Journal Article
. 2014 Dec; 27(1):138-48.
doi: 10.1016/j.ccell.2014.11.001.

Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies

Ann L White 1 H T Claude Chan 2 Ruth R French 2 Jane Willoughby 2 C Ian Mockridge 2 Ali Roghanian 2 Christine A Penfold 2 Steven G Booth 2 Ali Dodhy 2 Marta E Polak 3 Elizabeth A Potter 2 Michael R Ardern-Jones 3 J Sjef Verbeek 4 Peter W M Johnson 2 Aymen Al-Shamkhani 2 Mark S Cragg 2 Stephen A Beers 2 Martin J Glennie 2 
  • PMID: 25500122
  •     60 References
  •     61 citations


Monoclonal antibody (mAb) drugs that stimulate antitumor immunity are transforming cancer treatment but require optimization for maximum clinical impact. Here, we show that, unlike other immunoglobulin isotypes, human IgG2 (h2) imparts FcγR-independent agonistic activity to immune-stimulatory mAbs such as anti-CD40, -4-1BB, and -CD28. Activity is provided by a subfraction of h2, h2B, that is structurally constrained due its unique arrangement of hinge region disulfide bonds. Agonistic activity can be transferred from h2 to h1 by swapping their hinge and CH1 domains, and substitution of key hinge and CH1 cysteines generates homogenous h2 variants with distinct agonistic properties. This provides the exciting opportunity to engineer clinical reagents with defined therapeutic activity regardless of FcγR expression levels in the local microenvironment.

Structural and functional characterization of disulfide isoforms of the human IgG2 subclass.
Thomas M Dillon, Margaret Speed Ricci, +11 authors, Pavel V Bondarenko.
J Biol Chem, 2008 Mar 15; 283(23). PMID: 18339626    Free PMC article.
Immune activation and a 9-year ongoing complete remission following CD40 antibody therapy and metastasectomy in a patient with metastatic melanoma.
David L Bajor, Xiaowei Xu, +8 authors, Robert H Vonderheide.
Cancer Immunol Res, 2014 Sep 26; 2(11). PMID: 25252722    Free PMC article.
Disulfide connectivity of human immunoglobulin G2 structural isoforms.
Theresa Martinez, Amy Guo, +7 authors, Alain Balland.
Biochemistry, 2008 Jun 14; 47(28). PMID: 18549248
Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies.
Seung Y Chu, Igor Vostiar, +6 authors, John R Desjarlais.
Mol Immunol, 2008 Aug 12; 45(15). PMID: 18691763
Human IgG2 antibody disulfide rearrangement in vivo.
Y Diana Liu, Xiaoyu Chen, +3 authors, Gregory C Flynn.
J Biol Chem, 2008 Aug 21; 283(43). PMID: 18713741    Free PMC article.
Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses.
Pierre Bruhns, Bruno Iannascoli, +4 authors, Marc Daëron.
Blood, 2008 Nov 20; 113(16). PMID: 19018092
Highly Cited.
Interchain disulfide bonding in human IgG2 antibodies probed by site-directed mutagenesis.
Martin J Allen, Amy Guo, +8 authors, Alain Balland.
Biochemistry, 2009 Mar 04; 48(17). PMID: 19254029
Molecular mechanism and function of CD40/CD40L engagement in the immune system.
Raul Elgueta, Micah J Benson, +3 authors, Randolph J Noelle.
Immunol Rev, 2009 May 12; 229(1). PMID: 19426221    Free PMC article.
Highly Cited. Review.
Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma.
Ranjana Advani, Andres Forero-Torres, +6 authors, Jonathan G Drachman.
J Clin Oncol, 2009 Jul 29; 27(26). PMID: 19636010
Determination of Fab-hinge disulfide connectivity in structural isoforms of a recombinant human immunoglobulin G2 antibody.
Bing Zhang, Adam G Harder, +2 authors, Steven L Cockrill.
Anal Chem, 2009 Dec 31; 82(3). PMID: 20039682
Mutations within a human IgG2 antibody form distinct and homogeneous disulfide isomers but do not affect Fc gamma receptor or C1q binding.
Sandra Lightle, Serdar Aykent, +4 authors, Theodore Oliphant.
Protein Sci, 2010 Feb 02; 19(4). PMID: 20120022    Free PMC article.
Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant.
Ann L White, Alison L Tutt, +8 authors, Martin J Glennie.
Immunology, 2010 May 15; 131(1). PMID: 20465572    Free PMC article.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells.
Nicholas S Wilson, Becky Yang, +17 authors, Avi Ashkenazi.
Cancer Cell, 2011 Jan 22; 19(1). PMID: 21251615
Highly Cited.
CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies.
Holbrook E Kohrt, Roch Houot, +11 authors, Ronald Levy.
Blood, 2011 Jan 05; 117(8). PMID: 21193697    Free PMC article.
Highly Cited.
CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
Gregory L Beatty, Elena G Chiorean, +10 authors, Robert H Vonderheide.
Science, 2011 Mar 26; 331(6024). PMID: 21436454    Free PMC article.
Highly Cited.
The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility.
Peter Boross, Victoria L Arandhara, +16 authors, J Sjef Verbeek.
J Immunol, 2011 Jul 05; 187(3). PMID: 21724994
Interaction with FcγRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody.
Ann L White, H T Claude Chan, +10 authors, Martin J Glennie.
J Immunol, 2011 Jul 12; 187(4). PMID: 21742972
Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies.
Fubin Li, Jeffrey V Ravetch.
Science, 2011 Aug 20; 333(6045). PMID: 21852502    Free PMC article.
Highly Cited.
Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer.
Holbrook E Kohrt, Roch Houot, +11 authors, Ronald Levy.
J Clin Invest, 2012 Feb 14; 122(3). PMID: 22326955    Free PMC article.
Highly Cited.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagement.
Fubin Li, Jeffrey V Ravetch.
Proc Natl Acad Sci U S A, 2012 Jun 23; 109(27). PMID: 22723355    Free PMC article.
Translating basic mechanisms of IgG effector activity into next generation cancer therapies.
Falk Nimmerjahn, Jeffrey V Ravetch.
Cancer Immun, 2012 Aug 17; 12. PMID: 22896758    Free PMC article.
Agonistic CD40 antibodies and cancer therapy.
Robert H Vonderheide, Martin J Glennie.
Clin Cancer Res, 2013 Mar 06; 19(5). PMID: 23460534    Free PMC article.
Highly Cited.
Impact of immune complex size and glycosylation on IgG binding to human FcγRs.
Anja Lux, Xiaojie Yu, Chris N Scanlan, Falk Nimmerjahn.
J Immunol, 2013 Mar 20; 190(8). PMID: 23509345
Highly Cited.
Cysteine-rich domain 1 of CD40 mediates receptor self-assembly.
Cristian R Smulski, Julien Beyrath, +7 authors, Sylvie Fournel.
J Biol Chem, 2013 Mar 07; 288(15). PMID: 23463508    Free PMC article.
FcγRΙΙB controls the potency of agonistic anti-TNFR mAbs.
Ann L White, H T Claude Chan, +4 authors, Martin J Glennie.
Cancer Immunol Immunother, 2013 Apr 02; 62(5). PMID: 23543215
The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy.
Amy E Moran, Magdalena Kovacsovics-Bankowski, Andrew D Weinberg.
Curr Opin Immunol, 2013 Feb 19; 25(2). PMID: 23414607    Free PMC article.
Three-dimensional structure of the human myeloma IgG2.
Sergey Ryazantsev, Vladimir Tischenko, +2 authors, Vladimir Zav'yalov.
PLoS One, 2013 Jun 14; 8(6). PMID: 23762236    Free PMC article.
Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Antibody therapeutics in cancer.
Mark X Sliwkowski, Ira Mellman.
Science, 2013 Sep 14; 341(6151). PMID: 24031011
Highly Cited. Review.
A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.
Gregory L Beatty, Drew A Torigian, +8 authors, Peter J O'Dwyer.
Clin Cancer Res, 2013 Aug 29; 19(22). PMID: 23983255    Free PMC article.
Highly Cited.
Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo.
Fubin Li, Jeffrey V Ravetch.
Proc Natl Acad Sci U S A, 2013 Nov 13; 110(48). PMID: 24218606    Free PMC article.
Electrophoretic evidence for the presence of structural isoforms specific for the IgG2 isotype.
Amy Guo, Mei Han, +4 authors, Alain Balland.
Electrophoresis, 2008 May 22; 29(12). PMID: 18494039
Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets.
R A Clynes, T L Towers, L G Presta, J V Ravetch.
Nat Med, 2000 Mar 31; 6(4). PMID: 10742152
Highly Cited.
The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells.
Cory Ahonen, Eric Manning, +5 authors, Randolph J Noelle.
Nat Immunol, 2002 Apr 23; 3(5). PMID: 11967542    Free PMC article.
Human IgG2 can form covalent dimers.
Esther M Yoo, Letitia A Wims, Lisa A Chan, Sherie L Morrison.
J Immunol, 2003 Mar 11; 170(6). PMID: 12626570
Fc gamma Rs modulate cytotoxicity of anti-Fas antibodies: implications for agonistic antibody-based therapeutics.
Yuanyuan Xu, Alexander J Szalai, +5 authors, Robert P Kimberly.
J Immunol, 2003 Jul 09; 171(2). PMID: 12847219
The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy.
Junji Uchida, Yasuhito Hamaguchi, +4 authors, Thomas F Tedder.
J Exp Med, 2004 Jun 24; 199(12). PMID: 15210744    Free PMC article.
Highly Cited.
IgG2 subclass restriction of antibody to pneumococcal polysaccharides.
D J Barrett, E M Ayoub.
Clin Exp Immunol, 1986 Jan 01; 63(1). PMID: 3955880    Free PMC article.
Highly Cited.
Characterization of a new monoclonal anti-Fc gamma RII antibody, AT10, and its incorporation into a bispecific F(ab')2 derivative for recruitment of cytotoxic effectors.
J Greenman, A L Tutt, +3 authors, M J Glennie.
Mol Immunol, 1991 Nov 01; 28(11). PMID: 1835758
A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody.
S Angal, D J King, +5 authors, J R Adair.
Mol Immunol, 1993 Jan 01; 30(1). PMID: 8417368
CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help.
R R French, H T Chan, A L Tutt, M J Glennie.
Nat Med, 1999 May 06; 5(5). PMID: 10229232
Highly Cited.
Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo.
Brent A Hanks, Jianghong Jiang, +5 authors, David M Spencer.
Nat Med, 2005 Jan 25; 11(2). PMID: 15665830
Divergent immunoglobulin g subclass activity through selective Fc receptor binding.
Falk Nimmerjahn, Jeffrey V Ravetch.
Science, 2005 Dec 03; 310(5753). PMID: 16322460
Highly Cited.
Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy.
Yasuhito Hamaguchi, Yan Xiu, +2 authors, Thomas F Tedder.
J Exp Med, 2006 Mar 08; 203(3). PMID: 16520392    Free PMC article.
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
Ganesh Suntharalingam, Meghan R Perry, +4 authors, Nicki Panoskaltsis.
N Engl J Med, 2006 Aug 16; 355(10). PMID: 16908486
Highly Cited.
Combined TLR/CD40 stimulation mediates potent cellular immunity by regulating dendritic cell expression of CD70 in vivo.
Phillip J Sanchez, Jennifer A McWilliams, +2 authors, Ross M Kedl.
J Immunol, 2007 Jan 24; 178(3). PMID: 17237405
Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.
Jun Kurai, Hiroki Chikumi, +10 authors, Eiji Shimizu.
Clin Cancer Res, 2007 Mar 03; 13(5). PMID: 17332301
Highly Cited.
Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation.
Ruth R French, Vadim Y Taraban, +6 authors, Martin J Glennie.
Blood, 2007 Feb 22; 109(11). PMID: 17311995
Human IgG2 antibodies display disulfide-mediated structural isoforms.
Jette Wypych, Ming Li, +11 authors, Alain Balland.
J Biol Chem, 2008 Mar 15; 283(23). PMID: 18339624    Free PMC article.
Cell contact-dependent priming and Fc interaction with CD32+ immune cells contribute to the TGN1412-triggered cytokine response.
Patrick Bartholomaeus, Linda Y Semmler, +10 authors, Ulrich Kalinke.
J Immunol, 2014 Jan 29; 192(5). PMID: 24470499
Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer.
Lee P Richman, Robert H Vonderheide.
Cancer Immunol Res, 2014 Jan 15; 2(1). PMID: 24416732    Free PMC article.
Ex vivo assays of dendritic cell activation and cytokine profiles as predictors of in vivo effects in an anti-human CD40 monoclonal antibody ChiLob 7/4 phase I trial.
F Chowdhury, P W Johnson, M J Glennie, A P Williams.
Cancer Immunol Res, 2014 Apr 30; 2(3). PMID: 24778319    Free PMC article.
Targeting CD137 enhances the efficacy of cetuximab.
Holbrook E Kohrt, A Dimitrios Colevas, +20 authors, Ronald Levy.
J Clin Invest, 2014 May 20; 124(6). PMID: 24837434    Free PMC article.
Highly Cited.
OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.
Yannick Bulliard, Rose Jolicoeur, +3 authors, Jennifer L Brogdon.
Immunol Cell Biol, 2014 Apr 16; 92(6). PMID: 24732076
Highly Cited.
Fcγ receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization.
Ann L White, Lang Dou, +14 authors, Stephen A Beers.
J Immunol, 2014 Jul 16; 193(4). PMID: 25024386
Special Conference on Tumor Immunology and Immunotherapy: A New Chapter.
Katelyn T Byrne, Robert H Vonderheide, Elizabeth M Jaffee, Todd D Armstrong.
Cancer Immunol Res, 2015 May 15; 3(6). PMID: 25968457    Free PMC article.
Evolving synergistic combinations of targeted immunotherapies to combat cancer.
Ignacio Melero, David M Berman, +3 authors, John Haanen.
Nat Rev Cancer, 2015 Jul 25; 15(8). PMID: 26205340
Highly Cited. Review.
Principles of antibody-mediated TNF receptor activation.
H Wajant.
Cell Death Differ, 2015 Aug 22; 22(11). PMID: 26292758    Free PMC article.
Reformatting Rituximab into Human IgG2 and IgG4 Isotypes Dramatically Improves Apoptosis Induction In Vitro.
Jennifer D Könitzer, Annette Sieron, Angelika Wacker, Barbara Enenkel.
PLoS One, 2015 Dec 30; 10(12). PMID: 26713448    Free PMC article.
Influence of immunoglobulin isotype on therapeutic antibody function.
Stephen A Beers, Martin J Glennie, Ann L White.
Blood, 2016 Jan 15; 127(9). PMID: 26764357    Free PMC article.
Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
Joseph M Ryan, Jeffrey S Wasser, Adam J Adler, Anthony T Vella.
Expert Opin Biol Ther, 2016 Feb 09; 16(5). PMID: 26855028    Free PMC article.
Regulation of Monoclonal Antibody Immunotherapy by FcγRIIB.
Richard J Stopforth, Kirstie L S Cleary, Mark S Cragg.
J Clin Immunol, 2016 Feb 29; 36 Suppl 1. PMID: 26922075    Free PMC article.
Translating Inhibitory Fc Receptor Biology into Novel Therapeutic Approaches.
Falk Nimmerjahn.
J Clin Immunol, 2016 Mar 10; 36 Suppl 1. PMID: 26957094
Structure of the Plexin Ectodomain Bound by Semaphorin-Mimicking Antibodies.
Kei Suzuki, Hiroyuki Tsunoda, +8 authors, Junichi Takagi.
PLoS One, 2016 Jun 04; 11(6). PMID: 27258772    Free PMC article.
Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement.
Rony Dahan, Bryan C Barnhart, +3 authors, Jeffrey V Ravetch.
Cancer Cell, 2016 Jun 07; 29(6). PMID: 27265505    Free PMC article.
Highly Cited.
CIMT 2016: Mechanisms of efficacy in cancer immunotherapy - Report on the 14th Annual Meeting of the Association for Cancer Immunotherapy May 10-12 2016, Mainz, Germany.
Lena M Kranz, Matthias Birtel, +7 authors, Mustafa Diken.
Hum Vaccin Immunother, 2016 Jul 21; 12(11). PMID: 27435168    Free PMC article.
Rethinking the INN system for therapeutic antibodies.
Jérémy Pottier, Romane Chastang, Christophe Dumet, Hervé Watier.
MAbs, 2016 Nov 04; 9(1). PMID: 27808597    Free PMC article.
Fc Engineering Approaches to Enhance the Agonism and Effector Functions of an Anti-OX40 Antibody.
Di Zhang, Monica V Goldberg, Mark L Chiu.
J Biol Chem, 2016 Nov 20; 291(53). PMID: 27856634    Free PMC article.
Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists.
Gregory L Beatty, Yan Li, Kristen B Long.
Expert Rev Anticancer Ther, 2016 Dec 09; 17(2). PMID: 27927088    Free PMC article.
Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling.
Debra H Josephs, Heather J Bax, +38 authors, Sophia N Karagiannis.
Cancer Res, 2017 Jan 18; 77(5). PMID: 28096174    Free PMC article.
Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design.
Martyn A French, M Christian Tjiam, Laila N Abudulai, Sonia Fernandez.
Front Immunol, 2017 Jul 21; 8. PMID: 28725225    Free PMC article.
Tethered-variable CL bispecific IgG: an antibody platform for rapid bispecific antibody screening.
Hok Seon Kim, Diana Ronai Dunshee, +7 authors, Christoph Spiess.
Protein Eng Des Sel, 2017 Oct 07; 30(9). PMID: 28985411    Free PMC article.
Antibody Isotypes for Tumor Immunotherapy.
Anna Kretschmer, Ralf Schwanbeck, Thomas Valerius, Thies Rösner.
Transfus Med Hemother, 2017 Oct 27; 44(5). PMID: 29070977    Free PMC article.
Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications.
Mariona Cabo, Rienk Offringa, +3 authors, Lorenzo Galluzzi.
Oncoimmunology, 2017 Dec 07; 6(12). PMID: 29209572    Free PMC article.
Productive common light chain libraries yield diverse panels of high affinity bispecific antibodies.
Thomas Van Blarcom, Kevin Lindquist, +19 authors, Javier Chaparro-Riggers.
MAbs, 2017 Dec 12; 10(2). PMID: 29227213    Free PMC article.
Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies.
Xiaojie Yu, H T Claude Chan, +14 authors, Ann L White.
Cancer Cell, 2018 Mar 27; 33(4). PMID: 29576376    Free PMC article.
The Immune Revolution: A Case for Priming, Not Checkpoint.
Robert H Vonderheide.
Cancer Cell, 2018 Apr 11; 33(4). PMID: 29634944    Free PMC article.
Highly Cited. Review.
Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.
Jeremy D Waight, Dhan Chand, +14 authors, Nicholas S Wilson.
Cancer Cell, 2018 Jun 13; 33(6). PMID: 29894690    Free PMC article.
The promise and challenges of immune agonist antibody development in cancer.
Patrick A Mayes, Kenneth W Hance, Axel Hoos.
Nat Rev Drug Discov, 2018 Jun 16; 17(7). PMID: 29904196
Highly Cited. Review.
Evaluating Anti-CD32b F(ab) Conformation Using Molecular Dynamics and Small-Angle X-Ray Scattering.
Emma J Sutton, Richard T Bradshaw, +6 authors, Jonathan W Essex.
Biophys J, 2018 Jul 19; 115(2). PMID: 30021105    Free PMC article.
Rapid, automated characterization of disulfide bond scrambling and IgG2 isoform determination.
Anja Resemann, Lily Liu-Shin, +5 authors, Detlev Suckau.
MAbs, 2018 Oct 03; 10(8). PMID: 30277844    Free PMC article.
Immune Checkpoints as Therapeutic Targets in Autoimmunity.
Christopher Paluch, Ana Mafalda Santos, +2 authors, Simon J Davis.
Front Immunol, 2018 Oct 24; 9. PMID: 30349540    Free PMC article.
Considerations for the Design of Antibody-Based Therapeutics.
Dennis R Goulet, William M Atkins.
J Pharm Sci, 2019 Jun 08; 109(1). PMID: 31173761    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.
Human immunoglobulin G hinge regulates agonistic anti-CD40 immunostimulatory and antitumour activities through biophysical flexibility.
Xiaobo Liu, Yingjie Zhao, +8 authors, Fubin Li.
Nat Commun, 2019 Sep 29; 10(1). PMID: 31562320    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.
Targeted APC Activation in Cancer Immunotherapy to Enhance the Abscopal Effect.
Nathan Suek, Luis Felipe Campesato, Taha Merghoub, Danny N Khalil.
Front Immunol, 2019 Apr 20; 10. PMID: 31001249    Free PMC article.
FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy.
Xin Chen, Xiaomin Song, Kang Li, Tong Zhang.
Front Immunol, 2019 Mar 14; 10. PMID: 30863404    Free PMC article.
Highly Cited. Review.
Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency against Cancer.
Tae Hyun Kang, Sang Taek Jung.
Biomolecules, 2020 Mar 04; 10(3). PMID: 32121592    Free PMC article.
Harnessing the immune system via FcγR function in immune therapy: a pathway to next-gen mAbs.
Alicia M Chenoweth, Bruce D Wines, Jessica C Anania, P Mark Hogarth.
Immunol Cell Biol, 2020 Mar 12; 98(4). PMID: 32157732    Free PMC article.
Engineering nanoparticles to reprogram radiotherapy and immunotherapy: recent advances and future challenges.
Jing Jin, Qijie Zhao.
J Nanobiotechnology, 2020 May 16; 18(1). PMID: 32408880    Free PMC article.
Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity.
Xiaojie Yu, H T Claude Chan, +13 authors, Mark S Cragg.
Cancer Cell, 2020 May 23; 37(6). PMID: 32442402    Free PMC article.
FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion.
Robert J Oldham, C Ian Mockridge, +6 authors, Mark S Cragg.
J Immunother Cancer, 2020 Jun 20; 8(1). PMID: 32554613    Free PMC article.
Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies.
Da-Ke Li, Wen Wang.
Oncol Lett, 2020 Sep 17; 20(5). PMID: 32934743    Free PMC article.
The Ligands for Human IgG and Their Effector Functions.
Steven W de Taeye, Theo Rispens, Gestur Vidarsson.
Antibodies (Basel), 2019 Sep 24; 8(2). PMID: 31544836    Free PMC article.
Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma.
Lihui Zhuang, Rebecca J Fulton, +4 authors, Salim I Khakoo.
Hepatol Int, 2018 Nov 24; 13(1). PMID: 30467624    Free PMC article.
New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5).
Manuel Piechutta, Anna Sophie Berghoff.
ESMO Open, 2019 Jul 06; 4(Suppl 3). PMID: 31275618    Free PMC article.
Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies.
Jamie Valeich, Dan Boyd, +6 authors, Alexandre Ambrogelly.
Antibodies (Basel), 2020 Sep 27; 9(4). PMID: 32977708    Free PMC article.
Fusion of Bacterial Flagellin to a Dendritic Cell-Targeting αCD40 Antibody Construct Coupled With Viral or Leukemia-Specific Antigens Enhances Dendritic Cell Maturation and Activates Peptide-Responsive T Cells.
Saskia Schmitt, Siret Tahk, +12 authors, Marion Subklewe.
Front Immunol, 2020 Dec 08; 11. PMID: 33281829    Free PMC article.
APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application.
Erin L Filbert, Pia K Björck, +2 authors, Xiaodong Yang.
Cancer Immunol Immunother, 2021 Jan 05; 70(7). PMID: 33392713    Free PMC article.
Domain binding and isotype dictate the activity of anti-human OX40 antibodies.
Jordana Griffiths, Khiyam Hussain, +18 authors, Mark S Cragg.
J Immunother Cancer, 2021 Jan 12; 8(2). PMID: 33428585    Free PMC article.
Next-Generation Immunotherapies to Improve Anticancer Immunity.
Yaoyao Shi, Katarzyna Tomczak, +3 authors, Cara Haymaker.
Front Pharmacol, 2021 Jan 29; 11. PMID: 33505304    Free PMC article.
Bispecific antibody target pair discovery by high-throughput phenotypic screening using in vitro combinatorial Fab libraries.
Pallavi Bhatta, Kevin D Whale, +10 authors, Helene M Finney.
MAbs, 2021 Jan 26; 13(1). PMID: 33487120    Free PMC article.
Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint.
TingTing Tang, Xiang Cheng, +3 authors, Hong Wang.
Pharmacol Ther, 2020 Oct 23; 219. PMID: 33091428    Free PMC article.
Isotype selection for antibody-based cancer therapy.
N Vukovic, A van Elsas, J S Verbeek, D M W Zaiss.
Clin Exp Immunol, 2020 Nov 07; 203(3). PMID: 33155272    Free PMC article.
Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily.
Kirstin Kucka, Harald Wajant.
Front Cell Dev Biol, 2021 Mar 02; 8. PMID: 33644033    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.
Agonistic CD40 Antibodies in Cancer Treatment.
Dijana Djureinovic, Meina Wang, Harriet M Kluger.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33804039    Free PMC article.
OX40 as a novel target for the reversal of immune escape in colorectal cancer.
Lin-Hai Yan, Xiao-Liang Liu, +3 authors, Wei-Zhong Tang.
Am J Transl Res, 2021 Apr 13; 13(3). PMID: 33841630    Free PMC article.
Rigid monoclonal antibodies improve detection of SARS-CoV-2 nucleocapsid protein.
Curtis D Hodge, Daniel J Rosenberg, +4 authors, Michal Hammel.
MAbs, 2021 Apr 13; 13(1). PMID: 33843452    Free PMC article.
TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity.
Xiaojie Yu, Sonya James, +14 authors, Mark S Cragg.
Commun Biol, 2021 Jun 25; 4(1). PMID: 34162985    Free PMC article.
Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties.
Valentina Ceglia, Sandra Zurawski, +6 authors, Gerard Zurawski.
J Immunol, 2021 Sep 24; 207(8). PMID: 34551965    Free PMC article.
Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies.
Khiyam Hussain, Mark S Cragg, Stephen A Beers.
Cancers (Basel), 2021 Oct 14; 13(19). PMID: 34638388    Free PMC article.
Agonist antibody discovery: Experimental, computational, and rational engineering approaches.
John S Schardt, Harkamal S Jhajj, +3 authors, Peter M Tessier.
Drug Discov Today, 2021 Sep 28; 27(1). PMID: 34571277    Free PMC article.
Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.
Julia Moreno-Vicente, Jane E Willoughby, +11 authors, Stephen A Beers.
J Immunother Cancer, 2022 Jan 13; 10(1). PMID: 35017153    Free PMC article.
Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering.
Franziska Heckel, Anna H Turaj, +12 authors, Sean H Lim.
Commun Biol, 2022 Mar 16; 5(1). PMID: 35288635    Free PMC article.