CD98hc is a target for brain delivery of biotherapeutics

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 19, 2023

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report engineering and characterization a BBB transport vehicle targeting CD98 heavy chain (CD98hc or SLC3A2) heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic biodistribution properties CD98hc antibody (ATVCD98hc) are assessed in humanized knock-in mice cynomolgus monkeys. Compared to most existing platforms transferrin receptor, peripherally ATVCD98hc demonstrates differentiated brain delivery with markedly slower more prolonged kinetic properties. Specific profiles within parenchyma can be modulated introducing Fc mutations on that impact FcγR engagement, changing valency binding, altering extent target engagement Fabs. Our study establishes TVCD98hc as modular platform favorable kinetic, biodistribution, safety distinct from previously reported platforms.

Язык: Английский

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Nanobodies in cell-mediated immunotherapy: On the road to fight cancer

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Янв. 25, 2023

The immune system is essential in recognizing and eliminating tumor cells. unique characteristics of the microenvironment (TME), such as heterogeneity, reduced blood flow, hypoxia, acidity, can reduce efficacy cell-mediated immunity. primary goal cancer immunotherapy to modify cells or TME enable eliminate malignancies successfully. Nanobodies, known single-domain antibodies, are light chain-free antibody fragments produced from Camelidae antibodies. properties nanobodies, including high stability, immunogenicity, enhanced infiltration into solid tumors facile genetic engineering have led their promising application immunotherapy. They promote therapy either directly by bridging between targeting using cell-bound nanobodies indirectly blocking inhibitory ligands/receptors. T-cell activation be engaged through anti-CD3 anti-4-1BB bispecific (bispecific engagers (BiTEs)) trispecific (trispecific engager (TriTEs)) manners. Also, used natural killer (NK) cell (BiKEs, TriKEs, TetraKEs) create an synapse NK Nanobodies redirect attack a chimeric antigen receptor (CAR) incorporating nanobody against target antigen. Various antigens been targeted nanobody-based CAR-T CAR-NK for treating both hematological malignancies. also cause continuation surveillance stopping inappropriate inhibition checkpoints. Other roles include reprogramming macrophages metastasis angiogenesis, well preventing severe side effects occurring Here, we highlight critical functions various cells, T TME, discuss newly developed methods based on manipulation with nanobodies.

Язык: Английский

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Breaking barriers for glioblastoma with a path to enhanced drug delivery

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 22, 2023

Progress in treatment for glioblastoma is hindered by the blood-brain barrier (BBB). In genetic mouse models recapitulating brain invasion and abnormal angiogenesis of human glioblastoma, Cai colleagues demonstrate that optical modulation BBB with nanoparticles boosts intratumoural chemotherapy concentration, prolonging survival. We discuss prospects clinical translation exemplary innovative techniques.

Язык: Английский

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Receptor-mediated transcytosis for brain delivery of therapeutics: receptor classes and criteria

Frontiers in Drug Delivery, Год журнала: 2024, Номер 4

Опубликована: Март 12, 2024

The delivery of therapeutics into the brain is highly limited by blood-brain barrier (BBB). Although this essential to protect from potentially harmful material found in blood, it poses a great challenge for treatment diseases affecting central nervous system (CNS). Substances periphery that are required function must rely on active mechanisms entry. One such physiological pathway called receptor-mediated transcytosis (RMT). In process, ligands bind specific receptors expressed at luminal membrane endothelial cells composing BBB leading internalization receptor-ligand complex intracellular vesicles, their trafficking through various compartments and finally fusion with abluminal release cargo brain. Targeting RMT crossing represents an emerging clinically validated strategy increase permeability biologicals. However, choice appropriate receptor critical achieve best selectivity efficacy method. Whereas majority work has been focused transferrin (Tf) (TfR), search novel (BECs) can deliver protein or viral vector cargos across yielded several targets diverse molecular/structural properties biological functions, transcytosis. review, we summarize well-studied pathways, explore engaged transport receptors. We then discuss key criteria would be desired optimal target, based lessons-learned studies TfR accumulating experimental evidence ligands.

Язык: Английский

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Permeability Benchmarking: Guidelines for Comparing in Silico, in Vitro, and in Vivo Measurements

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Permeability is a measure of the degree to which cells can transport molecules across biological barriers. Units permeability are distance per unit time (typically cm/s), where accurate measurements needed define drug delivery in homeostasis and model dysfunction occurring during disease. This perspective offers set community-led guidelines benchmark data multidisciplinary approaches different contexts. First, we lay out analytical framework for three methodologies calculate permeability: silico assays using either transition-based counting or inhomogeneous-solubility diffusion approaches, vitro cultured 2D 3D geometries, vivo utilizing situ brain perfusion multiple time-point regression analysis. Then, demonstrate systematic benchmarking both vivo, depicting ways each sensitive choices assay design. Finally, outline seven recommendations best practices underscore significance tailored driving advancements research development. Our exploration encompasses discussion "generic" tissue-specific barriers, including blood–brain barrier (BBB), major hurdle therapeutic agents into brain. By addressing challenges reconciling simulated with experimental assays, aim provide insights essential optimizing accuracy reliability modeling.

Язык: Английский

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Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs

Cell chemical biology, Год журнала: 2023, Номер 31(2), С. 361 - 372.e8

Опубликована: Окт. 26, 2023

Язык: Английский

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Multivalent protein-drug conjugates – An emerging strategy for the upgraded precision and efficiency of drug delivery to cancer cells

Biotechnology Advances, Год журнала: 2023, Номер 67, С. 108213 - 108213

Опубликована: Июль 13, 2023

With almost 20 million new cases per year, cancer constitutes one of the most important challenges for public health systems. Unlike traditional chemotherapy, targeted anti-cancer strategies employ sophisticated therapeutics to precisely identify and attack cells, limiting impact drugs on healthy cells thereby minimizing unwanted side effects therapy. Protein drug conjugates (PDCs) are a rapidly growing group therapeutics, composed cancer-recognition factor covalently coupled cytotoxic drug. Several PDCs, mainly in form antibody-drug (ADCs) that monoclonal antibodies as molecules, used clinic many PDCs currently clinical trials. Highly selective, strong stable interaction PDC with tumor marker, combined efficient, rapid endocytosis receptor/PDC complex its subsequent effective delivery lysosomes, is critical efficacy therapy PDCs. However, bivalent architecture contemporary not optimal receptor recognition or internalization. In this review, we focus multivalent which represent evolving highly promising overcome limitations current enhancing precision efficiency cells. We present an expanding set protein scaffolds generate that, addition folding into well-defined molecular structures, enable site-specific conjugation ensure homogeneity. provide overview architectures developed date, emphasizing their treatment various cancers.

Язык: Английский

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Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 14, 2024

Abstract Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by blood-brain barrier (BBB). Bioengineered Adeno-Associated Virus (AAV) capsids have been shown penetrate BBB with great efficacy in mouse and non-human primate models, but their translational potential often limited species selectivity undefined mechanisms action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform generate VCAP-102, an AAV9 variant markedly increased brain tropism following intravenous delivery both rodents primates. VCAP-102 demonstrates a similar CNS cynomolgus macaque, african green monkey, marmoset mouse, showing 20- 400-fold transgene expression across multiple regions relative AAV9. We demonstrate that enhanced results from direct interaction alkaline phosphatase (ALPL), highly conserved membrane-associated protein expressed on vasculature. interacts human, murine ALPL isoforms, ectopic sufficient initiate receptor-mediated transcytosis vitro transwell model. Our work identifies as cross-species gene vector strong for clinical translation establishes shuttle capable efficient transport maximize biotherapeutics.

Язык: Английский

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Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6683 - 6683

Опубликована: Июнь 18, 2024

Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies Alzheimer’s disease approved, dozens testing phase, and one was withdrawn, other halted, likely due efficacy issues. However, these outcomes should have been evident since cannot enter sufficiently blood–brain barrier (BBB) protectant. all products be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model tested quickly at a low cost applied bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, their paper demonstrates conjugating transferrin does not alter such amyloid-β (Aβ) α-synuclein. We also present selection conjugate designs will allow cleavage upon entering prevent exocytosis while keeping fragments connected enable optimal proteins. The identified readily returned patients lowest regulatory delays. These engineered manufactured recombinant engineering, mRNA technology, more affordable solution meet dire need effectively.

Язык: Английский

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Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics

Pharmaceutics, Год журнала: 2023, Номер 15(6), С. 1748 - 1748

Опубликована: Июнь 16, 2023

The blood-brain barrier (BBB), while being the gatekeeper of central nervous system (CNS), is a bottleneck for treatment neurological diseases. Unfortunately, most biologicals do not reach their brain targets in sufficient quantities. antibody targeting receptor-mediated transcytosis (RMT) receptors an exploited mechanism that increases permeability. We previously discovered anti-human transferrin receptor (TfR) nanobody could efficiently deliver therapeutic moiety across BBB. Despite high homology between human and cynomolgus TfR, was unable to bind non-human primate receptor. Here we report discovery two nanobodies were able making these more clinically relevant. Whereas BBB00515 bound TfR with 18 times affinity than it did BBB00533 similar affinities. When fused anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) (1A11AM), each increase its permeability after peripheral injection. A 40% reduction Aβ1-40 levels be observed mice injected anti-TfR/BACE1 bispecific antibodies when compared vehicle-injected mice. In summary, found both potential used biologicals.

Язык: Английский

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