Omalizumab

Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.

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“…For 11 of 13 commercially available marketed mAbs, linear CL data were obtained from literature sources. [41][42][43][44][45][46][47][48]…”

Section: Fcrn Binding Affinity Methods Using Sprmentioning

confidence: 99%

Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics

Avery

Wade

Wang

et al. 2018

mAbs

126

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“…However, corticosteroids do not cure the pathology, and during extended use, it can cause systemic side effects as easy bruising and bone loss [ 6 – 8 ]. Moreover, omalizumab is used as a treatment in severely allergic asthmatics to reduce inhaled corticosteroid [ 9 ] and still adverse effects are observed [ 10 ]. Therefore, the search for news molecules for asthma prevention and/or treatment is required.…”

Section: Introductionmentioning

confidence: 99%

Schistosoma mansoni Tegument (Smteg) Induces IL-10 and Modulates Experimental Airway Inflammation

et al. 2016

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BackgroundPrevious studies have demonstrated that S. mansoni infection and inoculation of the parasite eggs and antigens are able to modulate airways inflammation induced by OVA in mice. This modulation was associated to an enhanced production of interleukin-10 and to an increased number of regulatory T cells. The S. mansoni schistosomulum is the first stage to come into contact with the host immune system and its tegument represents the host-parasite interface. The schistosomula tegument (Smteg) has never been studied in the context of modulation of inflammatory disorders, although immune evasion mechanisms take place in this phase of infection to guarantee the persistence of the parasite in the host.Methodology and Principal FindingsThe aim of this study was to evaluate the Smteg ability to modulate inflammation in an experimental airway inflammation model induced by OVA and to characterize the immune factors involved in this modulation. To achieve the objective, BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with OVA aerosol after Smteg intraperitoneal inoculation. Protein extravasation and inflammatory cells were assessed in bronchoalveolar lavage and IgE levels were measured in serum. Additionally, lungs were excised for histopathological analyses, cytokine measurement and characterization of the cell populations. Inoculation with Smteg led to a reduction in the protein levels in bronchoalveolar lavage (BAL) and eosinophils in both BAL and lung tissue. In the lung tissue there was a reduction in inflammatory cells and collagen deposition as well as in IL-5, IL-13, IL-25 and CCL11 levels. Additionally, a decrease in specific anti-OVA IgE levels was observed. The reduction observed in these inflammatory parameters was associated with increased levels of IL-10 in lung tissues. Furthermore, Smteg/asthma mice showed high percentage of CD11b+F4/80+IL-10+ and CD11c+CD11b+IL-10+ cells in lungs.ConclusionTaken together, these findings demonstrate that S. mansoni schistosomula tegument can modulates experimental airway inflammation.

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“…Omalizumab is a monoclonal anti-IgE antibody that was approved by the FDA in 2003 for the treatment of moderate-persistent uncontrolled allergic asthma with inhaled corticosteroids, being the first biologic used for type 2 inflammatory diseases. 13 , 15 , 16 , 17 Studies have shown improvements in asthma control, a reduction in the number of exacerbations, and a decreased need for oral corticosteroids and rescue medications. 15 In January 2021, the Brazilian National Health Surveillance Agency (ANVISA) approved omalizumab for use in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) as a complementary treatment to intranasal corticosteroids in adult patients above 18 years old.…”

Section: Omalizumab (Anti-ige)mentioning

confidence: 99%

Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update

Anselmo-Lima,

Romano,

Tamashiro

et al. 2024

Brazilian Journal of Otorhinolaryngology

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Omalizumab

Cited by 26 publications

References 13 publications

Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics

Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics

Schistosoma mansoni Tegument (Smteg) Induces IL-10 and Modulates Experimental Airway Inflammation

Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update

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