Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody.

Abstract:

:Reliable risk assessment for biotherapeutics requires accurate evaluation of risk factors associated with immunogenicity. Immunogenicity risk assessment tools were developed and applied to investigate the immunogenicity of a fully human therapeutic monoclonal antibody, ATR-107 [anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% of healthy subjects in a Phase 1 study. Because the ATR-107 target is expressed on dendritic cells (DCs), the immunogenicity risk related to engagement with DC and antigen presentation pathways was studied. Despite the presence of IL-21R on DCs, ATR-107 did not bind to the DCs more extensively than the control therapeutic antibody (PF-1) that had elicited low clinical ADA incidence. However, ATR-107, but not the control therapeutic antibody, was translocated to the DC late endosomes, co-localized with intracellular antigen-D related (HLA-DR) molecules and presented a dominant T cell epitope overlapping the complementarity determining region 2 (CDR2) of the light chain. ATR-107 induced increased DC activation exemplified by up-regulation of DC surface expression of CD86, CD274 (PD-L1) and CD40, increased expansion of activated DC populations expressing CD86(hi), CD40(hi), CD83(hi), programmed death ligand 1 (PD-L1)(hi), HLA-DR(hi) or CCR7(hi), as well as elevated secretion of tumour necrosis factor (TNF)-α by DCs. DCs exposed to ATR-107 stimulated an autologous T cell proliferative response in human donor cells, in concert with the detection of immunoglobulin (Ig)G-type anti-ATR-107 antibody response in clinical samples. Collectively, the enhanced engagement of antigen presentation machinery by ATR-107 was suggested. The approaches and findings described in this study may be relevant to identifying lower immunogenicity risk targets and therapeutic molecules.

journal_name

Clin Exp Immunol

authors

Xue L,Hickling T,Song R,Nowak J,Rup B

doi

10.1111/cei.12711

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

102-13

issue

1

eissn

0009-9104

issn

1365-2249

journal_volume

183

pub_type

杂志文章
  • A controlled trial of treatment of acquired immunodeficiency in severe measles with thymic humoral factor.

    abstract::A randomized controlled trial of treatment with thymic humoral factor (THF) in 20 children with severe complicated acute measles infection, resulted in objective benefit as evidenced by improvement in the ESR and a fall in C-reactive protein, fewer complications and a reduced incidence of secondary herpes infection. A...

    journal_title:Clinical and experimental immunology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:

    authors: Beatty DW,Handzel ZT,Pecht M,Ryder CR,Hughes J,McCabe K,Trainin N

    更新日期:1984-06-01 00:00:00

  • Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia.

    abstract::We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repai...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.2001.01625.x

    authors: Racioppi L,Cancrini C,Romiti ML,Angelini F,Di Cesare S,Bertini E,Livadiotti S,Gambarara MG,Matarese G,Lago Paz F,Stefanini M,Rossi P

    更新日期:2001-12-01 00:00:00

  • Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis.

    abstract::A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/cei.13010

    authors: Cameron SA,White SM,Arrollo D,Shulman ST,Rowley AH

    更新日期:2017-11-01 00:00:00

  • Role of membrane-associated lymphotoxin (mLT) in the killing activity of lymphokine-activated killer (LAK) cells towards various tumour cell lines.

    abstract::Human lymphokine-activated killer (LAK) cells developed by an incubation of peripheral mononuclear cells with IL-2 express the membrane-associated lymphotoxin (LT)-related molecule (mLT). By a further cultivation of mLT expressing (mLT-positive) LAK cells for 24 h without IL-2, mLT disappears (mLT-negative LAK cells)....

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.1994.tb06245.x

    authors: Horiuchi A,Abe Y,Miyake M,Kimura K,Hitsumoto Y,Takeuchi N,Kimura S

    更新日期:1994-04-01 00:00:00

  • Seroreactivity with the Plasmodium falciparum blood stage antigen Pf332 in adults and children from malaria-endemic regions.

    abstract::It has earlier been reported that the human monoclonal antibody (MoAb 33G2) and polyclonal antibodies reactive with Pf332 may interfere in vitro with the erythrocytic cycle of Plasmodium falciparum at two potential target sites for protective antibodies, indicating that the antigen may constitute an important target f...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.1993.tb05979.x

    authors: Iqbal J,Perlmann P,Greenwood BM,Berzins K

    更新日期:1993-10-01 00:00:00

  • T- and B-lymphocyte subpopulations following radiotherapy for invasive squamous cell carcinoma of the uterine cervix.

    abstract::Lymphocyte subpopulations in patients with cervical carcinoma were studied before and after radiotherapy. T lymphocytes were recognized by their ability to form spontaneous rosettes with sheep erythrocytes (E rosettes). Two surface marker characteristics were used to detect B lymphocytes: receptors for activated compl...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Rand RJ,Jenkins DM,Bulmer R

    更新日期:1978-07-01 00:00:00

  • The immune response to phichi174 in man. IV. Primary and secondary antibody production in patients with chronic lymphatic leukaemia.

    abstract::Ten patients with chronic lymphatic leukaemia (CLL) were injected with the antigen phichi174 intravenously on two occasions to test their capacity for antibody production. Nine out of ten patients failed to develop a primary response, and five out of ten failed to develop a secondary response. Only one out of the ten ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Hamblin TJ,Jones JV,Peacock DB

    更新日期:1975-07-01 00:00:00

  • Regulation of immunoglobulin synthesis by monocytes in multiple myeloma and benign monoclonal gammopathy.

    abstract::The distribution and regulatory function of immunoglobulin (Ig) synthesis by monocytes were assessed using several monoclonal antibodies and a cell sorter in samples from 13 patients with multiple myeloma (MM) and nine patients with benign monoclonal gammopathy (BMG). Since all of these cells were separated directly w...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Takeshita A

    更新日期:1986-12-01 00:00:00

  • Lymphocyte expression of a 90 kD brush border antigen.

    abstract::This study analyses the expression by rat lymphocytes of six renal brush border (BB) antigens defined by a set of monoclonal antibodies and demonstrates that a 90 kD protein (gp 90), synthesized by BB and glomeruli is found on the surface of T and B cells. The other antigens, including the 330 kD protein involved in H...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Van Leer EH,Moullier P,Ronco P,Verroust P

    更新日期:1987-03-01 00:00:00

  • Decrease of peripheral large granular lymphocytes in Graves' disease.

    abstract::Peripheral large granular lymphocytes (LGL) were enumerated in normal subjects and patients with autoimmune thyroid diseases. In normal subjects, the percentage of LGL was significantly lower in women (mean +/- s.d., 17.0 +/- 3.6%; n = 35; P less than 0.05) than in men (19.5 +/- 5.3%; n = 20). In untreated patients wi...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Iwatani Y,Amino N,Kabutomori O,Mori H,Tamaki H,Motoi S,Izumiguchi Y,Miyai K

    更新日期:1984-01-01 00:00:00

  • Requirement of functional T-cells in the production of autoimmune glomerulotubular nephropathy in mice.

    abstract::In order to study T-cell function related to the production of autoimmune nephropathy, we immunized random-bred mice, homozygous athymic nude (nu/nu) mice and heterozygous hairy (nu/+) mice with human glomeruli contained in Freund's complete adjuvant. The random-bred and heterozygous hairy mice developed circulating a...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Bolton WK,Benton FR,Lobo PI

    更新日期:1978-09-01 00:00:00

  • Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation.

    abstract::To define the role of quantitative graft composition and donor killer-cell immunoglobulin-like receptor (KIR) genotype in clinical outcome following unmanipulated peripheral blood stem cell transplantation (PBSCT) from human leucocyte antigen (HLA)-identical siblings, 43 consecutive transplants for haematological mali...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.2007.03360.x

    authors: Clausen J,Wolf D,Petzer AL,Gunsilius E,Schumacher P,Kircher B,Gastl G,Nachbaur D

    更新日期:2007-06-01 00:00:00

  • The costimulatory molecules CD80, CD86 and OX40L are up-regulated in Aspergillus fumigatus sensitized mice.

    abstract::Aspergillus fumigatus (Af) is a fungus associated with allergic bronchopulmonary aspergillosis (ABPA) and other allergic diseases. Immune responses in these diseases are due to T and B cell responses. T cell activation requires both Af-specific engagement of the T-cell-receptor as well as interaction of antigen indepe...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.2005.02905.x

    authors: Barrios CS,Johnson BD,D Henderson J Jr,Fink JN,Kelly KJ,Kurup VP

    更新日期:2005-11-01 00:00:00

  • Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages.

    abstract::Lung cancer is strongly associated with cigarette smoking. More than 20 lung carcinogens have been identified in cigarette smoke and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We hypothesized that NNK modulates alveolar macrophage (AM) mediator production, thus contributing to ca...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.2003.02142.x

    authors: Therriault MJ,Proulx LI,Castonguay A,Bissonnette EY

    更新日期:2003-05-01 00:00:00

  • Up-regulation of ICAM-1, CD11a/CD18 and CD11c/CD18 on human THP-1 monocytes stimulated by Streptococcus suis serotype 2.

    abstract::Streptococcus suis serotype 2 is known to be a major pathogen of swine, causing mainly meningitis. It is also a zoonotic agent leading predominantly to meningitis in humans working in close contact with pigs. In this study, we investigated the ability of S. suis to up-regulate the expression of adhesion molecules invo...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.2003.02189.x

    authors: Al-Numani D,Segura M,Doré M,Gottschalk M

    更新日期:2003-07-01 00:00:00

  • Impaired Ca2+ mobilization by X-linked agammaglobulinaemia (XLA) B cells in response to ligation of the B cell receptor (BCR).

    abstract::XLA bone marrow samples were shown to contain B cells expressing IgM, and pre-B cells that express the mu-surrogate light chain (mu psiLC) complex, albeit at a reduced frequency to that found in normal bone marrow. Antibody ligation of mu heavy chain on these cells and an XLA B cell line did not induce a Ca2+ flux, wh...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.1997.4581478.x

    authors: Genevier HC,Callard RE

    更新日期:1997-12-01 00:00:00

  • Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies.

    abstract::A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospecti...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章,多中心研究

    doi:10.1111/cei.12866

    authors: Borte M,Kriván G,Derfalvi B,Maródi L,Harrer T,Jolles S,Bourgeois C,Engl W,Leibl H,McCoy B,Gelmont D,Yel L

    更新日期:2017-01-01 00:00:00

  • Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).

    abstract::Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.1997.d01-1019.x

    authors: George J,Blank M,Hojnik M,Bar-Meir E,Koike T,Matsuura E,Lorber M,Aviram M,Shoenfeld Y

    更新日期:1997-05-01 00:00:00

  • Long-term serological evaluation of patients with cystic echinococcosis treated with benzimidazole carbamates.

    abstract::Seeking better immunological markers indicating the long-term outcome of cystic echinococcosis (CE) after chemotherapy we studied 23 patients receiving albendazole, clinically followed for 8 years, and grouped ultrasonographically according to therapeutic outcome. Antibody responses against a partially purified fracti...

    journal_title:Clinical and experimental immunology

    pub_type: 临床试验,杂志文章

    doi:10.1046/j.1365-2249.2002.01925.x

    authors: Riganò R,Ioppolo S,Ortona E,Margutti P,Profumo E,Ali MD,Di Vico B,Teggi A,Siracusano A

    更新日期:2002-09-01 00:00:00

  • Differing surface marker characteristics in plasma cell dyscrasias with particular reference to IgM myeloma.

    abstract::Immunological marker studies using direct immunofluorescence and rosette methods were performed on the bone marrow and peripheral blood of an IgM myeloma, and on the peripheral blood of two cases of IgA myeloma and one IgG myeloma. These studies confirmed the peripheral blood involvement in plasma cell dyscrasias. In ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Burns GF,Cawley JC,Barker CR,Worman CP,Raper CG,Hayhoe FG

    更新日期:1978-03-01 00:00:00

  • Adhesion of polymorphonuclear cells to human endothelial cells. Adhesion-molecule-dependent, and Fc receptor-mediated adhesion-molecule-independent mechanisms.

    abstract::Activation of human umbilical vein endothelial (HUVE) cells with the inflammatory mediators tumour necrosis factor-alpha (TNF), interleukin-1 (IL-1), lipopolysaccharide (LPS) and phorbol esters enhanced their adhesiveness for leucocytes. The appearance of an activation antigen ELAM-1, recognized by a monoclonal antibo...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.1990.tb05362.x

    authors: Leeuwenberg JF,Jeunhomme GM,Buurman WA

    更新日期:1990-09-01 00:00:00

  • Interleukin-2 inhibits polarization to T helper type 1 cells and prevents mouse acute graft-versus-host disease through up-regulating suppressors of cytokine signalling-3 expression of naive CD4+ T cells.

    abstract::T helper type 1 (Th1)-type polarization plays a critical role in the pathophysiology of acute graft-versus-host disease (aGVHD). The differentiation of T cells into this subtype is dictated by the nature of the donor naive CD4(+) T cell-host antigen presenting cell (APC) interaction. Suppressors of cytokine signalling...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.2010.04089.x

    authors: Zhao J,Zhang T,He H,Xie Y

    更新日期:2010-06-01 00:00:00

  • Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry.

    abstract::Acute RSV infection in infancy may produce some asthma-like symptoms and may be followed by a recurrent wheeze later in childhood. It has been proposed that RSV infection stimulates type-2 cytokine responses, resembling those found in atopy and asthma. Peripheral blood cells were obtained from RSV-infected infants (n ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.2000.01297.x

    authors: Bendelja K,Gagro A,Bace A,Lokar-Kolbas R,Krsulovic-Hresic V,Drazenovic V,Mlinaric-Galinovic G,Rabatic S

    更新日期:2000-08-01 00:00:00

  • Pre-neutralization of C5a-mediated effects by the monoclonal antibody 137-26 reacting with the C5a moiety of native C5 without preventing C5 cleavage.

    abstract::Complement C5a is aetiologically linked to inflammatory tissue damage in conditions like septicaemia, immune complex diseases and ischaemia-reperfusion injury. We here describe a monoclonal antibody (mAb), 137-26, that binds to the C5a moiety of human C5 and neutralizes the effects of C5a without interfering with C5 c...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1046/j.1365-2249.2003.02213.x

    authors: Fung M,Lu M,Fure H,Sun W,Sun C,Shi NY,Dou Y,Su J,Swanson X,Mollnes TE

    更新日期:2003-08-01 00:00:00

  • Anti-atherogenic peptide Ep1.B derived from apolipoprotein E induces tolerogenic plasmacytoid dendritic cells.

    abstract::Tolerogenic dendritic cells (DCs) play a critical role in the induction of regulatory T cells (Tregs ), which in turn suppress effector T cell responses. We have previously shown the induction of DCs from human and mouse monocytic cell lines, mouse splenocytes and human peripheral blood monocytes by a novel apolipopro...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/cei.12370

    authors: Bellemore SM,Nikoopour E,Au BC,Krougly O,Lee-Chan E,Haeryfar SM,Singh B

    更新日期:2014-09-01 00:00:00

  • The immune response to the cell wall of Mycobacterium bovis BCG.

    abstract::Mice were immunized with the cell wall of BCG suspended in an oil-in-saline emulsion, and examined against time for the emergence of T cell-mediated acquired immunity. Evidence is presented that shows that levels of acquired resistance expressed in these animals over the first month following inoculation, and which en...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Orme IM

    更新日期:1988-03-01 00:00:00

  • Interferon production by cultured peripheral leucocytes of MS patients.

    abstract::Peripheral blood leucocytes from multiple sclerosis (MS) patients and from normal individuals were tested for their interferon (IFN) producing capacity after stimulation in vitro with various lectins and viruses. The lectins, Con A, PHA and PWM, induced IFN-gamma. In a kinetic study, the response to Con A revealed its...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:

    authors: Vervliet G,Carton H,Meulepas E,Billiau A

    更新日期:1984-10-01 00:00:00

  • Macrophage migration inhibitory factor deficiency protects pancreatic islets from cytokine-induced apoptosis in vitro.

    abstract::During pathogenesis of diabetes, pancreatic islets are exposed to high levels of cytokines and other inflammatory mediators that induce deterioration of insulin-producing beta cells. Macrophage migration inhibitory factor (MIF) plays a key role in the onset and development of several immunoinflammatory diseases and al...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2249.2012.04607.x

    authors: Stojanovic I,Saksida T,Nikolic I,Nicoletti F,Stosic-Grujicic S

    更新日期:2012-08-01 00:00:00

  • H-ferritin and CD68(+) /H-ferritin(+) monocytes/macrophages are increased in the skin of adult-onset Still's disease patients and correlate with the multi-visceral involvement of the disease.

    abstract::Adult-onset Still's disease (AOSD) patients may show an evanescent salmon-pink erythema appearing during febrile attacks and reducing without fever. Some patients may experience this eruption for many weeks. During AOSD, exceptionally high serum levels of ferritin may be observed; it is an iron storage protein compose...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/cei.12826

    authors: Ruscitti P,Cipriani P,Ciccia F,Di Benedetto P,Liakouli V,Berardicurti O,Carubbi F,Guggino G,Di Bartolomeo S,Triolo G,Giacomelli R

    更新日期:2016-10-01 00:00:00

  • Antigen-specific over-expression of human cartilage glycoprotein 39 on CD4+ CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose-6-phosphate isomerase-induced arthritis.

    abstract::Human cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a glucose-6-phosphate isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. ...

    journal_title:Clinical and experimental immunology

    pub_type: 杂志文章

    doi:10.1111/cei.12349

    authors: Tanaka Y,Matsumoto I,Inoue A,Umeda N,Takai C,Sumida T

    更新日期:2014-08-01 00:00:00