Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis

Edavettal, Suzanne C.; Cejudo–Martín, Pilar; Dasgupta, B.; Yang, Danlin; Buschman, Matthew D.; Domingo, Derrick; Kolen, Kristof Van; Jaiprasat, Pharavee; Gordon, Renata E.; Schutsky, Keith; Geist, Brian; Taylor, Natalie; Soubrane, Camille Helene; Helm, Elisabeth Van Der; LaCombe, Ann; Ainekulu, Zemeda; Lacy, Eilyn R.; Aligo, Jason; Ho, Jason; Lebowitz, Peter F.; Patterson, James T.; Scheer, Justin M.; Singh, Sanjaya

doi:10.1016/j.medj.2022.09.007

Cited by 28 publications

(33 citation statements)

References 108 publications

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“…Another key aspect of our work is the 2x1 bispecific antibody format, which deserves further consideration. While there are many possible formats for bispecific antibodies 41 , including those that have been used as BBB shuttles 4,8,18,20,28,[42][43][44][45][46][47][48][49] , the 2x1 format reported previously for TfR-1 shuttles (IgG fused to one single-chain Fab) 8 and used in this work (IgG fused to one scFv) is compelling for multiple reasons.…”

Section: Discussionmentioning

confidence: 99%

“…A 2016 study demonstrated the potential of CD98hc-mediated antibody shuttling, showing that it was capable of achieving greater brain uptake than that typically seen with TfR-1 shuttles in mice 17 . A more recent (2022) study investigated CD98hc-mediated brain delivery of IgGs in cynomolgus monkeys 18 .…”

Section: Introductionmentioning

confidence: 99%

“…These previous studies 17,18 , while groundbreaking, have several limitations that are the focus of this work. First, the 2016 report only demonstrates brain shuttling of antibody fragments (Fabs) using a socalled '1×1 shuttle' format -i.e., one Fab arm against a brain target (β-secretase) and the other Fab arm against CD98hc 17 .…”

Section: Introductionmentioning

confidence: 99%

“…This is critical, as reformatting bivalent IgGs into monovalent Fabs for incorporation into a 1×1 shuttle inevitably results in loss of binding affinity and avidity, which is likely to compromise biological function in the brain parenchyma. While the 2022 study addresses this limitation, the reported CD98hc shuttles cannot be used in mice as they are not cross-reactive with mouse CD98hc 18 . Second, the investigators in both studies did not publish the CD98hc antibody sequences, preventing validation of their results or use of the reported shuttles for brain delivery of other antibodies.…”

Section: Introductionmentioning

confidence: 99%

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

Pornnoppadol

Bond

Lucas

et al. 2023

Preprint

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The inability of antibodies and other biologics to penetrate the blood-brain barrier (BBB) is a key limitation to their use in diagnostic, imaging, and therapeutic applications. One promising strategy is to deliver IgGs using a bispecific BBB shuttle, which involves fusing an IgG with a second affinity ligand that engages a cerebrovascular endothelial target and facilitates transport across the BBB. Nearly all prior efforts have focused on the transferrin receptor (TfR-1) as the prototypical endothelial target despite inherent delivery and safety challenges. Here we report bispecific antibody shuttles that engage CD98hc (also known as 4F2 and SLC3A2), the heavy chain of the large neutral amino acid transporter (LAT1), and efficiently transport IgGs into the brain parenchyma. Notably, CD98hc shuttles lead to much longer-lived brain retention of IgGs than TfR-1 shuttles while enabling more specific brain targeting due to limited CD98hc engagement in the brain parenchyma. We demonstrate the broad utility of the CD98hc shuttles by reformatting three existing IgGs as CD98hc bispecific shuttles and delivering them to the mouse brain parenchyma that either agonize a neuronal receptor (TrkB) or target other endogenous antigens on specific types of brain cells (neurons and astrocytes).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Pornnoppadol

Bond

Lucas

et al. 2023

Preprint

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“…Moreover, their monomeric single-domain nature facilitates their genetic fusion to additional proteins, reporter molecules, or proteinaceous drugs ( 14 , 15 ). Although the passage of antibodies and their derivatives through the blood-brain barrier (BBB) is a major challenge for treating brain diseases ( 16 , 17 ), the small size of nanobodies may increase their chance of crossing the BBB either naturally or as a result of cancer-induced BBB leakage ( 18 , 19 ). However, some nanobodies have limited BBB permeability which may be improved by different delivery methods ( 20 ), such as adeno-associated virus (AAV)-based delivery ( 16 ) and carrier-mediated transport ( 21 ).…”

Section: Nanobodies: the Smaller Variant Of Antibodiesmentioning

confidence: 99%

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

et al. 2023

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

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Applications of radiolabeled antibodies in neuroscience and neuro‐oncology

Pakula

Scott

2023

Labelled Comp Radiopharmac

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Positron emission tomography (PET) is a powerful tool in medicine and drug development, allowing for non‐invasive imaging and quantitation of biological processes in live organisms. Targets are often probed with small molecules, but antibody‐based PET is expanding because of many benefits, including ease of design of new antibodies toward targets, as well as the very strong affinities that can be expected. Application of antibodies to PET imaging of targets in the central nervous system (CNS) is a particularly nascent field, but one with tremendous potential. In this review, we discuss the growth of PET in imaging of CNS targets, present the promises and progress in antibody‐based CNS PET, explore challenges faced by the field, and discuss questions that this promising approach will need to answer moving forward for imaging and perhaps even radiotherapy.

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Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis

Cited by 28 publications

References 108 publications

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

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

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

Applications of radiolabeled antibodies in neuroscience and neuro‐oncology

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