scholarly journals Fc Engineering Strategies to Advance IgA Antibodies as Therapeutic Agents

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 70
Author(s):  
Geert van Tetering ◽  
Mitchell Evers ◽  
Chilam Chan ◽  
Marjolein Stip ◽  
Jeanette Leusen
Keyword(s):  
Half Life ◽  
Therapeutic Agents ◽  
Igg Antibodies ◽  
Iga Antibodies ◽  
Tumor Killing ◽  
Alternative Approaches ◽  
Therapeutic Monoclonal Antibodies ◽  
The Impact ◽  
Tumor Eradication

In the past three decades, a great interest has arisen in the use of immunoglobulins as therapeutic agents. In particular, since the approval of the first monoclonal antibody Rituximab for B cell malignancies, the progress in the antibody-related therapeutic agents has been incremental. Therapeutic antibodies can be applied in a variety of diseases, ranging from cancer to autoimmunity and allergy. All current therapeutic monoclonal antibodies used in the clinic are of the IgG isotype. IgG antibodies can induce the killing of cancer cells by growth inhibition, apoptosis induction, complement activation (CDC) or antibody-dependent cellular cytotoxicity (ADCC) by NK cells, antibody-dependent cellular phagocytosis (ADCP) by monocytes/macrophages, or trogoptosis by granulocytes. To enhance these effector mechanisms of IgG, protein and glyco-engineering has been successfully applied. As an alternative to IgG, antibodies of the IgA isotype have been shown to be very effective in tumor eradication. Using the IgA-specific receptor FcαRI expressed on myeloid cells, IgA antibodies show superior tumor-killing compared to IgG when granulocytes are employed. However, reasons why IgA has not been introduced in the clinic yet can be found in the intrinsic properties of IgA posing several technical limitations: (1) IgA is challenging to produce and purify, (2) IgA shows a very heterogeneous glycosylation profile, and (3) IgA has a relatively short serum half-life. Next to the technical challenges, pre-clinical evaluation of IgA efficacy in vivo is not straightforward as mice do not naturally express the FcαR. Here, we provide a concise overview of the latest insights in these engineering strategies overcoming technical limitations of IgA as a therapeutic antibody: developability, heterogeneity, and short half-life. In addition, alternative approaches using IgA/IgG hybrid and FcαR-engagers and the impact of engineering on the clinical application of IgA will be discussed.

scholarly journals Broadly Neutralizing Hemagglutinin Stalk-Specific Antibodies Induce Potent Phagocytosis of Immune Complexes by Neutrophils in an Fc-Dependent Manner

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Caitlin E. Mullarkey ◽  
Mark J. Bailey ◽  
Diana A. Golubeva ◽  
Gene S. Tan ◽  
Raffael Nachbagauer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Fc Receptor ◽  
Igg Antibodies ◽  
Specific Antibodies ◽  
Effector Functions ◽  
Iga Antibodies ◽  
Specific Igg ◽  
Optimal Protection ◽  
Specific Igg Antibodies

ABSTRACTBroadly neutralizing antibodies that recognize the conserved hemagglutinin (HA) stalk have emerged as exciting new biotherapeutic tools to combat seasonal and pandemic influenza viruses. Our general understanding of the mechanisms by which stalk-specific antibodies achieve protection is rapidly evolving. It has recently been demonstrated that broadly neutralizing HA stalk-specific IgG antibodies require Fc-Fcγ receptor (FcγR) interactions for optimal protectionin vivo. Here we examine the neutrophil effector functions induced by stalk-specific antibodies. As the most abundant subset of blood leukocytes, neutrophils represent a critical innate effector cell population and serve an instrumental role in orchestrating downstream adaptive responses to influenza virus infection. Yet, the interplay of HA stalk-specific IgG, Fc-FcγR engagement, and neutrophils has remained largely uncharacterized. Using anin vitroassay to detect the production of reactive oxygen species (ROS), we show that human and mouse monoclonal HA stalk-specific IgG antibodies are able to induce the production of ROS by neutrophils, while HA head-specific antibodies do not. Furthermore, our results indicate that the production of ROS is dependent on Fc receptor (FcR) engagement and phagocytosis. We went on to assess the ability of monoclonal HA stalk-specific IgA antibodies to induce ROS. Consistent with our findings for monoclonal IgGs, only HA stalk-specific IgA antibodies elicited ROS production by neutrophils. This induction is dependent on the engagement of FcαR1. Taken together, our findings describe a novel FcR-dependent effector function induced by HA stalk-specific IgG and IgA antibodies, and importantly, our studies shed light on the mechanisms by which HA stalk-specific antibodies achieve protection.IMPORTANCEThe present study provides evidence that broadly neutralizing HA stalk-specific antibodies induce downstream Fc-mediated neutrophil effector functions. In addition to their ability to neutralize, this class of antibodies has been shown to rely on Fc-Fc receptor interactions for optimal protectionin vivo. Curiously, neutralizing antibodies that bind the HA head domain do not require such interactions. Our findings build on these previous observations and provide a more complete picture of the relationship between stalk-specific antibodies and cells of the innate immune compartment. Furthermore, our data suggest that the ability of HA stalk-specific antibodies to mediate Fc-Fc receptor engagement is epitope dependent. Overall, this work will inform the rational design of improved influenza virus vaccines and therapeutics.

Nano-graphene oxide-manganese dioxide nanocomposites for overcoming tumor hypoxia and enhancing cancer radioisotope therapy

Nanoscale ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 5114-5123 ◽  
Author(s):  
Yugui Tao ◽  
Longlong Zhu ◽  
Yunayuan Zhao ◽  
Xuan Yi ◽  
Longbao Zhu ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Manganese Dioxide ◽  
Tumor Hypoxia ◽  
Therapeutic Agents ◽  
Tumor Killing ◽  
Nano Graphene ◽  
Radioisotope Therapy

In this work, we developed 131I labeled rGO-MnO2-PEG nanocomposites as therapeutic agents for in vivo tumor radioisotope therapy (RIT), achieving excellent tumor killing.

Pharmacokinetics of an Implanted Osmotic Pump Delivering Sufentanil for the Treatment of Chronic Pain

2003 ◽  
Vol 99 (4) ◽  
pp. 929-937 ◽  
Author(s):  
Dennis M. Fisher ◽  
Norma Kellett ◽  
Rainer Lenhardt
Keyword(s):  
Chronic Pain ◽  
Release Rate ◽  
Half Life ◽  
Local Heating ◽  
Osmotic Pump ◽  
Population Pharmacokinetic ◽  
Systematic Effect ◽  
The Impact

Background A matchstick-sized implanted osmotic pump (Chronogesic) that delivers sufentanil subcutaneously for more than 90 days is being developed to treat chronic pain. This study evaluates pharmacokinetic characteristics related to the absorption of sufentanil using a prototype 60-day system. Methods Twelve opioid-naive volunteers were given naltrexone to prevent opioid effects. Sufentanil, 60 microg, was infused intravenously over 6 h, then 48 h later, the pump was implanted subcutaneously in the upper arm under local anesthesia. Pumps were removed 9 days later. In six volunteers, fever (1.6-3.3 degrees C) was induced with interleukin-2. Plasma was sampled and population pharmacokinetic modeling was performed to estimate in vivo release rate and absorption half-life. Bioavailability was calculated by comparing in vivo to in vitro release rates. The impact of perturbations in release rate on sufentanil plasma concentration (Cp) was simulated. Results Fever had no systematic effect on Cp. Release rate estimated in vivo was similar to that measured in vitro; bioavailability did not differ from 100%. Absorption half-life was 16.2 h. Simulation demonstrated that supplemental release of sufentanil from the implant (as might occur with local heating) increases Cp an average of 2.5-2.8% per hours supplemental dose. Conclusions An implantable osmotic pump delivered sufentanil in vivo at the rate predicted from in vitro experiments. The rate at which sufentanil was absorbed from the subcutaneous space (half-life > 16 h) was markedly slower than reported with subcutaneous or intramuscular administration of large volumes of dilute opioids; this slow absorption dampens potential changes in Cp if release rate is perturbed.

scholarly journals Imaging of Inflammation in Spinal Cord Injury: Novel Insights on the Usage of PFC-Based Contrast Agents

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 379
Author(s):  
Francesca Garello ◽  
Marina Boido ◽  
Martina Miglietti ◽  
Valeria Bitonto ◽  
Marco Zenzola ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Magnetic Resonance ◽  
Half Life ◽  
Cell Tracking ◽  
Resonance Spectroscopy ◽  
Cord Injury ◽  
The Impact

Labeling of macrophages with perfluorocarbon(PFC)-based compounds allows the visualization of inflammatory processes by 19F-magnetic resonance imaging (19F-MRI), due to the absence of endogenous background. Even if PFC-labeling of monocytes/macrophages has been largely investigated and used, information is lacking about the impact of these agents over the polarization towards one of their cell subsets and on the best way to image them. In the present work, a PFC-based nanoemulsion was developed to monitor the course of inflammation in a model of spinal cord injury (SCI), a pathology in which the understanding of immunological events is of utmost importance to select the optimal therapeutic strategies. The effects of PFC over macrophage polarization were studied in vitro, on cultured macrophages, and in vivo, in a mouse SCI model, by testing and comparing various cell tracking protocols, including single and multiple administrations, the use of MRI or Point Resolved Spectroscopy (PRESS), and application of pre-saturation of Kupffer cells. The blood half-life of nanoemulsion was also investigated by 19F Magnetic Resonance Spectroscopy (MRS). In vitro and in vivo results indicate the occurrence of a switch towards the M2 (anti-inflammatory) phenotype, suggesting a possible theranostic function of these nanoparticles. The comparative work presented here allows the reader to select the most appropriate protocol according to the research objectives (quantitative data acquisition, visual monitoring of macrophage recruitment, theranostic purpose, rapid MRI acquisition, etc.). Finally, the method developed here to determine the blood half-life of the PFC nanoemulsion can be extended to other fluorinated compounds.

Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14000-e14000
Author(s):  
John M Burke ◽  
Anna Katharina Wilkins ◽  
Andrew Matteson ◽  
Lore Gruenbaum ◽  
Josh F Apgar
Keyword(s):  
Half Life ◽  
Computational Models ◽  
Systems Pharmacology ◽  
Antibody Drug Conjugate ◽  
Quantitative Systems Pharmacology ◽  
Drug Conjugate ◽  
Drug Antibody Ratio ◽  
The Impact ◽  
Antibody Drug

e14000 Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Results: Using QSP approaches, the model (1) describes the kinetics of individual DAR species and agrees well with typical ADC PK, individual DAR PK, and average DAR measurements in vivo; (2), quantitatively describes the trade-off between higher DAR and lower exposure; consequently, we predict that ADC2 is half as potent as ADC4 and ADC8, which are equipotent; (3) longer mAb half-life reduces payload delivery after multiple doses; and (4) ADC half-life affects the percent of payload delivered through different mechanisms. Conclusions: A QSP model describing mechanism is a useful tool to translate and understand PK from preclinical species to human, by acting as a central repository of data, knowledge, and hypotheses. It provided a rational basis to generate testable hypotheses and provide early insights into complex ADC PK data and established the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.

Antigen-specific systemic and reproductive tract antibodies in foxes immunized with Salmonella typhimuriumexpressing bacterial and sperm proteins

1999 ◽  
Vol 11 (5) ◽  
pp. 219 ◽  
Author(s):  
James de Jersey ◽  
Peter H. Bird ◽  
Naresh K. Verma ◽  
Mark P. Bradley
Keyword(s):  
Reproductive Tract ◽  
Red Fox ◽  
Antigen Expression ◽  
High Titre ◽  
Igg Antibodies ◽  
Safe Delivery ◽  
B Subunit ◽  
Iga Antibodies ◽  
Control Plasmid

Attenuated Salmonella typhimurium strains are potential ‘safe’ delivery vectors of an oral immunocontraceptive vaccine for the European red fox (Vulpes vulpes). In the present study, model bacterial (Escherichia coli heat-labile enterotoxin B subunit, LTB) and fox sperm (fSP10) antigens were expressed in S. typhimurium SL3261 (DaroA) under the control of the trc promoter. Adult female foxes were given three oral immunizations with SL3261 containing either LTB (SL3261/pLTB), fSP10 (SL3261/pFSP10) or a control plasmid (pKK233-2 or pTrc99A). All foxes raised serum (IgG) and vaginal (IgG and IgA) antibodies against S. typhimurium lipopolysaccharide (LPS). Each fox that received SL3261/pLTB raised high titre LTB-specific serum and vaginal IgG antibodies. However, only one of four foxes immunized with SL3261/pFSP10 raised an anti-fSP10 immune response, in the form of low titre serum and vaginal IgG antibodies. No vaginal IgA antibodies were raised against either LTB or fSP10 in these experiments. The immune responses against recombinant LTB and fSP10 resulted chiefly from the initial dose of antigen in the inocula and were minimally influenced by continued in vivo antigen expression. This study demonstrates for the first time in the female red fox that oral Salmonella can elicit specific systemic and reproductive tract antibodies against heterologous, recombinant proteins.

scholarly journals AB0020 ACPA ILLUSTRATING THE IMPACT OF IGG FAB-GLYCOSYLATION ON TRANSPLACENTAL TRANSFER OF ANTIBODIES AND THEIR BINDING TO THE NEONATAL FC-RECEPTOR (FCRN)

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1044.1-1044
Author(s):  
M. Volkov ◽  
K. Van Schie ◽  
A. Bondt ◽  
T. Kissel ◽  
M. Brinkhaus ◽  
...  
Keyword(s):  
Affinity Chromatography ◽  
Half Life ◽  
Igg Antibodies ◽  
Ideal Model ◽  
Research Support ◽  
Blood Samples ◽  
Transplacental Transfer ◽  
Potential Impact ◽  
The Impact ◽  
Citrullinated Protein

Background:Fc neonatal receptor (FcRn) is crucial for IgG half-life and transplacental transport. Different sites of IgG carry glycans which may affect binding to FcRn. While the effect of Fc-glycans has been investigated, the impact of Fab-glycosylation (~14% IgG) on IgG-FcRn interaction remains unclear. Anti-citrullinated protein antibodies (ACPA) of rheumatoid arthritis patients exhibit remarkably high Fab-glycosylation (~90%). This makes ACPA an ideal model to investigate how Fab-glycosylation influences IgG-FcRn interaction.Objectives:To investigate the potential impact of IgG Fab-glycosylation on IgG transplacental transfer and interaction with FcRn.Methods:To investigate transplacental transport of ACPA and total IgG, serum of ACPA-positive RA patients (mothers) as well as of healthy mothers and their respective newborns was analyzed. IgG Fab- and Fc-glycosylation was investigated with liquid chromatography and mass-spectrometry. Furthemore, ACPA monoclonal IgG were produced and glycoengineered to acquire several variants of the same monoclonal antibody differing only in their glycosylation profile. These glycovariants were then used to investigate the impact of Fab-glycans on the affinity of IgG for FcRn. Surface plasmon resonance (SPR) and affinity chromatography were implemented.Results:When measured in mothers’ serum and cord blood samples, Fab-glycosylation of IgG antibodies was ~20% lower in newborns compared to their mothers, which was observed for ACPA IgG, non-ACPA IgG in RA patients and total IgG of healthy controls (Figure 1). This may indicate that transplacental transfer of Fab-glycosylated antibodies is impaired. SPR results suggested that presence of Fab-glycans slightly lowered the affinity of IgG for FcRn. However, presence of Fab-glycans did not have a significant effect on the results of FcRn affinity chromatography. Together, these results suggest that Fab-glycans may impair association of IgG with FcRn, while dissociation likely stays intact.Conclusion:Our results suggest that Fab-glycans inhibit IgG-FcRn binding which negatively affects the transplacental transfer of Fab-glycosylated IgG. The impact of Fab-glycosylation on IgG half-life requires further investigation.Figure 1.Disclosure of Interests:Mikhail Volkov: None declared, Karin van Schie: None declared, Albert Bondt: None declared, Theresa Kissel: None declared, Maximilian Brinkhaus Grant/research support from: argenx, Arthur Bentlage: None declared, Carolien Koeleman: None declared, Steven de Taeye Grant/research support from: Genmab, Radboud Dolhain: None declared, Manfred Wuhrer: None declared, Rene Toes: None declared, Gestur Vidarsson: None declared, Diane van der Woude: None declared

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

Half-Life of Platelet Factor 4 (PF-4) in Plasma and Platelets from Macaca Mulatta

1977 ◽  
Vol 37 (01) ◽  
pp. 073-080 ◽  
Author(s):  
Knut Gjesdal ◽  
Duncan S. Pepper
Keyword(s):  
Macaca Mulatta ◽  
Half Life ◽  
Human Platelet ◽  
Gel Filtration ◽  
Platelet Factor 4 ◽  
Active Protein ◽  
Platelet Factor ◽  
Membrane Bound

SummaryHuman platelet factor 4 (PF-4) showed a reaction of complete identity with PF-4 from Macaca mulatta when tested against rabbit anti-human-PF-4. Such immunoglobulin was used for quantitative precipitation of in vivo labelled PF-4 in monkey serum. The results suggest that the active protein had an intra-platelet half-life of about 21 hours. In vitro 125I-labelled human PF-4 was injected intravenously into two monkeys and isolated by immuno-precipita-tion from platelet-poor plasma and from platelets disrupted after gel-filtration. Plasma PF-4 was found to have a half-life of 7 to 11 hours. Some of the labelled PF-4 was associated with platelets and this fraction had a rapid initial disappearance rate and a subsequent half-life close to that of plasma PF-4. The results are compatible with the hypothesis that granular PF-4 belongs to a separate compartment, whereas membrane-bound PF-4 and plasma PF-4 may interchange.

Turnover of Human Extrinsic (Tissue-Type) Plasminogen Activator in Rabbits

1981 ◽  
Vol 46 (03) ◽  
pp. 658-661 ◽  
Author(s):  
C Korninger ◽  
J M Stassen ◽  
D Collen
Keyword(s):  
Plasminogen Activator ◽  
Intravenous Injection ◽  
Active Site ◽  
Half Life ◽  
Degradation Products ◽  
Gel Filtration ◽  
Tissue Type ◽  
Organ Distribution ◽  
Small Rise

SummaryThe turnover of highly purified human extrinsic plasminogen activator (EPA) (one- and two-chain form) was studied in rabbits. Following intravenous injection, EPA-activity declined rapidly. The disappearance rate of EPA from the plasma could adequately be described by a single exponential term with a t ½ of approximately 2 min for both the one-chain and two-chain forms of EPA.The clearance and organ distribution of EPA was studied by using 125I-labeled preparations. Following intravenous injection of 125I-1abeled EPA the radioactivity disappeared rapidly from the plasma also with a t ½ of approximately 2 min down to a level of 15 to 20 percent, followed by a small rise of blood radioactivity. Gel filtration of serial samples revealed that the secondary increase of the radioactivity was due to the reappearance of radioactive breakdown products in the blood. Measurement of the organ distribution of 125I at different time intervals revealed that EPA was rapidly accumulated in the liver, followed by a release of degradation products in the blood.Experimental hepatectomy markedly prolonged the half-life of EPA in the blood. Blocking the active site histidine of EPA had no effect on the half-life of EPA in blood nor on the gel filtration patterns of 125I in serial plasma samples.It is concluded that human EPA is rapidly removed from the blood of rabbits by clearance and degradation in the liver. Recognition by the liver does not require a functional active site in the enzyme. Neutralization in plasma by protease inhibitors does not represent a significant pathway of EPA inactivation in vivo.

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