Prediction of intraocular antibody drug stability using ex-vivo ocular model

Patel, Sulabh; Stracke, Jan Olaf; Altenburger, Ulrike; Mahler, Hanns‐Christian; Metzger, Philipp; Shende, Pankaj; Jere, Dhananjay

doi:10.1016/j.ejpb.2016.10.028

Cited by 12 publications

(7 citation statements)

References 18 publications

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“…Different in vitro models developed elsewhere, used static incubation 8,9,[35][36][37] or a dialysis setup. 7,10,11,13,27,38 Dialysis simulates a slow influx of the SC interstitial fluid 13,27 and allows to diffuse small molecules (excipients) across the membrane, whilst retaining the therapeutic protein locally. Such events have been argued to occur after SC administration.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies developed models using a dialysis membrane. 10,11,13,27 We evaluated the applicability of dialysis cassettes compared to conventional 10 mL Nalgene bottles, in regards to assessing subvisible particle (SbVP) formation. Triplicates of Nalgene bottles, Slide-A-Lyzer, and Float-A-Lyzer cassettes were filled with 5 mL of AF.…”

Section: Development Of a Physiologic In Vitro Modelmentioning

confidence: 99%

“…Thus, a number of groups developed in vitro models simulating human in vivo conditions. For example using the desired biological fluid such as serum/plasma 7−9 (related to intravenous administration), vitreous humor 7,10,11 (related to intravitreal injections), artificial SC fluid, 12−15 or SC tissue homogenate 16 (related to SC administration). Simulating the SC tissue is particularly challenging as the SC interstitial fluid is not readily accessible.…”

Section: Introductionmentioning

confidence: 99%

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Stability of monoclonal antibodies after simulated subcutaneous administration

Schuster

Mahler

Joerg

et al. 2021

Journal of Pharmaceutical Sciences

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Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients. We assessed the stability of two monoclonal antibodies (mAbs) in four different protein-free fluids under physiologic conditions. We monitored protein stability over two weeks using a range of analytical methods, in analogy to testing purposes of a drug product. Both mAbs showed an increase of protein aggregates, fragments, and acidic species. mAb1 was consistently more stable in this in vitro model than mAb2, highlighting the importance of comparing the stability of different mAbs under physiologic conditions. Throughout the study, both mAbs were substantially less stable in bicarbonate buffers as compared to phosphate-buffered saline. In summary, our developed model was able to differentiate stability between molecules. Bicarbonate buffers were more suitable compared to phosphate-buffered saline in regards to simulating the in vivo conditions and evaluating protein liabilities.

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Section: Discussionmentioning

confidence: 99%

Section: Development Of a Physiologic In Vitro Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stability of monoclonal antibodies after simulated subcutaneous administration

Schuster

Mahler

Joerg

et al. 2021

Journal of Pharmaceutical Sciences

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“…Studies on therapeutic protein stability, aggregation, and immunogenicity after intravitreal administration are still, however, scarce. Although not studied here, in situ stability concerns are equally pertinent with IVT CNTF, warranting further investigations that could, for example, be carried out by adopting recently described ex vivo approaches [ 72 , 73 ] to study these aspects with rhCNTF.…”

Section: Discussionmentioning

confidence: 99%

Characterization, Stability, and In Vivo Efficacy Studies of Recombinant Human CNTF and Its Permeation into the Neural Retina in Ex Vivo Organotypic Retinal Explant Culture Models

et al. 2020

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Ciliary neurotrophic factor (CNTF) is one of the most studied neuroprotective agents with acknowledged potential in treating diseases of the posterior eye segment. Although its efficacy and mechanisms of action in the retina have been studied extensively, it is still not comprehensively understood which retinal cells mediate the therapeutic effects of CNTF. As with therapeutic proteins in general, it is poorly elucidated whether exogenous CNTF administered into the vitreous can enter and distribute into the retina and hence reach potentially responsive target cells. Here, we have characterized our purified recombinant human CNTF (rhCNTF), studied the protein’s in vitro bioactivity in a cell-based assay, and evaluated the thermodynamic and oligomeric status of the protein during storage. Biological activity of rhCNTF was further evaluated in vivo in an animal model of retinal degeneration. The retinal penetration and distribution of rhCNTF after 24 h was studied utilizing two ex vivo retina models. Based on our characterization findings, our rhCNTF is correctly folded and biologically active. Moreover, based on initial screening and subsequent follow-up, we identified two buffers in which rhCNTF retains its stability during storage. Whereas rhCNTF did not show photoreceptor preservative effect or improve the function of photoreceptors in vivo, this could possibly be due to the used disease model or the short duration of action with a single intravitreal injection of rhCNTF. On the other hand, the lack of in vivo efficacy was shown to not be due to distribution limitations; permeation into the retina was observed in both retinal explant models as in 24 h rhCNTF penetrated the inner limiting membrane, and being mostly observed in the ganglion cell layer, distributed to different layers of the neural retina. As rhCNTF can reach deeper retinal layers, in general, having direct effects on resident CNTF-responsive target cells is plausible.

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“…More recently, the same group proposed an ex vivo intravitreal horizontal stability model employed to assess the long-term stability of a bi-specific monoclonal antibody (mAb) named ExVit-HS. It consisted of a two-compartment dynamic model (VH- and buffer-compartment) separated by a diffusion controlling membrane (MWCO of 50 kDa) [115]. The vitreous-compartment was filled with VH isolated from porcine eyes with an incision placed near the conjunctiva.…”

Section: In Vitro and In Silico Models To Test Intraocular Ddsmentioning

confidence: 99%

Ocular Drug Delivery: A Special Focus on the Thermosensitive Approach

et al. 2019

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The bioavailability of ophthalmic therapeutics is reduced because of the presence of physiological barriers whose primary function is to hinder the entry of exogenous agents, therefore also decreasing the bioavailability of locally administered drugs. Consequently, repeated ocular administrations are required. Hence, the development of drug delivery systems that ensure suitable drug concentration for prolonged times in different ocular tissues is certainly of great importance. This objective can be partially achieved using thermosensitive drug delivery systems that, owing to their ability of changing their state in response to temperature variations, from room to body temperature, may increase drug bioavailability. In the case of topical instillation, in situ forming gels increase pre-corneal drug residence time as a consequence of their enhanced adhesion to the corneal surface. Otherwise, in the case of intraocular and periocular, i.e., subconjunctival, retrobulbar, peribulbar administration, among others, they have the undoubted advantage of being easily injectable and, owing to their sudden thickening at body temperature, have the ability to form an in situ drug reservoir. As a result, the frequency of administration can be reduced, also favoring the patient’s adhesion to therapy. In the main section of this review, we discuss some of the most common treatment options for ocular diseases, with a special focus on posterior segment treatments, and summarize the most recent improvement deriving from thermosensitive drug delivery strategies. Aside from this, an additional section describes the most widespread in vitro models employed to evaluate the functionality of novel ophthalmic drug delivery systems.

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Prediction of intraocular antibody drug stability using ex-vivo ocular model

Cited by 12 publications

References 18 publications

Stability of monoclonal antibodies after simulated subcutaneous administration

Stability of monoclonal antibodies after simulated subcutaneous administration

Characterization, Stability, and In Vivo Efficacy Studies of Recombinant Human CNTF and Its Permeation into the Neural Retina in Ex Vivo Organotypic Retinal Explant Culture Models

Ocular Drug Delivery: A Special Focus on the Thermosensitive Approach

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