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JCI Insight Dec 2023IL-12 is a potent cytokine that can promote innate and adaptive anticancer immunity, but its clinical development has been limited by toxicity when delivered...
IL-12 is a potent cytokine that can promote innate and adaptive anticancer immunity, but its clinical development has been limited by toxicity when delivered systemically. Intratumoral (i.t.) administration can expand the therapeutic window of IL-12 and other cytokines but is in turn limited by rapid drug clearance from the tumor, which reduces efficacy, necessitates frequent administration, and increases systemic accumulation. To address these limitations, we developed an anchored IL-12 designated ANK-101, composed of an engineered IL-12 variant that forms a stable complex with the FDA-approved vaccine adjuvant aluminum hydroxide (Alhydrogel). Following i.t. administration of murine ANK-101 (mANK-101) in early intervention syngeneic mouse tumors, the complex formed a depot that was locally retained for weeks as measured by IVIS or SPECT/CT imaging, while unanchored protein injected i.t. was cleared within hours. One or 2 i.t. injections of mANK-101 induced single-agent antitumor activity across a diverse range of syngeneic tumors, including models resistant to checkpoint blockade at doses where unanchored IL-12 had no efficacy. Local treatment with mANK-101 further induced regressions of noninjected lesions, especially when combined with systemic checkpoint blockade. Antitumor activity was associated with remodeling of the tumor microenvironment, including prolonged IFN-γ and chemokine expression, recruitment and activation of T and NK cells, M1 myeloid cell skewing, and increased antigen processing and presentation. Subcutaneous administration of ANK-101 in cynomolgus macaques was well tolerated. Together, these data demonstrate that ANK-101 has an enhanced efficacy and safety profile and warrants future clinical development.
Topics: Mice; Animals; Interleukin-12; Aluminum Hydroxide; Tumor Microenvironment; Cytokines; Neoplasms
PubMed: 38063196
DOI: 10.1172/jci.insight.168224 -
Journal of the American Chemical Society May 2022Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of...
Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (T) and the deactivation of T helper 17 cells (T17). Both and results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.
Topics: Aluminum; Aluminum Hydroxide; Calcium; Calcium Hydroxide; Humans; Osteoporosis
PubMed: 35549335
DOI: 10.1021/jacs.2c00749 -
Antimicrobial Agents and Chemotherapy Apr 2023Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label,... (Clinical Trial)
Clinical Trial
Effect of an Antacid (Aluminum Hydroxide/Magnesium Hydroxide/Simethicone) or a Proton Pump Inhibitor (Omeprazole) on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects.
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.
Topics: Adult; Humans; Administration, Oral; Aluminum Hydroxide; Antacids; Anti-Ulcer Agents; Cross-Over Studies; Drug Interactions; Magnesium Hydroxide; Omeprazole; Proton Pump Inhibitors; Simethicone
PubMed: 36943038
DOI: 10.1128/aac.01495-22 -
Journal of Nephrology Dec 2021
Topics: Aluminum Hydroxide; Antacids; Humans; Hypophosphatemia; Magnesium
PubMed: 33502727
DOI: 10.1007/s40620-020-00963-2 -
Vaccine Apr 2020Aluminum based adjuvants are widely used in commercial vaccines, since they are known to be safe and effective with a variety of antigens. The effect of antigen...
Aluminum based adjuvants are widely used in commercial vaccines, since they are known to be safe and effective with a variety of antigens. The effect of antigen adsorption onto Aluminum Hydroxide is a complex area, since several mechanisms are involved simultaneously, whose impact is both antigen and formulation conditions dependent. Moreover, the mode of action of Aluminum Hydroxide is itself complex, with many mechanisms operating simultaneously. Within the literature there are contrasting theories regarding the effect of adsorption on antigen integrity and stability, with reports of antigen being stabilized by adsorption onto Aluminum Hydroxide, but also with contrary reports of antigen being destabilized. With the aim to understand the impact of adsorption on three recombinant proteins which, following in vivo immunization, are able to induce functional bactericidal antibodies against Neisseria meningitidis type B, we used a range of physico-chemical tools, such as DSC and UPLC, along with in vitro binding of antibodies that recognize structural elements of the proteins, and supported the in vitro data with in vivo evaluation in mice studies. We showed that, following exposure to accelerated degradation conditions involving heat, the recombinant proteins, although robust, were stabilized by adsorption onto Aluminum Hydroxide and retain their structural integrity unlike the not adsorbed proteins. The measure of the Melting Temperature was a useful tool to compare the behavior of proteins adsorbed and not adsorbed on Aluminum Hydroxide and to predict protein stability.
Topics: Adjuvants, Immunologic; Adsorption; Aluminum Hydroxide; Animals; Antigens; Mice; Vaccines
PubMed: 32063436
DOI: 10.1016/j.vaccine.2020.02.001 -
Journal of Trace Elements in Medicine... Dec 2021Aluminum is inevitable component of many vaccines. The benefit of the vaccines is undeniable but effects of aluminum toxicity might be underestimated and neglected. In... (Review)
Review
Aluminum is inevitable component of many vaccines. The benefit of the vaccines is undeniable but effects of aluminum toxicity might be underestimated and neglected. In this review, we highlighted the mechanims of aluminum toxicity, which is still in debate. So far, all the papers that disscused the adverse aluminum effects pointed two mechanisms responsible for Al toxicity, direct Al toxicity and aluminum induced cell damage via the oxidative metabolism. According to our knowledge, which is based on basic principles of biochemistry and inorganic chemistry, we suggested that aluminum highly interferes with iron metabolism eventually resulting in iron-mediated cell damage. More importantly, in this paper, we offered easily feasible solutions, in order to avoid aluminum toxicity in the future. We suggest that as it once was, Calcium Phosphate again to be used as the adjuvant or better solution that the vaccine adjuvants should be based on zinc compounds or even better would be non-metal adjuvants, such as microcrystalline tyrosine and monosodium urate. Until an adequate adjuvant is provided, we suggest instant postponement of vaccination with vaccines which use aluminum as the adjuvant until the 12 months of age.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Aluminum; Aluminum Compounds; Aluminum Hydroxide; Iron; Vaccines
PubMed: 34333362
DOI: 10.1016/j.jtemb.2021.126822 -
International Journal of Nanomedicine 2020Aluminum salts, although they have been used as adjuvants in many vaccine formulations since 1926, exclusively induce a Th2-biased immune response, thereby limiting...
Crystalline and Amorphous Preparation of Aluminum Hydroxide Nanoparticles Enhances Protective Antigen Domain 4 Specific Immunogenicity and Provides Protection Against Anthrax.
INTRODUCTION
Aluminum salts, although they have been used as adjuvants in many vaccine formulations since 1926, exclusively induce a Th2-biased immune response, thereby limiting their use against intracellular pathogens like .
METHODS AND RESULTS
Herein, we synthesized amorphous and crystalline forms of aluminum hydroxide nanoparticles (AH nps) of 150-200 nm size range. Using protective antigen domain 4 (D4) as a model antigen, we demonstrated that both amorphous and crystalline forms of AH nps displayed enhanced antigen D4 uptake by THP1 cells as compared to commercial adjuvant aluminum hydroxide gel (AH gel). In a mouse model, both amorphous and crystalline AH nps triggered an enhanced D4-specific Th2- and Th1-type immune response and conferred superior protection against anthrax spore challenge as compared to AH gel. Physicochemical characterization of crystalline and amorphous AH nps revealed stronger antigen D4 binding and release than AH gel.
CONCLUSION
These results demonstrate that size and crystallinity of AH nps play important roles in mediating enhanced antigen presenting cells (APCs) activation and potentiating a strong antigen-specific immune response, and are critical parameters for the rational design of alum-based Th1-type adjuvant to induce a more balanced antigen-specific immune response.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Anthrax; Anthrax Vaccines; Antigens, Bacterial; Bacterial Toxins; Cell Line; Disease Models, Animal; Dynamic Light Scattering; Female; Humans; Metal Nanoparticles; Mice; RAW 264.7 Cells; Spectroscopy, Fourier Transform Infrared; Th1 Cells
PubMed: 32021177
DOI: 10.2147/IJN.S219647 -
Methods in Molecular Biology (Clifton,... 2015Conjugation to carrier proteins is necessary for peptides to be able to induce antibody formation when injected into animals together with a suitable adjuvant. This is...
Conjugation to carrier proteins is necessary for peptides to be able to induce antibody formation when injected into animals together with a suitable adjuvant. This is usually performed by conjugation in solution followed by mixing with the adjuvant. Alternatively, the carrier may be adsorbed onto a solid support followed by activation and conjugation with the peptide by solid-phase chemistry. Different reagents can be used for conjugation through peptide functional groups (-SH, -NH2, -COOH) and various carrier proteins may be used depending on the peptides and the intended use of the antibodies. The solid phase may be an ion-exchange matrix, from which the conjugate can subsequently be eluted and mixed with adjuvant. Alternatively, the adjuvant aluminum hydroxide may be used as the solid-phase matrix, whereupon the carrier is immobilized and conjugated with peptide. The resulting adjuvant-carrier-peptide complexes may then be used directly for immunization.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies; Antibody Formation; Carrier Proteins; Immunization; Mice; Peptides; Rabbits; Solid-Phase Synthesis Techniques
PubMed: 26424263
DOI: 10.1007/978-1-4939-2999-3_7 -
Vaccine Nov 2018Accidental freezing of aluminum-based vaccines occurs during their storage and transportation, in both developed and developing countries. Freezing damages the...
Accidental freezing of aluminum-based vaccines occurs during their storage and transportation, in both developed and developing countries. Freezing damages the freeze-sensitive aluminum adjuvanted vaccines, through separation of lattice between aluminum adjuvant and antigen, leading to formation of aluminum aggregates, and loss of potency. In this study, we examined Alhydrogel™ ([AlO(OH)]xnHO, aluminum hydroxide, hydrated for adsorption) stored under recommended conditions, and exposed to freezing temperature until solid-frozen. The main purpose of our research was to determine the destruction areas of the solid-frozen Alhydrogel™ using selected methods of scanning electron microscopy, energy dispersive X-ray spectroscopy, Raman spectroscopy, Fourier-transform infrared spectroscopy and transmission electron microscopy working in diffraction mode. The Zeta potential evaluation, measurements of albumin adsorption power, thermogravimetric analysis and estimation of the mass loss after drying indicated significant structural (physical) and chemical differences between the freeze-damaged and non-frozen vaccine adjuvant. The presented results are important to better understand the type and nature of damages occurring in freeze-damaged aluminum-based vaccines. These results can be used in future studies to improve the temperature stability of aluminum adjuvanted vaccines.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Chemical Phenomena; Freezing; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Spectrometry, X-Ray Emission; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman
PubMed: 30322744
DOI: 10.1016/j.vaccine.2018.10.023 -
Environmental Technology Jan 2022Magnesium hydroxide is commonly used as a coagulant for treating reactive dyes wastewater. However, the flocs are relatively small and coagulation process needs longer...
Magnesium hydroxide is commonly used as a coagulant for treating reactive dyes wastewater. However, the flocs are relatively small and coagulation process needs longer sedimentation time. Large flocs and short operation time are important for good coagulation performance. Coagulation floc formation and growth processes using magnesium hydroxide and polyacrylamide (PAM) dual-coagulant were investigated with controlled experiments through flocculation index (FI), floc size distribution, zeta potential, scanning electron microscopy and Fourier transform infrared spectroscopy. The final average floc size reached 58.5 and 4.96 μm with and absence of PAM addition during slow mixing periods. PAM feeding time and magnesium hydroxide formation time can affect the floc formation and growth processes. The results showed that floc formed rapidly during magnesium hydroxide generation within 90 s and flocs aggregated together by PAM bridging function. Reactive orange removal efficiency reached 99.3% with rapid mixing 250 rpm at 90 s during 100 mg/L magnesium ion addition, then adding 6 mg/L PAM at the beginning of slow mixing period in dual-coagulant system.
Topics: Acrylic Resins; Aluminum Hydroxide; Azo Compounds; Flocculation; Magnesium Hydroxide; Sulfuric Acid Esters; Water Purification
PubMed: 32633211
DOI: 10.1080/09593330.2020.1791970