 Dec 13; 94(6). PMID: 31827000    Free PMC article.
Engineering a human IgG2 antibody stable at low pH.
Seiji Saito, Hiroshi Namisaki, +2 authors, Shigeru Iida.
Protein Sci, 2020 Mar 07; 29(5). PMID: 32142185    Free PMC article.
Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.
Xiao-Yan Zhao, Andreas Wilmen, +32 authors, Volker Laux.
Nat Commun, 2020 Jun 14; 11(1). PMID: 32532974    Free PMC article.
An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy.
Hui Wang, Qian Xu, +22 authors, Jiang Gu.
J Immunother Cancer, 2020 Aug 21; 8(2). PMID: 32819973    Free PMC article.
The Binding of Human IgG to Minipig FcγRs - Implications for Preclinical Assessment of Therapeutic Antibodies.
Jerome Egli, Tilman Schlothauer, +4 authors, Antonio Iglesias.
Pharm Res, 2019 Feb 06; 36(3). PMID: 30721414    Free PMC article.
Coming together at the hinges: Therapeutic prospects of IgG3.
Thach H Chu, Edward F Patz, Margaret E Ackerman.
MAbs, 2021 Feb 20; 13(1). PMID: 33602056    Free PMC article.
Review.
Identifying biophysical assays and in silico properties that enrich for slow clearance in clinical-stage therapeutic antibodies.
Boris Grinshpun, Nels Thorsteinson, +4 authors, Yves Fomekong Nanfack.
MAbs, 2021 Jun 13; 13(1). PMID: 34116620    Free PMC article.
Malaria transmission-blocking conjugate vaccine in ALFQ adjuvant induces durable functional immune responses in rhesus macaques.
Puthupparampil V Scaria, Charles Anderson, +15 authors, Patrick E Duffy.
NPJ Vaccines, 2021 Dec 11; 6(1). PMID: 34887448    Free PMC article.
Elimination of plasma soluble antigen in cynomolgus monkeys by combining pH-dependent antigen binding and novel Fc engineering.
Yuji Hori, Ken Ohmine, +14 authors, Tomoyuki Igawa.
MAbs, 2022 Apr 29; 14(1). PMID: 35482905    Free PMC article.