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Brain pharmacokinet...
Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size
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- Faresjö, Rebecca (author)
- Uppsala universitet,Geriatrik
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- Bonvicini, Gillian (author)
- Uppsala universitet,Geriatrik,Uppsala Univ, Dept Publ Healt & Caring Sci, Rudbeck Lab, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.;BioArctic AB, Warfvinges Vag 35, S-11251 Stockholm, Sweden.
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- Fang, Xiaotian T. (author)
- Yale Univ, Yale PET Ctr, Dept Radiol & Biomed Imaging, 801 Howard Ave, New Haven, CT 06520 USA.
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- Aguilar, Ximena (author)
- Uppsala universitet,Geriatrik
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- Sehlin, Dag, 1976- (author)
- Uppsala universitet,Geriatrik
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- Syvänen, Stina (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Geriatrik
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(creator_code:org_t)
- 2021-06-02
- 2021
- English.
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In: Fluids and Barriers of the CNS. - : BioMed Central (BMC). - 2045-8118. ; 18:1
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Abstract
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- Background Transferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the brain pharmacokinetics, i.e. brain entry, distribution and elimination are still not fully understood for this class of antibodies. The overall aim of the study was to compare the brain pharmacokinetics of two BBB-penetrating bispecific antibodies of different size (210 vs 58 kDa). Specifically, we wanted to investigate if the faster systemic clearance of the smaller non-IgG antibody di-scFv3D6-8D3, in comparison with the IgG-based bispecific antibody mAb3D6-scFv8D3, was also reflected in the brain. Methods Wild-type (C57/Bl6) mice were injected with I-125-iodinated ([I-125]) mAb3D6-scFv8D3 (n = 46) or [I-125]di-scFv3D6-8D3 (n = 32) and euthanized 2, 4, 6, 8, 10, 12, 16, or 24 h post injection. Ex vivo radioactivity in whole blood, peripheral organs and brain was measured by gamma-counting. Ex vivo autoradiography and nuclear track emulsion were performed on brain sections to investigate brain and parenchymal distribution. Capillary depletion was carried out at 2, 6, and 24 h after injection of [I-125]mAb3D6-scFv8D3 (n = 12) or [I-125]di-scFv3D6-8D3 (n = 12), to estimate the relative levels of radiolabelled antibody in brain capillaries versus brain parenchyma. In vitro binding kinetics for [I-125]mAb3D6-scFv8D3 or [I-125]di-scFv3D6-8D3 to murine TfR were determined by LigandTracer. Results [I-125]di-scFv3D6-8D3 showed faster elimination from blood, lower brain C-max, and T-max, a larger parenchymal-to-capillary concentration ratio, and a net elimination from brain at an earlier time point after injection compared with the larger [I-125]mAb3D6-scFv8D3. However, the elimination rate from brain did not differ between the antibodies. The study also indicated that [I-125]di-scFv3D6-8D3 displayed lower avidity than [I-125]mAb3D6-scFv8D3 towards TfR1 in vitro and potentially in vivo, at least at the BBB. Conclusion A smaller size and lower TfR1 avidity are likely important for fast parenchymal delivery, while elimination of brain-associated bispecific antibodies may not be dependent on these characteristics.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Keyword
- Bispecific antibody
- Brain pharmacokinetics
- Transferrin receptor
- BBB
Publication and Content Type
- ref (subject category)
- art (subject category)
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