Antibody Buffering in the Brain

O’Hear, Carol; Foote, Jefferson

doi:10.1016/j.jmb.2006.09.029

Cited by 4 publications

(5 citation statements)

References 21 publications

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“…Pharmacodynamic studies using a 1-compartment model, supported by the first-order elimination process, show an elimination rate constant (k e ) of 0.0443 ± 0.099 h À1 for RW03-IgG (Figure S2). From k e , the antibody has a half-life (t 1/2 ) of 15.6 h, which is similar to reported antibody t 1/2 values with minimal Fc receptor (12.8 h) binding within brain tissue (O'Hear and Foote, 2006;Wolak et al, 2015), suggesting that RW03-IgG clearance is not Fc-receptor-mediated elimination.…”

Section: In Vitro and In Vivo Efficacy Of Anti-cd133 Human Synthetic Antibodysupporting

confidence: 76%

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

et al. 2020

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CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo-and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133. All three showed activity against patient-derived CD133+ GBM cells, and CART133 cells demonstrated superior efficacy in patient-derived GBM xenograft models without causing adverse effects on normal CD133+ hematopoietic stem cells in humanized CD34+ mice. Thus, CART133 cells may be a therapeutically tractable strategy to target CD133+ CSCs in human GBM or other treatment-resistant primary cancers.ll Clinical and Translational Report

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Section: In Vitro and In Vivo Efficacy Of Anti-cd133 Human Synthetic Antibodysupporting

confidence: 76%

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

et al. 2020

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“…As IgG efflux/elimination from the brain or specific cellular uptake would also likely involve Fc receptor-dependent processes, the lack of a large increase in D* after co-injecting Fc suggests elimination and/or uptake did not play an important role in IgG’s low D* under our experimental conditions; indeed, the total imaging time used here for IOI in brain (~5 min or less) was significantly shorter than the expected in vivo clearance half-life of IgG (e.g. reported IgG t 1/2 values in brain have ranged from 48 min[41] to 12.8 hr[42]). It is possible that fluorophore conjugation to IgG may have altered the affinity of its interaction with endogenous Fc receptors.…”

Section: Discussionmentioning

confidence: 98%

“…As already mentioned, clearance half-lives for IgG have been reported to vary widely (e.g. from 48 min[41] to 12.8 hr[42] in the rat); comparison of these reported values with literature turnover times for rat CSF ( t 1/2 = 29–71 min)[3] indicate a higher IgG k e ( t 1/2 = 48 min) may be more appropriate to describe the kinetics of IgG elimination from the CSF compartment. Utilizing this higher k e and our IOI-derived D* for IgG, predicted IgG concentration profiles resulting from diffusive transport in brains of different size are shown in Figure 5B.…”

Section: Discussionmentioning

confidence: 99%

Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging

Wolak

Pizzo

Thorne

2015

Journal of Controlled Release

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Antibody-based therapeutics exhibit great promise in the treatment of central nervous system (CNS) disorders given their unique customizable properties. Although several clinical trials have evaluated therapeutic antibodies for treatment of CNS disorders, success to date has likely been limited in part due to complex issues associated with antibody delivery to the brain and antibody distribution within the CNS compartment. Major obstacles to effective CNS delivery of full length immunoglobulin G (IgG) antibodies include transport across the blood-brain and blood-cerebrospinal fluid barriers. IgG diffusion within brain extracellular space (ECS) may also play a role in limiting central antibody distribution; however, IgG transport in brain ECS has not yet been explored using established in vivo methods. Here, we used real-time integrative optical imaging to measure the diffusion properties of fluorescently labeled, non-targeted IgG after pressure injection in both free solution and in adult rat neocortex in vivo, revealing IgG diffusion in free medium is ~10-fold greater than in brain ECS. The pronounced hindered diffusion of IgG in brain ECS is likely due to a number of general factors associated with the brain microenvironment (e.g. ECS volume fraction and geometry/width) but also molecule-specific factors such as IgG size, shape, charge and specific binding interactions with ECS components. Co-injection of labeled IgG with an excess of unlabeled Fc fragment yielded a small yet significant increase in the IgG effective diffusion coefficient in brain, suggesting that binding between the IgG Fc domain and endogenous Fc-specific receptors may contribute to the hindered mobility of IgG in brain ECS. Importantly, local IgG diffusion coefficients from integrative optical imaging were similar to those obtained from ex vivo fluorescence imaging of transport gradients across the pial brain surface following controlled intracisternal infusions in anesthetized animals. Taken together, our results confirm the importance of diffusive transport in the generation of whole brain distribution profiles after infusion into the cerebrospinal fluid, although convective transport in the perivascular spaces of cerebral blood vessels was also evident. Our quantitative in vivo diffusion measurements may allow for more accurate prediction of IgG brain distribution after intrathecal or intracerebroventricular infusion into the cerebrospinal fluid across different species, facilitating the evaluation of both new and existing strategies for CNS immunotherapy.

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“…When an mAb and its small chemical hapten were coadministered, the half‐life of the hapten in vivo increased 17 times relative to an mAb control 9 . Furthermore, the mAb could be recharged in situ with fresh hapten, even days after the initial antibody infusion 10 . In other animal studies, endogenous antibodies against a small chemical molecule were found to serve as carriers and result in substantial decreases in clearance relative to mock controls 11 .…”

Section: Chance Encounter: Cause For Concernmentioning

confidence: 99%

Drug‐binding Cavities in Long‐Lived Biologics: Cause for Concern but Also Potential Benefit

Panayotatos

2008

The Journal of Clinical Pharma

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Universally present but overlooked cavities or pockets in long-lived biopharmaceuticals, such as monoclonal antibodies (mAbs), are capable of binding small drugs. Such direct interactions can alter the pharmacokinetics of drugs and potentially affect clinical outcome. The extreme differences in the pharmacokinetic properties of these 2 classes of drugs largely account for such effects. This overlooked mechanism of biologic-chemical drug interaction should be considered before approval of new long-lived entities.

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Antibody Buffering in the Brain

Cited by 4 publications

References 21 publications

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging

Drug‐binding Cavities in Long‐Lived Biologics: Cause for Concern but Also Potential Benefit

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