Abstract:
:A common feature of human IgG1 antibodies used for cancer treatment is that their anti-tumour efficacy requires high serum trough levels and continued therapy for several months. Treatment cycles, thereby, consume several grams of IgG1 translating into significant drug needs and costs. The basis for the low in vivo efficacy, which is in contrast to high in vitro antibody-dependent cellular cytotoxicity (ADCC), is not well understood. Here, we have explored factors contributing to this discrepancy using adecatumumab (MT201), a fully human monoclonal IgG1 against epithelial cell adhesion molecule (Ep-CAM) and trastuzumab (Herceptin), a humanized IgG1 with specificity for the human epithelial growth factor receptor type 2 (HER-2) antigen. We found that physiological levels of human sera strongly inhibited ADCC of both IgG1 antibodies. Effects showed some dependence on the density of Ep-CAM and HER-2 targets, the tumour cell line tested and on effector cell and serum donors. Removal of IgG by affinity chromatography abolished the inhibitory effect of a serum pool. Inhibition of ADCC was fully restored by adding back the IgG fraction or by an equal amount of IgG from a commercial source. We further demonstrate that CD56-positive lymphocytes within human PBMC contributed >90% to ADCC and that normal serum levels of IgG effectively competed for in vitro binding of an IgG1 antibody to low-affinity Fcgamma receptor type III (CD16), as is present on natural killer (NK) cells. Competition of serum IgG for binding of therapeutic IgG1 to NK cell may be one important reason why high antibody doses are required in the clinic for treatment of cancer by an ADCC-based mechanism.
journal_name
Mol Immunoljournal_title
Molecular immunologyauthors
Preithner S,Elm S,Lippold S,Locher M,Wolf A,da Silva AJ,Baeuerle PA,Prang NSdoi
10.1016/j.molimm.2005.07.010subject
Has Abstractpub_date
2006-03-01 00:00:00pages
1183-93issue
8eissn
0161-5890issn
1872-9142pii
S0161-5890(05)00286-5journal_volume
43pub_type
杂志文章abstract::Excessive production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) plays a key role in the pathophysiological development of osteoarthritis (OA). Orexin A is an important peptide of hypothalamic origin, which has displayed its multiple biological functions in several chronic diseases via activation of i...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2018.05.012
更新日期:2018-09-01 00:00:00
abstract::Effective immunization with short polypeptide antigens has typically only been possible when the peptide is conjugated to a large carrier substance, usually a protein. Such immunizations suffer from difficulties in producing conjugates of reliable composition, and from unwanted anti-carrier immune responses. When a ch...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(84)90084-1
更新日期:1984-01-01 00:00:00
abstract::The ragweed allergens Amb t 5 and Amb a 5 are among the smallest inhaled protein allergens known, containing a single, immunodominant T-cell epitope. In this study we analyzed the B-cell epitope structure of Amb t 5. The three-dimensional structures of Amb t 5 and Amb a 5 have been determined by NMR spectroscopy, prov...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/s0161-5890(99)00054-1
更新日期:1998-06-01 00:00:00
abstract::Despite the fact that was one of the first systems to be discovered and investigated in the innate immunity, Complement is continuing to receive growing attention by the scientific community. Complement is involved in several diseases such as diabetes, atherosclerosis or Systemic Lupus Erythematous. Successful therape...
journal_title:Molecular immunology
pub_type: 历史文章,杂志文章,评审
doi:10.1016/j.molimm.2015.06.003
更新日期:2015-11-01 00:00:00
abstract::Of the antioxidant/prooxidant mechanisms mediating the regulation of inflammatory mediators, particularly cytokines, oxidative stress-related pathways remain a cornerstone. It is conspicuous that there is a strong association between free radical accumulation (ROS/RNS; oxidative stress) and the evolution of inflammati...
journal_title:Molecular immunology
pub_type: 杂志文章,评审
doi:10.1016/j.molimm.2004.09.029
更新日期:2005-05-01 00:00:00
abstract::The antigenicity of Human Immunodeficiency Virus type 1 (HIV-1) matrix p18 protein was evaluated by analyzing the specificity of anti-p18 antibodies elicited either in HIV-1 infected humans, or in HIV-1 infected or immunized chimpanzees, against a panel of long and short overlapping synthetic peptides [from 12 to 46 a...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(93)90118-u
更新日期:1993-04-01 00:00:00
abstract::Glycophorin, one of the major glycoproteins of erythrocytes (E), was extracted from human E (glycophorin-Hu) and guinea pig E (glycophorin-GP) and adsorbed to rabbit-E. The adsorption of glycophorin-Hu and glycophorin-GP to rabbit-E made the E resistant to hemolysis by human serum and guinea pig serum, respectively, v...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(83)90148-7
更新日期:1983-11-01 00:00:00
abstract::The mechanisms of each subset of immune cells contributing to the pathogenesis of viral hepatitis remain incompletely understood. In this study, we examined the role of liver CD4(-) CD8(-) (double negative, DN) T cells during murine hepatitis virus strain 3 (MHV-3)-induced hepatitis in C3H/HeJ mice. We demonstrate tha...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2012.05.017
更新日期:2012-10-01 00:00:00
abstract::The role of secondary structures and base mutability at different levels of transcription and supercoiling is analyzed in variable region antibody genes VH5, VH94 and VH186.2. The data are consistent with a model of somatic hypermutation in which increasing levels of transcription and secondary structure stability cor...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2008.05.012
更新日期:2008-08-01 00:00:00
abstract::Whether bovine myelin basic protein (BP) and bovine spinal cord protein (SCP) cross-react at the humoral immune level was assessed with a sensitive solid-phase enzyme immunoassay. We found that a hyperimmune anti-SCP serum reacted strongly with SCP and cross-reacted nearly as well with BP. A hyperimmune anti-BP serum ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(84)90159-7
更新日期:1984-10-01 00:00:00
abstract::Recent studies suggest that CD8(+) T cells with down-regulated CD8 expression (CD3(+)CD8(low) T cells) represented as a distinct phenotype of CD8(+) T cells are increased and linked to disease severity in some chronically persistent infection, such as chronic HIV and parasite infection. However, the role of CD3(+)CD8(...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2013.07.003
更新日期:2013-12-01 00:00:00
abstract::Systemic lupus erythematosus (SLE) is a typical autoimmune disease with unclear etiology. Aberrant self-DNA recognition has been proven critical for the initiation of excessive immune responses in lupus. Consistently, we previously reported that a sort of self-DNA, activated lymphocyte-derived DNA (ALD-DNA) could pote...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2015.01.023
更新日期:2015-05-01 00:00:00
abstract::Rheumatoid arthritis (RA) is a destructive polyarthritis in which synovial-like fibroblasts (SFs) invade and erode cartilage by expressing membrane-anchored type 1 matrix metalloproteinase (MT1-MMP). The mitogen activated protein kinase (MAPK) pathway is activated in RA SFs, but the mechanism of activation is unknown....
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2013.02.001
更新日期:2013-10-01 00:00:00
abstract::It is well established that aggregation of cell surface immunoglobulin is involved in signal transduction by cells of the immune system. It is less well understood what special properties of these cell surface aggregates are important in initiating the signal cascade. Several authors have proposed that cells respond t...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(94)90160-0
更新日期:1994-12-01 00:00:00
abstract::Innate lymphoid cells (ILCs) contribute to the regulation of gastrointestinal (GI) homeostasis. Over the past 15 years, there has been a large effort to dissect the mechanisms required for GI homeostasis, with a major focus on different immune cell populations and the cytokines that they produce. In contrast to T-help...
journal_title:Molecular immunology
pub_type: 杂志文章,评审
doi:10.1016/j.molimm.2017.11.013
更新日期:2019-06-01 00:00:00
abstract::The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword t...
journal_title:Molecular immunology
pub_type: 杂志文章,评审
doi:10.1016/j.molimm.2017.05.028
更新日期:2017-09-01 00:00:00
abstract::Since secretion of IgE antibodies is known to be blocked by tunicamycin, the first aim of the present study was to determine at which step of glycosylation or processing secretion was restored. For this purpose, murine hybridoma cells secreting an anti beta-lactoglobulin IgE were incubated either in the presence of in...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(87)90187-8
更新日期:1987-08-01 00:00:00
abstract::Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (CD46...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2006.08.004
更新日期:2007-03-01 00:00:00
abstract::C-reactive protein (CRP) is a pattern recognition molecule that binds several microbial and host ligands. Ligand-bound CRP activates the complement system via the classical pathway. Previously, we identified human complement factor H-related protein 4 (CFHR4), a member of the factor H protein family, as a CRP binding ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2009.12.005
更新日期:2010-03-01 00:00:00
abstract::Previous work on the cis-acting elements that control heavy chain variable region (VH) gene somatic hypermutation has indicated the presence of an as yet unidentified element(s) 3' of the intron enhancer that is necessary for high rate mutation. Examination of cis-acting elements involved in kappa light chain V gene h...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/s0161-5890(97)00065-5
更新日期:1997-04-01 00:00:00
abstract::We have examined the regulation of the AP-1 DNA transcription complex during T cell activation in response to interleukin 1 (IL-1) and phorbol ester (TPA) treatment of the IL-1 responsive murine thymoma T cell line, EL4 6.1 C 10. IL-1 synergistically enhances the stimulatory effect of TPA on AP-1-mediated gene express...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(95)00055-j
更新日期:1995-08-01 00:00:00
abstract::Natural killer cells fail to lyse target cells expressing sufficient levels of self MHC class I molecules, providing one mechanism to secure self tolerance. Inhibition of lysis is mediated by inhibitory receptors expressed by NK cells, such as the murine Ly49 receptors, human KIR receptors and CD94/NKG2A, expressed by...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2004.07.018
更新日期:2005-02-01 00:00:00
abstract::The site of the murine IgG1 molecule that regulates catabolism has recently been shown to encompass amino acids that are located at the CH2-CH3 domain interface. The CH2 and CH3 domains are connected to each other by a relatively flexible "mini-hinge" region, and flexibility in this region could clearly affect the ori...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(95)00019-b
更新日期:1995-05-01 00:00:00
abstract::Complement plays a dual role in the progression of systemic lupus erythematosus since it has important protective functions, such as the clearance of immune complexes and apoptotic cells, but is also a mediator of renal inflammation. To investigate this balance in a clinically relevant setting, we investigated how tar...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2011.09.015
更新日期:2011-10-01 00:00:00
abstract::In Drosophila the synthesis of antimicrobial peptides in response to microbial infections is under the control of the Toll and immune deficiency (Imd) signaling pathways. The Toll signaling pathway responds mainly to Gram-positive bacterial and fungal infection while the Imd pathway mediates the response to Gram-negat...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2008.01.015
更新日期:2008-05-01 00:00:00
abstract::IL-10 plays a critical role in controlling inflammation and the anti-inflammatory functions of IL-10 are regulated based on its coordinated expression from various cellular sources, most notably T cells. Although nearly all CD4+ subpopulations can express IL-10, surprisingly little is known about the molecular mechani...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2010.09.009
更新日期:2010-11-01 00:00:00
abstract::Aggregation of therapeutic proteins is a key factor in the generation of unwanted immunogenicity, and can result in reduced serum half-life, neutralization of function and adverse health effects. There is currently little information regarding how aggregates interact with B-cell receptors or cognate antibodies at the ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2018.11.020
更新日期:2019-01-01 00:00:00
abstract::PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2020.06.013
更新日期:2020-09-01 00:00:00
abstract::Neutrophil migration is essential for battling against infections but also drives chronic inflammation. Since primary neutrophils are terminally differentiated and not genetically tractable, leukemia cells such as HL-60 are differentiated into neutrophil-like cells to study mechanisms underlying neutrophil migration. ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/j.molimm.2019.06.001
更新日期:2019-08-01 00:00:00
abstract::The high affinity receptor for IgE, which mediates allergic reactions, is found exclusively on mast cells, basophils and epidermal Langerhans cells. It is composed of an alpha, beta and two gamma-polypeptide chains, inserted as a complex into the plasma membrane. The alpha and beta-subunits are produced only by these ...
journal_title:Molecular immunology
pub_type: 杂志文章
doi:10.1016/0161-5890(96)84614-1
更新日期:1996-07-01 00:00:00