An Affibody Molecule Is Actively Transported into the Cerebrospinal Fluid via Binding to the Transferrin Receptor

Meister, Sebastian; Hjelm, Linnea Charlotta; Dannemeyer, Melanie; Tegel, Hanna; Lindberg, Hanna; Ståhl, Stefan; Löfblom, John

doi:10.3390/ijms21082999

Cited by 16 publications

(10 citation statements)

References 50 publications

(76 reference statements)

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“…Anti-HER2 cytotoxic Affibody conjugate was generated and showed inhibition activity on tumor growth [205]. Recently, a trispecific affibody fusion protein consisting of antiamyloid beta, a scFv against TfR and an albumin binding domain, was shown to increase uptake into the cerebrospinal fluid 24 h after injection [206].…”

Section: Small-scaffold Multispecific Modalitiesmentioning

confidence: 99%

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Zhong

D’Antona

2021

Antibodies

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Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this “one target one drug” paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed.

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Section: Small-scaffold Multispecific Modalitiesmentioning

confidence: 99%

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Zhong

D’Antona

2021

Antibodies

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“…Nanoparticles can also serve as a new platform for CAR T-cell delivery into the CNS [ 103 ]. Recently, an affibody molecule (ZSYM73) was discovered to potentially increase the penetration into the CNS via attaching to the transferrin receptor (TfR) [ 104 ], which might be applied to the transportation of CAR T cells into the CNS.…”

Section: Current Challenges Of Car-t Therapy In Pediatric Brain Tumentioning

confidence: 99%

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

Lin

Chen

et al. 2021

IJMS

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Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematological malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, including pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents. However, the employment of CAR T-cell therapy in pediatric brain tumors still faces multiple challenges, such as CAR T-cell transportation and expansion through the blood–brain barrier, and identification of the specific target antigen on the tumor surface and immunosuppressive tumor microenvironment. Nevertheless, encouraging outcomes in both clinical and preclinical trials are coming to light. In this article, we outline the current propitious progress and discuss the obstacles needed to be overcome in order to unveil a new era of treatment in pediatric brain tumors.

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“…Non-IgG delivery systems targeting the BBB TfR include cystine-dense peptides, which have a high affinity for the TfR [19]. Novel IgG-based delivery systems targeting the BBB TfR include binding sites engineered in the Fc region [6,20], variable domain of IgG (VNAR) single domain TfRMAbs [21,22], and a single chain Fv (ScFv) TfRMAb fused to an albumin-binding domain, which is fused to a therapeutic affibody [23].…”

Section: Introductionmentioning

confidence: 99%

“…The affinity of the BBB Trojan horses targeting the TfR range over several log orders of magnitude. High affinity TfRMAbs have a dissociation constant (K D ) of binding to the TfR ranging from 0.1 to 3 nM [21][22][23][24][25][26][27][28]. Moderate-affinity TfRMAbs have a KD of binding to the TfR ranging from 14 to 76 nM [26,27,[29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

Pardridge

2021

Pharmaceuticals

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Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.

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An Affibody Molecule Is Actively Transported into the Cerebrospinal Fluid via Binding to the Transferrin Receptor

Cited by 16 publications

References 50 publications

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

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