Innate Immunity Modulating Impurities and the Immunotoxicity of Nanobiotechnology-Based Drug Products

Holley, Claire K.; Dobrovolskaia, Marina A.

doi:10.3390/molecules26237308

Cited by 9 publications

(7 citation statements)

References 84 publications

(307 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This section will discuss assays for assessing nanoparticle effects on the integrity and function of immune cells commonly used in preclinical research. Nanoparticles must undergo analysis for sterility and contamination with innate immunity-modulating impurities prior to in vitro and in vivo immunotoxicity studies since microbes and their components (e.g., endotoxin, beta-glucans, and CpG DNA) may confound the results of such studies ( 185 ). Challenges with endotoxin and beta-glucans detection in nanomaterials from NCL’s experience have been described earlier ( 19 , 32 , 186 – 190 ).…”

Section: Available Methods and Models To Study Immunotoxicitymentioning

confidence: 99%

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Dobrovolskaia

2022

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Nanotechnology carriers have become common in pharmaceutical products because of their benefits to drug delivery, including reduced toxicities and improved efficacy of active pharmaceutical ingredients due to targeted delivery, prolonged circulation time, and controlled payload release. While available examples of reduced drug toxicity through formulation using a nanocarrier are encouraging, current data also demonstrate that nanoparticles may change a drug’s biodistribution and alter its toxicity profile. Moreover, individual components of nanoparticles and excipients commonly used in formulations are often not immunologically inert and contribute to the overall immune responses to nanotechnology-formulated products. Said immune responses may be beneficial or adverse depending on the indication, dose, dose regimen, and route of administration. Therefore, comprehensive toxicology studies are of paramount importance even when previously known drugs, components, and excipients are used in nanoformulations. Recent data also suggest that, despite decades of research directed at hiding nanocarriers from the immune recognition, the immune system’s inherent property of clearing particulate materials can be leveraged to improve the therapeutic efficacy of drugs formulated using nanoparticles. Herein, I review current knowledge about nanoparticles’ interaction with the immune system and how these interactions contribute to nanotechnology-formulated drug products’ safety and efficacy through the lens of over a decade of nanoparticle characterization at the Nanotechnology Characterization Laboratory.

show abstract

Section: Available Methods and Models To Study Immunotoxicitymentioning

confidence: 99%

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Dobrovolskaia

2022

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is known that some chemicals, even in low concentrations (order of 1 ppm), can denature proteins leading to loss of their immunogenicity [72]. In fact, different substances are used as drugs in homeopathic medicines and, as discussed earlier (Sec.5), they are expected to modulate the conformations of the protein molecules and, in effect, their immunogenicity.…”

Section: Why Is the 'Law Of Infinitesimals' So Important In Homeopathy?mentioning

confidence: 99%

“…In fact, different substances are used as drugs in homeopathic medicines and, as discussed earlier (Sec.5), they are expected to modulate the conformations of the protein molecules and, in effect, their immunogenicity. However, as proteins are very sensitive to many chemicals [66][67][68][69]72], the concentration of the drugs in the medicines during the initial stages of preparation of homeopathic medicines can be high enough to modulate the protein molecules inordinately resulting in the degradation or loss of their immunogenicity. After adequate dilution in subsequent stages, when the concentration of the drugs in the medicines goes below certain levels, the unfolded proteins (denatured proteins) begin to refold and gain immunogenicity, provided, the denaturation is not irreversible.…”

Section: Why Is the 'Law Of Infinitesimals' So Important In Homeopathy?mentioning

confidence: 99%

Conformationally modulated immunogenic proteins in homeopathic medicines: Does protein-based mucosal immunotherapy have the potential to treat diverse diseases?

Sen¹

2022

Preprint

View full text Add to dashboard Cite

The absence of any drug in the ultra-diluted homeopathic medicines coupled with unfavourable clinical trial results has painted homeopathic remedies as placebos. Different mechanisms have been forwarded to explain the anomalies but with little success. Here it is proposed that homeopathy is a form of protein-based immunotherapy and the immunogenic proteins exist in the microbial lysates, which are present in the homeopathic medicines. The microbial lysates are formed in the homeopathic medicines during their preparation, when microbes from the surrounding environment are unwittingly incorporated into the homeopathic medicines and the microbial cell lysis is induced by alcohol, a component of the drug vehicle (water-alcohol mixture), and augmented by powerful shaking. The drugs in the homeopathic medicines modulate the conformations and, in essence, the immunogenicity of the proteins present in the medicines. The modulated proteins act as immunostimulants and help in boosting and tuning both innate and adaptive immunity. In addition, bystander T cell activation and trained immunity are expected to play important roles in the therapeutic and prophylactic actions of the homeopathic medicines. The importance of dilution in homeopathy vis-à-vis the ‘law of infinitesimals’ can be appreciated by considering the effect of dilution on protein folding and the immunogenicity of proteins. In the case of ultra-diluted homeopathic medicines devoid of any drug molecule, it has been suggested that in the absence of drug-protein interaction, protein-protein interaction leads to the conformational modulation of protein molecules, where allosteric communication and synchronization of vibrating of the protein molecules play key roles. The dictum ‘like cures like’ can be understood by considering the mimicry between the antigens present on the invading pathogen and the antigens present on the proteins in the selected homeopathic medicine. The discrepancies in the clinical trial results of homeopathic medicines arising from the heterogeneities inherent in immunotherapy as well as from a strong placebo response in the clinical trials in some diseases may partly be mitigated by conducting modified clinical trials.

show abstract

“… 19 , 20 The presence of innate immune response modulating impurities (IIRMIs), including host-cell proteins and other contaminants derived from the manufacturing and purification process, in preparations of therapeutic proteins is a safety and immunogenicity concern. 21 , 22 Clearance of IIRMIs from the final product is a goal of the purification process. When a therapeutic protein is administered to a patient, residual IIRMIs may induce inflammation directly by inducing the release of cytokines or indirectly by acting as adjuvants to enhance potential immunogenicity of the therapeutic protein.…”

Section: Introductionmentioning

confidence: 99%

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results

Callanan¹,

Khurana²,

Maturi³

et al. 2023

OPTH

View full text Add to dashboard Cite

Purpose To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD). Methods A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (<15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events. Results Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% [3/123]), moderate (4.9% [6/123]), or severe (1.6% [2/123]) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥95.9% (≥118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 μm). Conclusion Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.

show abstract

Innate Immunity Modulating Impurities and the Immunotoxicity of Nanobiotechnology-Based Drug Products

Cited by 9 publications

References 84 publications

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Conformationally modulated immunogenic proteins in homeopathic medicines: Does protein-based mucosal immunotherapy have the potential to treat diverse diseases?

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results

Contact Info

Product

Resources

About