Showing papers on "Antibody published in 2007"
TL;DR: Trastuzumab, a humanized monoclonal antibody that targets HER2, is approved by the Food and Drug Administration for patients with invasive breast cancers that overexpress HER2.
Abstract: Overexpression of human epidermal growth factor receptor type 2 (HER2) in breast cancer is associated with decreased overall survival. Trastuzumab, a humanized monoclonal antibody that targets HER2, is approved by the Food and Drug Administration for patients with invasive breast cancers that overexpress HER2. This review considers the mechanism of action and the use of this agent.
2,315 citations
TL;DR: Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8+ T lymphocyte count are independent prognostic factors and the PD-1/PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer.
Abstract: The ligands for programmed cell death 1 (PD-1), an immunoinhibitory receptor belonging to CD28/cytotoxic T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls) Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells Although an inverse correlation between the expression level of PD-Ls and patients' prognosis has been reported for several malignant tumors, the follow-up period was limited because of the lack of the antibody (Ab) applicable to paraffin-embedded specimens Here we generated a new Ab against PD-1 ligand 1 (PD-L1) and analyzed the expression level of PD-Ls in human ovarian cancer using paraffin-embedded specimens Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression Although patients with higher expression of PD-1 ligand 2 also had a poorer prognosis, the difference was not statistically significant A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8+ T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8+ T cells Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8+ T lymphocyte count are independent prognostic factors The PD-1/PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer
1,308 citations
TL;DR: Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality.
Abstract: A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.
1,191 citations
TL;DR: Quantitative analysis of serologic memory for multiple antigens in subjects followed longitudinally over the course of more than one decade suggests that peripheral memory B cells and antibody-secreting plasma cells may represent independently regulated cell populations and may play different roles in the maintenance of protective immunity.
Abstract: We performed a longitudinal analysis of antibody titers specific for viral antigens (vaccinia, measles, mumps, rubella, varicella–zoster virus, and Epstein–Barr virus) and nonreplicating antigens (tetanus and diphtheria) in 45 subjects for a period of up to 26 years. In addition, we measured antigen-specific memory B cells by means of limiting-dilution analysis, and we compared memory B-cell frequencies to their corresponding serum antibody levels. Results Antiviral antibody responses were remarkably stable, with half-lives ranging from an estimated 50 years for varicella–zoster virus to more than 200 years for other viruses such as measles and mumps. Antibody responses against tetanus and diphtheria antigens waned more quickly, with estimated half-lives of 11 years and 19 years, respectively. B-cell memory was long-lived, but there was no significant correlation between peripheral memory B-cell numbers and antibody levels for five of the eight antigens tested. Conclusions These studies provide quantitative analysis of serologic memory for multiple antigens in subjects followed longitudinally over the course of more than one decade. In cases in which multiple exposures or repeated vaccinations were common, memory B-cell numbers did not correlate with antibody titers. This finding suggests that peripheral memory B cells and antibody-secreting plasma cells may represent independently regulated cell populations and may play different roles in the maintenance of protective immunity.
1,043 citations
TL;DR: There is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody.
Abstract: Many effective vaccines act by inducing neutralizing antibodies, and this approach is a top priority in work on HIV vaccines. But a new study suggests that anti-HIV antibodies are most effective when they act in two ways: through neutralization — killing the virus outright and blocking its entry into T cells — and by killing infected cells. The use of engineered versions of a neutralizing human antibody that protects against HIV in a monkey model shows that protection is dependent not only the antibody's neutralizing activity, but also on its interaction with Fc receptors on effector cells, which may act to reduce virus yield from infected cells. This work suggests that the best results might be achieved with vaccines that recruit both neutralizing antibodies and cell-mediated immunity via agents such as macrophages and cytokinins, rather than antibodies. Passively administered neutralizing antibodies have been shown to protect macaques against challenge by the HIV/SIV chimeric SHIV. The antiviral effects of the monoclonal antibody b12 are crucially dependent on antibody effector mechanisms. Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.
882 citations
TL;DR: IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.
Abstract: Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.
879 citations
TL;DR: This double-blind, placebo-controlled trial demonstrates the therapeutic efficacy of an interleukin-12/23 monoclonal antibody in psoriasis and provides further evidence of a role of the interleUKin- 12/23 p40 cytokines in the pathophysiology of Psoriasis.
Abstract: Background Skin-infiltrating lymphocytes expressing type 1 cytokines have been linked to the pathophysiology of psoriasis. We evaluated the safety and efficacy of a human interleukin-12/23 monoclonal antibody in treating psoriasis. Methods In this double-blind, placebo-controlled trial, 320 patients with moderate-to-severe plaque psoriasis underwent randomization to treatment with the interleukin-12/23 monoclonal antibody (one 45-mg dose, one 90-mg dose, four weekly 45-mg doses, or four weekly 90-mg doses) or placebo; 64 patients were randomly assigned to each group. Patients assigned to the interleukin-12/23 monoclonal antibody received one additional dose at week 16 if needed. Patients assigned to placebo crossed over to receive one 90-mg dose of interleukin-12/23 monoclonal antibody at week 20. Results There was at least 75% improvement in the psoriasis area-and-severity index at week 12 (the primary end point) in 52% of patients who received 45 mg of the interleukin-12/23 monoclonal antibody, in 59% o...
784 citations
TL;DR: Using two-photon microscopy of mouse lymph nodes, it is revealed that GC B cells are highly motile and extend long cell processes, and a model in which competition for T cell help plays a more dominant role in the selection of GC B Cells is proposed.
Abstract: The germinal center (GC) is an important site for the generation and selection of B cells bearing high-affinity antibodies, yet GC cell migration and interaction dynamics have not been directly observed. Using two-photon microscopy of mouse lymph nodes, we revealed that GC B cells are highly motile and extend long cell processes. They transited between GC dark and light zones and divided in both regions, although these B cells resided for only several hours in the light zone where antigen is displayed. GC B cells formed few stable contacts with GC T cells despite frequent encounters, and T cells were seen to carry dead B cell blebs. On the basis of these observations, we propose a model in which competition for T cell help plays a more dominant role in the selection of GC B cells than previously appreciated.
769 citations
TL;DR: The authors' data indicate that bacteria elicit IgA(2) class switching by linking lamina propria B cells with IECs through a TLR-inducible signaling program requiring APRIL.
693 citations
TL;DR: Foxp3+ and Foxp3− precursor cells give rise to peripheral IL-10-expressing Treg cells by a mechanism dependent on transforming growth factor-β and independent of IL- 10.
Abstract: CD4(+) regulatory T cells (T(reg) cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track T(reg) subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3(+)IL-10(-) T(reg) cells, whereas the large and small intestine had enrichment of Foxp3(+)IL-10(+) and Foxp3(-)IL-10(+) T(reg) cells, respectively. Although negative for Il10 expression, both Foxp3(+) and Foxp3(-) CD4(+) thymic precursor cells gave rise to peripheral IL-10(+) T(reg) cells, with only Foxp3(-) precursor cells giving rise to all T(reg) subsets. Each T(reg) subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-beta. Thus, Foxp3(+) and Foxp3(-) precursor cells give rise to peripheral IL-10-expressing T(reg) cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10.
594 citations
TL;DR: The results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.
TL;DR: In this article, the authors established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay.
Abstract: NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel. Recently, we established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay. So far, there has been no large-scale study on anti-AQP4 antibody titre in NMO and related disorders. We tested 148 sera of patients with NMO, high-risk syndrome of NMO, multiple sclerosis (MS), clinically isolated syndrome suggestive of MS and miscellaneous diseases. We analysed the relation of anti-AQP4 antibody titres and clinical and laboratory parameters. The sensitivity of anti-AQP4 antibody assay was 91% (95% CI 79-100) for NMO and 85% (65-100) for high-risk syndrome, and the specificity was 100% (91-100) for NMO and high-risk syndrome, that is, none with the other disorders was positive. Among 21 anti-AQP4 antibody-positive cases whose NMO-IgG were tested, 15 were NMO-IgG-positive and 6 were NMO-IgG-negative. Higher anti-AQP4 antibody titres were associated with complete blindness and extensive or large cerebral lesions on MRI. The lengths of spinal cord lesions on MRI were positively correlated with the titres of anti-AQP4 antibody at the nadir of exacerbations. A few patients who had short (approx. one to two vertebral segments) spinal cord lesions on MRI were also seropositive with low anti-AQP4 antibody titres, but did have other clinical and MRI features of NMO. Anti-AQP4 antibody titres became lower after high-dose methylprednisolone, and a follow-up showed anti-AQP4 antibody titres remained low in relapse-free periods under immunosuppression. Cerebrospinal fluid (CSF)-anti-AQP4 antibody was detected when the serum-antibody titres exceeded 512x, at the ratio of 1 (CSF) to 500 (serum). Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti-AQP4 antibody titres have significant clinical and immunological implications in NMO.
TL;DR: B7-H1 expression by MM cells represents a possible immune escape mechanism that could be targeted therapeutically through inhibition of MyD88/TRAF6 and MEK/ERK/STAT1.
TL;DR: These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.
Abstract: Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.
Journal Article•
TL;DR: Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti- AQP 4 antibody titres have significant clinical and immunological implications in NMO.
Abstract: NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel. Recently, we established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay. So far, there has been no large-scale study on anti-AQP4 antibody titre in NMO and related disorders. We tested 148 sera of patients with NMO, high-risk syndrome of NMO, multiple sclerosis (MS), clinically isolated syndrome suggestive of MS and miscellaneous diseases.We analysed the relation of anti-AQP4 antibody titres and clinical and laboratory parameters. The sensitivity of anti-AQP4 antibody assay was 91% (95% Cl 79-100) for NMO and 85% (65-100) for high-risk syndrome, and the specificity was 100% (91-100) for NMO and high-risk syndrome, that is, none with the other disorders was positive. Among 21 anti-AQP4 antibody-positive cases whose NMO-IgG were tested, 15 were NMO-lgG-positive and 6 were NMO-lgG-negative. Higher anti-AQP4 antibody titres were associated with complete blindness and extensive or large cerebral lesions on MRI. The lengths of spinal cord lesions on MRI were positively correlated with the titres of anti-AQP4 antibody at the nadir of exacerbations. A few patients who had short (approx. one to two vertebral segments) spinal cord lesions on MRI were also seropositive with low anti-AQP4 antibody titres, but did have other clinical and MRI features of NMO. Anti-AQP4 antibody titres became lower after high-dose methylprednisolone, and a follow-up showed anti-AQP4 antibody titres remained low in relapse-free periods under immunosuppression. Cerebrospinal fluid (CSF)-anti-AQP4 antibody was detected when the serum-antibody titres exceeded 512x, at the ratio of I (CSF) to 500 (serum). Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti-AQP4 antibody titres have significant clinical and immunological implications in NMO.
TL;DR: A minimized SPA derivative has been constructed and a domain originating from SPA has been improved to withstand the harsh environment employed in industrial purifications.
TL;DR: The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity, and a dose-related upregulation of costimulatory molecules after treatment was found.
Abstract: Purpose The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study. Patients and Methods Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response. Results Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocyte...
TL;DR: Surprisingly, it was found that self-reactive antibodies including anti-nuclear antibodies were frequently expressed by IgG(+) memory B cells in healthy donors.
TL;DR: The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently.
Abstract: Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells and primary CD4(+) T cells are formed, cell-associated transfer of virus is 18,000-fold more efficient than uptake of cell-free virus. Furthermore, in contrast to cell-free virus uptake, the VS deposits virus rapidly into focal, trypsin-resistant compartments in target T cells. This massive virus internalization requires Env-CD4 receptor interactions but is resistant to inhibition by patient-derived neutralizing antisera that inhibit homologous cell-free virus. Deleting the Env cytoplasmic tail does not abrogate VS-mediated transfer, but it renders the VS sensitive to neutralizing antibodies, suggesting that the tail limits exposure of VS-neutralizing epitopes on the surface of infected cells. Dynamic live imaging of the VS reveals that HIV-expressing cells are polarized and make sustained, Env-dependent contacts with target cells through uropod-like structures. The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently. Future studies will discern to what extent this massive viral transfer contributes to productive infection or viral dissemination through the migration of virus-carrying T cells.
TL;DR: During chronic infection HCV is subjected to selection pressures from both humoral and cellular immunity, resulting in the continuous generation of escape variants.
TL;DR: Presensitization of kidney-transplant recipients against MICA antigens is associated with an increased frequency of graft loss and might contribute to allograft loss among recipients who are well matched for HLA.
Abstract: Background Good HLA-A, HLA-B, and HLA-DR matches do not guarantee rejection-free renal transplantation. Some kidney transplants fail despite such matches, suggesting that other antigens might be targets for rejection. Major-histocompatibility-complex (MHC) class I–related chain A (MICA) antigens are polymorphic and can elicit antibody production. We sought to determine whether an immune response to MICA antigens might play a role in the failure of kidney allografts. Methods Pretransplantation serum samples from 1910 recipients of kidney transplants from deceased donors were tested for anti-MICA antibodies with an assay in which single MICA antigens were attached to polystyrene microspheres. Results Antibodies against MICA alleles were detected in 217 of the 1910 patients (11.4%). The presence of MICA antibodies was associated with renal-allograft rejection. The mean (±SE) 1-year graft-survival rate was 88.3±2.2% among recipients with anti-MICA antibodies as compared with 93.0±0.6% among recipients without...
TL;DR: It is demonstrated that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease.
Abstract: The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.
TL;DR: Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4–binding region of HIV-1 gp120.
Abstract: We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4–binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1–infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.
TL;DR: Recent advances support the hypothesis that enhanced states of local humoral and innate immune activation, in combination with suppressed cellular immunity and failed cytotoxic T cell anti-tumor immunity, alter cancer risk and therefore represent powerful targets for anti-cancer immunotherapeutics.
TL;DR: Although no significant difference of human neonatal Fc receptor (FcRn)-binding affinity was observed among the three types, the complex type showed longer serum half-lives than the other types irrespective of core fucosylation in mice, which suggests the contribution of the nonreducing end structure.
Abstract: The structure of asparagine-linked oligosaccharides attached to the antibody constant region (Fc) of human immunoglobulin G1 (IgG1) has been shown to affect the pharmacokinetics and antibody effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, it is still unclear how differences in the N-linked oligosaccharide structures impact the biological activities of antibodies, especially those lacking core fucose. Here, we succeeded in generating core fucose-lacking human IgG1 antibodies with three different N-linked Fc oligosaccharides, namely, a high-mannose, hybrid, and complex type, using the same producing clone, and compared their activities. Cultivation of an a-1,6-fucosyltransferase (FUT8) knockout Chinese hamster ovary cell line in the presence or absence of a glycosidase inhibitor (either swainsonine or kifunensine) yielded antibody production of each of the three types without contamination by the others. Two of three types of nonnaturally occurring atypical oligosaccharide IgG1, except the complex type, reduced the affinity for both human lymphocyte receptor IIIa (FcgRIIIa) and the C1q component of the complement, resulting in reduction of ADCC and CDC. The bulky structure of the nonreducing end of N-linked Fc oligosaccharides is considered to contribute the CDC change, whereas the structural change in the reducing end, i.e. the removal of core fucose, causes ADCC enhancement through improved FcgRIIIa binding. In the pharmacokinetic profile, although no significant difference of human neonatal Fc receptor (FcRn)-binding affinity was observed among the three types, the complex type showed longer serum half-lives than the other types irrespective of core fucosylation in mice, which also suggests the contribution of the nonreducing end structure. The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities.
TL;DR: It is suggested that HCV can transmit in vitro by at least two routes, cell‐free virus infection and direct transfer between cells, with the latter offering a novel route for evading nAbs.
TL;DR: In vitro analyses of pairs of monoclonal human IgG Abs that differ in the amount of sialic acid in their Fc glycans reveal the first example of an Fc glycan structure impacting antigen binding and suggest that avoiding Fc Glycan sialylation can offer another means of optimizing ADCC activity of Abs.
TL;DR: The most potent immunotoxins are made from bacterial and plant toxins as discussed by the authors, which are composed of an antibody fragment linked to a toxin, and the immunotoxin binds to a surface antigen on a cancer cell, enters the cell by endocytosis, and kills it.
Abstract: Immunotoxins are proteins used to treat cancer that are composed of an antibody fragment linked to a toxin. The immunotoxin binds to a surface antigen on a cancer cell, enters the cell by endocytosis, and kills it. The most potent immunotoxins are made from bacterial and plant toxins. Refinements over many years have produced recombinant immunotoxins; these therapeutic proteins are made using protein engineering. Individual immunotoxins are designed to treat specific cancers. To date, most success has been achieved treating hematologic tumors. Obstacles to successful treatment of solid tumors include poor penetration into tumor masses and the immune response to the toxin component of the immunotoxin, which limits the number of cycles that can be given. Strategies to overcome these limitations are being pursued.
TL;DR: ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.
Abstract: Purpose: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines. Experimental Design: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h 51 Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells. Results: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 μg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients. Conclusions: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.
TL;DR: It is confirmed that significant viral amplification could occur during DENV infections in humans with prior infection or with maternally transferred immunity, possibly leading to severe dengue.
Abstract: Infection with dengue virus (DENV) or any other flavivirus induces cross-reactive, but weakly neutralizing or nonneutralizing, antibodies that recognize epitopes involving the fusion peptide in the envelope glycoprotein. Humanized mAb IgG 1A5, derived from a chimpanzee, shares properties of cross-reactive antibodies. mAb IgG 1A5 up-regulated DENV infection by a mechanism of antibody-dependent enhancement (ADE) in a variety of Fc receptor-bearing cells in vitro. A 10- to 1,000-fold increase of viral yield in K562 cells, dependent on the DENV serotype, was observed over a range of subneutralizing concentrations of IgG 1A5. A significant increase of DENV-4 viremia titers (up to 100-fold) was also demonstrated in juvenile rhesus monkeys immunized with passively transferred dilutions of IgG 1A5. These results, together with earlier findings of ADE of DENV-2 infection by a polyclonal serum, establish the primate model for analysis of ADE. Considering the abundance of these cross-reactive antibodies, our observations confirm that significant viral amplification could occur during DENV infections in humans with prior infection or with maternally transferred immunity, possibly leading to severe dengue. Strategies to eliminate ADE were explored by altering the antibody Fc structures responsible for binding to Fc receptors. IgG 1A5 variants, containing amino acid substitutions from the Fc region of IgG2 or IgG4 antibodies, reduced but did not eliminate DENV-4-enhancing activity in K562 cells. Importantly, a 9-aa deletion at the N terminus of the CH2 domain in the Fc region abrogated the enhancing activity.