Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice

Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer’s disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16–41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45–65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect.

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Assessing the Effect of Mycotoxin Combinations: Which Mathematical Model Is (the Most) Appropriate?

Toxins ◽

10.3390/toxins12030153 ◽

2020 ◽

Vol 12 (3) ◽

pp. 153 ◽

Cited By ~ 4

Author(s):

Domagoj Kifer ◽

Daniela Jakšić ◽

Maja Šegvić Klarić

Keyword(s):

Mathematical Models ◽

Combination Index ◽

Dose Effect ◽

Additive Effects ◽

Biological Models ◽

Advantages And Disadvantages ◽

The Past ◽

Surface Code ◽

Definition Of ◽

Bliss Independence

In the past decades, many studies have examined the nature of the interaction between mycotoxins in biological models classifying interaction effects as antagonisms, additive effects, or synergisms based on a comparison of the observed effect with the expected effect of combination. Among several described mathematical models, the arithmetic definition of additivity and factorial analysis of variance were the most commonly used in mycotoxicology. These models are incorrectly based on the assumption that mycotoxin dose-effect curves are linear. More appropriate mathematical models for assessing mycotoxin interactions include Bliss independence, Loewe’s additivity law, combination index, and isobologram analysis, Chou-Talalays median-effect approach, response surface, code for the identification of synergism numerically efficient (CISNE) and MixLow method. However, it seems that neither model is ideal. This review discusses the advantages and disadvantages of these mathematical models.

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Correction: Liu et al., “Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice”

Journal of Neuroscience ◽

10.1523/jneurosci.0488-17.2017 ◽

2017 ◽

Vol 37 (13) ◽

pp. 3734.1-3734

Keyword(s):

Monoclonal Antibody ◽

Transgenic Mice ◽

Tau Pathology

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Lack of interaction of hyperpnoea with methacholine and histamine in asthma

Clinical Science ◽

10.1042/cs0950611 ◽

1998 ◽

Vol 95 (5) ◽

pp. 611-619 ◽

Cited By ~ 2

Author(s):

Suree SOMPRADEEKUL ◽

Rana HEJAL ◽

Melissa McLANE ◽

K. A. LENNER ◽

J. A. NELSON ◽

...

Keyword(s):

Blood Flow ◽

Forced Expiratory Volume ◽

Additive Effects ◽

Positive Interaction ◽

Bronchial Responsiveness ◽

Individual Effects ◽

The Individual ◽

Airway Calibre ◽

Effector Mechanisms

1.The thermal precipitants of asthma (exercise and hyperventilation) appear to have a unique pathogenesis that does not alter bronchial responsiveness. In the present work, we tested whether hyperpnoea interacts with other constrictor stimuli. 2.To provide data on this issue, we exposed 17 subjects with asthma to isocapnic hyperventilation of frigid air (HV), methacholine (METH) and histamine (HIS) alone and in combination. 3.With HV (mean ventilation = 55.6±7.7 litres/min), METH (2.20±0.7 ;mmol/l) and HIS (10.35±5.04 ;mmol/l) alone, the decrements in forced expiratory volume in 1 ;s (FEV1) from baseline were 27.4±3.4, 27.4±3.8 and 32.4±3% respectively (n = 9). Giving the agonists simultaneously did not produce additive effects (ΔFEV1 HV+METH = 32.8±3.6%; HV+HIS = 28.7±5.1%). None of the individual or combined responses was significantly different from each other. Changing the sequence of the experiments and giving METH at the height of the HV-induced bronchial narrowing, instead of during hyperpnoea, did not alter the findings (n = 8). The maximum fall in FEV1 after both bronchoconstrictors in this experiment (ΔFEV1 = 32.3±4.3%) was not significantly different from either alone (HV = 22.8±1.0%; METH = 27.3±1.9%). When METH and HIS were administered together, however (n = 5), a positive interaction ensued (METH = 1.53±0.56 ;mmol/l, ΔFEV1 = 15.6±4.6%; HIS = 4.77±2.07 ;mmol/l, ΔFEV1 = 18.8±3.1%; METH+HIS ΔFEV1 = 33.4±5.2%; P< 0.001 compared with the individual effects). 4.These results indicate that HV does not interact with stimuli that directly or indirectly modulate airway calibre. It is unclear if this effect represents protection conferred from increased bronchial blood flow or derives from differences in effector mechanisms between the thermal and pharmacological agonists.

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A Virus-Neutralising Monoclonal Antibody Expressed in the Milk of Transgenic Mice

Advances in Experimental Medicine and Biology - The Nidoviruses ◽

10.1007/978-1-4615-1325-4_61 ◽

2001 ◽

pp. 411-414 ◽

Cited By ~ 2

Author(s):

A. F. Kolb ◽

J. Webster ◽

C. B. A. Whitelaw ◽

S. G. Siddell

Keyword(s):

Monoclonal Antibody ◽

Transgenic Mice

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P1-099: COMBINATION OF A GLUTAMINYL CYCLASE INHIBITOR (PQ912) AND A PYROGLUTAMATE-Aβ SPECIFIC ANTIBODY (PBD-M06) SHOWS ADDITIVE EFFECTS IN A MOUSE MODEL WITH ALZHEIMER'S DISEASE-LIKE PATHOLOGY

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.101 ◽

2006 ◽

Vol 14 (7S_Part_5) ◽

pp. P309-P309

Author(s):

Torsten Hoffmann ◽

Martina Farcher ◽

Birgit Hutter-Paier ◽

Cynthia A. Lemere ◽

Stephan Schilling ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Specific Antibody ◽

Additive Effects ◽

Glutaminyl Cyclase ◽

Pyroglutamate Aβ

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Liquid-chromatographic measurement of p-aminobenzoic acid and its metabolites in serum.

Clinical Chemistry ◽

10.1093/clinchem/34.11.2235 ◽

1988 ◽

Vol 34 (11) ◽

pp. 2235-2238 ◽

Cited By ~ 6

Author(s):

L L Yung-Jato ◽

P R Durie ◽

S J Soldin

Keyword(s):

High Performance ◽

Internal Standard ◽

High Performance Liquid Chromatographic ◽

Peak Height ◽

Individual Compound ◽

Aminobenzoic Acid ◽

Serum Samples ◽

The Individual ◽

A Minor ◽

Liquid Chromatographic

Abstract This is a high-performance liquid-chromatographic method for measuring p-aminobenzoic acid (PABA) and its metabolites in plasma or serum. Samples are deproteinized, then extracted with organic solvents before chromatography. For quantification, the peak height of the individual compound is compared with that of the internal standard. Analytical recoveries ranged from 41% to 100%, depending on the compound studied. Comparison of patients' samples after oral administration of either N-benzoyl-L-tyrosyl-p-aminobenzoic acid or free PABA revealed that PABA is extensively metabolized and conjugated to either p-acetamidobenzoic acid, p-aminohippuric acid, or p-acetamidohippuric acid. PABA concentrations in serum as measured with the Bratton-Marshall ultraviolet spectrophotometric procedure would appear predominantly to reflect measurements of metabolites, with only a minor contribution from PABA itself.

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Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

The Journal of Immunology ◽

10.4049/jimmunol.1300409 ◽

2013 ◽

Vol 191 (8) ◽

pp. 4174-4183 ◽

Cited By ~ 61

Author(s):

Li-Zhen He ◽

Naseem Prostak ◽

Lawrence J. Thomas ◽

Laura Vitale ◽

Jeffrey Weidlick ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Transgenic Mice ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation

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Farnesol increases the activity of echinocandins against Candida auris biofilms

Medical Mycology ◽

10.1093/mmy/myz057 ◽

2019 ◽

Vol 58 (3) ◽

pp. 404-407 ◽

Cited By ~ 6

Author(s):

Fruzsina Nagy ◽

Zoltán Tóth ◽

Lajos Daróczi ◽

Adrien Székely ◽

Andrew M Borman ◽

...

Keyword(s):

Inhibitory Concentration ◽

Candida Auris ◽

Independence Model ◽

Microscope Images ◽

Vitro Effect ◽

Volume Range ◽

Quorum Sensing Molecule ◽

Bliss Independence ◽

Scanning Electron

Abstract Candida auris biofilms exhibit decreased susceptibility to echinocandins, which is associated with poorer clinical outcomes. Farnesol is a quorum-sensing molecule enhancing the activity of antifungals; therefore, we evaluated the in vitro effect of farnesol with anidulafungin, caspofungin, or micafungin against biofilms using fractional inhibitory concentration indexes (FICI), Bliss independence model, LIVE/DEAD-assay and scanning electron microscopy. Based on mathematical models, farnesol caused synergism in eleven out of twelve cases (FICIs range 0.133-0.507; Bliss synergy volume range 70.39–204.6 μM2%). This was confirmed by microscope images of combination-exposed biofilms. Our study showed the prominent effect of farnesol with echinocandins against C. auris biofilms.

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