Journal Article
. 2018 Apr; 13(4):e0191926.
doi: 10.1371/journal.pone.0191926.

Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody

Randi B Gombos 1 Ana Gonzalez 1 Mariana Manrique 1 Dhan Chand 1 David Savitsky 1 Benjamin Morin 2 Ekaterina Breous-Nystrom 3 Christopher Dupont 4 Rebecca A Ward 1 Cornelia Mundt 3 Benjamin Duckless 4 Hao Tang 4 Mark A Findeis 2 Andrea Schuster 3 Jeremy D Waight 1 Dennis Underwood 2 Christopher Clarke 5 Gerd Ritter 6 Taha Merghoub 7 David Schaer 7 Jedd D Wolchok 7 Marc van Dijk 8 Jennifer S Buell 9 Jean-Marie Cuillerot 9 Robert Stein 10 Elise E Drouin 4 Nicholas S Wilson 1 
  • PMID: 29617360
  •     65 References
  •     9 citations


CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

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.
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.
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.
CD28-mediated co-stimulation: a quantitative support for TCR signalling.
Oreste Acuto, Frédérique Michel.
Nat Rev Immunol, 2003 Dec 04; 3(12). PMID: 14647476
Highly Cited. Review.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
Michael A Curran, Welby Montalvo, Hideo Yagita, James P Allison.
Proc Natl Acad Sci U S A, 2010 Feb 18; 107(9). PMID: 20160101    Free PMC article.
Highly Cited.
OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer.
Ryan Montler, R Bryan Bell, +8 authors, Andrew Weinberg.
Clin Transl Immunology, 2016 May 20; 5(4). PMID: 27195113    Free PMC article.
T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.
Enfu Hui, Jeanne Cheung, +8 authors, Ronald D Vale.
Science, 2017 Mar 11; 355(6332). PMID: 28280247    Free PMC article.
Highly Cited.
The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance.
Todd N Eagar, Nitin J Karandikar, Jeffrey A Bluestone, Stephen D Miller.
Eur J Immunol, 2002 Mar 29; 32(4). PMID: 11920563
Cytokine release assays for the prediction of therapeutic mAb safety in first-in man trials--Whole blood cytokine release assays are poorly predictive for TGN1412 cytokine storm.
S Vessillier, D Eastwood, +6 authors, R Stebbings.
J Immunol Methods, 2015 May 12; 424. PMID: 25960173    Free PMC article.
OX40 is a potent immune-stimulating target in late-stage cancer patients.
Brendan D Curti, Magdalena Kovacsovics-Bankowski, +20 authors, Andrew D Weinberg.
Cancer Res, 2013 Nov 02; 73(24). PMID: 24177180    Free PMC article.
Highly Cited.
Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40.
E Oflazoglu, I J Stone, +6 authors, H-P Gerber.
Br J Cancer, 2008 Dec 11; 100(1). PMID: 19066610    Free PMC article.
Affinity and cross-reactivity engineering of CTLA4-Ig to modulate T cell costimulation.
Zhenghai Xu, Veronica Juan, +6 authors, Yoshiko Akamatsu.
J Immunol, 2012 Sep 29; 189(9). PMID: 23018459
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.
P Waterhouse, J M Penninger, +6 authors, T W Mak.
Science, 1995 Nov 10; 270(5238). PMID: 7481803
Highly Cited.
Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction.
Revital Levy, Ziv Rotfogel, +5 authors, Raymond Kaempfer.
Proc Natl Acad Sci U S A, 2016 Oct 30; 113(42). PMID: 27708164    Free PMC article.
The in vitro resistance of IgG2 to proteolytic attack concurs with a comparative paucity of autoantibodies against peptide analogs of the IgG2 hinge.
Randall J Brezski, Allison Oberholtzer, Brandy Strake, Robert E Jordan.
MAbs, 2011 Nov 30; 3(6). PMID: 22123056    Free PMC article.
CTLA-4 blockade in tumor models: an overview of preclinical and translational research.
Joseph F Grosso, Maria N Jure-Kunkel.
Cancer Immun, 2013 Feb 08; 13. PMID: 23390376    Free PMC article.
Highly Cited. Review.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.
Isabelle Le Mercier, J Louise Lines, Randolph J Noelle.
Front Immunol, 2015 Sep 09; 6. PMID: 26347741    Free PMC article.
Highly Cited. Review.
Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells.
Xuguang Tai, François Van Laethem, +9 authors, Alfred Singer.
Blood, 2012 Mar 10; 119(22). PMID: 22403258    Free PMC article.
Highly Cited.
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
Michael A Postow, Jason Chesney, +18 authors, F Stephen Hodi.
N Engl J Med, 2015 Apr 22; 372(21). PMID: 25891304    Free PMC article.
Highly Cited.
Tumor immunotherapy directed at PD-1.
Antoni Ribas.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658126
Highly Cited.
Identification of an alternative CTLA-4 ligand costimulatory for T cell activation.
K S Hathcock, G Laszlo, +3 authors, R J Hodes.
Science, 1993 Nov 05; 262(5135). PMID: 7694361
Highly Cited.
Translational control of interleukin 2 messenger RNA as a molecular mechanism of T cell anergy.
J A Garcia-Sanz, D Lenig.
J Exp Med, 1996 Jul 01; 184(1). PMID: 8691129    Free PMC article.
CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.
Elizabeth I Buchbinder, Anupam Desai.
Am J Clin Oncol, 2015 Nov 13; 39(1). PMID: 26558876    Free PMC article.
Highly Cited. Review.
Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response.
Pia Kvistborg, Daisy Philips, +13 authors, Ton N Schumacher.
Sci Transl Med, 2014 Sep 19; 6(254). PMID: 25232180
Highly Cited.
Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody.
Nadja Spindler, Uschi Diestel, +5 authors, Yves A Muller.
PLoS Pathog, 2014 Oct 10; 10(10). PMID: 25299639    Free PMC article.
Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma.
Dirk Schadendorf, F Stephen Hodi, +7 authors, Jedd D Wolchok.
J Clin Oncol, 2015 Feb 11; 33(17). PMID: 25667295    Free PMC article.
Highly Cited.
CTLA-4 control over Foxp3+ regulatory T cell function.
Kajsa Wing, Yasushi Onishi, +5 authors, Shimon Sakaguchi.
Science, 2008 Oct 11; 322(5899). PMID: 18845758
Highly Cited.
Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo.
Rituparna Das, Rakesh Verma, +8 authors, Kavita M Dhodapkar.
J Immunol, 2014 Dec 30; 194(3). PMID: 25539810    Free PMC article.
Highly Cited.
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
Scott Antonia, Sarah B Goldberg, +8 authors, Naiyer A Rizvi.
Lancet Oncol, 2016 Feb 10; 17(3). PMID: 26858122    Free PMC article.
Highly Cited.
Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.
Celine Boutros, Ahmad Tarhini, +14 authors, Caroline Robert.
Nat Rev Clin Oncol, 2016 May 05; 13(8). PMID: 27141885
Highly Cited. Review.
Characterization of in vitro antibody-dependent cell-mediated cytotoxicity activity of therapeutic antibodies - impact of effector cells.
Shan Chung, Yuwen L Lin, +6 authors, An Song.
J Immunol Methods, 2014 Apr 08; 407. PMID: 24704820
The Ki-67 protein: from the known and the unknown.
T Scholzen, J Gerdes.
J Cell Physiol, 2000 Feb 01; 182(3). PMID: 10653597
Highly Cited. Review.
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Alexandra Snyder, Vladimir Makarov, +18 authors, Timothy A Chan.
N Engl J Med, 2014 Nov 20; 371(23). PMID: 25409260    Free PMC article.
Highly Cited.
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.
E A Tivol, F Borriello, +3 authors, A H Sharpe.
Immunity, 1995 Nov 01; 3(5). PMID: 7584144
Highly Cited.
CTLA-4 antibodies: new directions, new combinations.
Samuel A Funt, David B Page, Jedd D Wolchok, Michael A Postow.
Oncology (Williston Park), 2014 Nov 13; 28 Suppl 3. PMID: 25387681
T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor.
Elke Valk, Rufina Leung, +3 authors, Helga Schneider.
Immunity, 2006 Oct 31; 25(5). PMID: 17070077
Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis.
T Moreau, A Coles, +4 authors, A Compston.
Brain, 1996 Feb 01; 119 ( Pt 1). PMID: 8624684
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.
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.
Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.
C C Stamper, Y Zhang, +7 authors, L Mosyak.
Nature, 2001 Mar 30; 410(6828). PMID: 11279502
Highly Cited.
Retrocyte Display® technology: generation and screening of a high diversity cellular antibody library.
Ekaterina Breous-Nystrom, Kornelia Schultze, +10 authors, Marc A van Dijk.
Methods, 2013 Sep 17; 65(1). PMID: 24036249
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.
Hye Sun Kuehn, Weiming Ouyang, +33 authors, Gulbu Uzel.
Science, 2014 Sep 13; 345(6204). PMID: 25213377    Free PMC article.
Highly Cited.
B70 antigen is a second ligand for CTLA-4 and CD28.
M Azuma, D Ito, +4 authors, C Somoza.
Nature, 1993 Nov 04; 366(6450). PMID: 7694153
Highly Cited.
M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro.
Marzia Leidi, Elisa Gotti, +7 authors, Josée Golay.
J Immunol, 2009 Mar 21; 182(7). PMID: 19299742
Highly Cited.
CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics.
P A van der Merwe, D L Bodian, +2 authors, S J Davis.
J Exp Med, 1997 Feb 03; 185(3). PMID: 9053440    Free PMC article.
Highly Cited.
Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength.
Jackson G Egen, James P Allison.
Immunity, 2002 Feb 05; 16(1). PMID: 11825563
Highly Cited.
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment.
Max Warncke, Thomas Calzascia, +4 authors, Christoph Heusser.
J Immunol, 2012 Mar 31; 188(9). PMID: 22461693
Cytokine release assays: current practices and future directions.
D Finco, C Grimaldi, +12 authors, P K Narayanan.
Cytokine, 2014 Jan 15; 66(2). PMID: 24412476
CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: a potential role for tyrosine phosphatases.
Christine Guntermann, Denis R Alexander.
J Immunol, 2002 Apr 24; 168(9). PMID: 11970985
Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes.
Lidia Robert, Christina Harview, +8 authors, Antoni Ribas.
Oncoimmunology, 2014 Aug 02; 3. PMID: 25083336    Free PMC article.
Selective induction of B7/BB-1 on interferon-gamma stimulated monocytes: a potential mechanism for amplification of T cell activation through the CD28 pathway.
A S Freedman, G J Freeman, K Rhynhart, L M Nadler.
Cell Immunol, 1991 Oct 15; 137(2). PMID: 1716521
Highly Cited.
The B7-CD28 superfamily.
Arlene H Sharpe, Gordon J Freeman.
Nat Rev Immunol, 2002 Mar 26; 2(2). PMID: 11910893
Highly Cited. Review.
Neoantigens in cancer immunotherapy.
Ton N Schumacher, Robert D Schreiber.
Science, 2015 Apr 04; 348(6230). PMID: 25838375
Highly Cited. Review.
T-cell-dependent antibody response: assay development in cynomolgus monkeys.
Joseph R Piccotti, James D Alvey, James F Reindel, Roberto E Guzman.
J Immunotoxicol, 2008 Oct 30; 2(4). PMID: 18958673
Regulation of antigen presentation and cross-presentation in the dendritic cell network: facts, hypothesis, and immunological implications.
Nicholas S Wilson, Jose A Villadangos.
Adv Immunol, 2005 Feb 12; 86. PMID: 15705424
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.
Matthew D Hellmann, Naiyer A Rizvi, +14 authors, Scott J Antonia.
Lancet Oncol, 2016 Dec 10; 18(1). PMID: 27932067    Free PMC article.
Highly Cited.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
Crystal structure of a SEA variant in complex with MHC class II reveals the ability of SEA to crosslink MHC molecules.
Karin Petersson, Marjolein Thunnissen, Göran Forsberg, Björn Walse.
Structure, 2002 Dec 07; 10(12). PMID: 12467569
CTLA-4 and PD-1 Pathway Blockade: Combinations in the Clinic.
Margaret K Callahan, Michael A Postow, Jedd D Wolchok.
Front Oncol, 2015 Feb 03; 4. PMID: 25642417    Free PMC article.
Highly Cited. Review.
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.
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
Highly Cited.
Fcγ receptors enable anticancer action of proapoptotic and immune-modulatory antibodies.
Jeong M Kim, Avi Ashkenazi.
J Exp Med, 2013 Aug 28; 210(9). PMID: 23980122    Free PMC article.
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.
Anti-CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control.
Emilio Sanseviero, Erin M O'Brien, +16 authors, Erica L Stone.
Cancer Immunol Res, 2019 Jun 27; 7(8). PMID: 31239316    Free PMC article.
The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.
Anne Månsson Kvarnhammar, Niina Veitonmäki, +16 authors, Peter Ellmark.
J Immunother Cancer, 2019 Apr 13; 7(1). PMID: 30975201    Free PMC article.
Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells.
Margherita Passariello, Simona Camorani, +3 authors, Claudia De Lorenzo.
Cancers (Basel), 2020 Feb 07; 12(2). PMID: 32024070    Free PMC article.
Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution.
Vaia Florou, Andrew E Rosenberg, +7 authors, Breelyn A Wilky.
J Immunother Cancer, 2019 Aug 10; 7(1). PMID: 31395100    Free PMC article.
Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells.
Margherita Passariello, Cinzia Vetrei, +7 authors, Claudia De Lorenzo.
Cancers (Basel), 2020 Aug 13; 12(8). PMID: 32781690    Free PMC article.
Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment.
Rena Liu, Robert J Oldham, +2 authors, Mark S Cragg.
Antibodies (Basel), 2020 Nov 21; 9(4). PMID: 33212886    Free PMC article.
The foundations of immune checkpoint blockade and the ipilimumab approval decennial.
Alan J Korman, Sarah C Garrett-Thomson, Nils Lonberg.
Nat Rev Drug Discov, 2021 Dec 24;. PMID: 34937915
Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study.
David M O'Malley, Maryna Neffa, +12 authors, Iwona Lugowska.
J Clin Oncol, 2021 Dec 22; 40(7). PMID: 34932394    Free PMC article.