Neuronal delivery of antibodies has therapeutic effects in animal models of botulism

Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets.

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A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding

Scientific Reports ◽

10.1038/s41598-017-07457-5 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Guorui Yao ◽

Kwok-ho Lam ◽

Jasmin Weisemann ◽

Lisheng Peng ◽

Nadja Krez ◽

...

Keyword(s):

Receptor Binding ◽

Botulinum Neurotoxin ◽

Single Domain ◽

Single Domain Antibody ◽

Botulinum Neurotoxin A ◽

Domain Antibody

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Faculty Opinions recommendation of Crystal structure of a shark single-domain antibody V region in complex with lysozyme.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1024018.285841 ◽

2005 ◽

Author(s):

Christopher Garcia

Keyword(s):

Crystal Structure ◽

Single Domain ◽

Single Domain Antibody ◽

Domain Antibody ◽

V Region

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CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch

Leukemia ◽

10.1038/s41375-021-01208-2 ◽

2021 ◽

Author(s):

Xin He ◽

Zijie Feng ◽

Jian Ma ◽

Xuyao Zhang ◽

Sunbin Ling ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Domain ◽

Single Domain Antibody ◽

Car T Cells ◽

Domain Antibody ◽

Car T ◽

Acute Myeloid

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Effective Treatment of Neurological Symptoms with Normal Doses of Botulinum Neurotoxin in Wilson’s Disease: Six Cases and Literature Review

Toxins ◽

10.3390/toxins13040241 ◽

2021 ◽

Vol 13 (4) ◽

pp. 241

Author(s):

Harald Hefter ◽

Sara Samadzadeh

Keyword(s):

Botulinum Neurotoxin ◽

Wilson’S Disease ◽

Animal Experiments ◽

Symptomatic Treatment ◽

Wilson's Disease ◽

University Hospital ◽

Laboratory Findings ◽

Dose Information ◽

High Doses ◽

The University

Background: Recent cell-based and animal experiments have demonstrated an effective reduction in botulinum neurotoxin A (BoNT/A) by copper. Aim: We aimed to analyze whether the successful symptomatic BoNT/A treatment of patients with Wilson’s disease (WD) corresponds with unusually high doses per session. Methods: Among the 156 WD patients regularly seen at the outpatient department of the university hospital in Düsseldorf (Germany), only 6 patients had been treated with BoNT/A during the past 5 years. The laboratory findings, indications for BoNT treatment, preparations, and doses per session were extracted retrospectively from the charts. These parameters were compared with those of 13 other patients described in the literature. Results: BoNT/A injection therapy is a rare (<4%) symptomatic treatment in WD, only necessary in exceptional cases, and is often applied only transiently. In those cases for which dose information was available, the dose per session and indication appear to be within usual limits. Conclusion: Despite the evidence that copper can interfere with the botulinum toxin in preclinical models, patients with WD do not require higher doses of the toxin than other patients with dystonia.

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Production, characterization and in-vitro applications of single-domain antibody against thyroglobulin selected from novel T7 phage display library

Journal of Immunological Methods ◽

10.1016/j.jim.2021.112990 ◽

2021 ◽

Vol 492 ◽

pp. 112990

Author(s):

Jothivel Kumarasamy ◽

Samar Kumar Ghorui ◽

Chandrakala Gholve ◽

Bharti Jain ◽

Yogesh Dhekale ◽

...

Keyword(s):

Phage Display ◽

Phage Display Library ◽

Single Domain ◽

Single Domain Antibody ◽

Domain Antibody ◽

T7 Phage Display ◽

T7 Phage

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A Single-Domain Antibody-Based Anti-PSMA Recombinant Immunotoxin Exhibits Specificity and Efficacy for Prostate Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22115501 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5501

Author(s):

Yutong Xing ◽

Keyuan Xu ◽

Shixiong Li ◽

Li Cao ◽

Yue Nan ◽

...

Keyword(s):

Prostate Cancer ◽

Animal Studies ◽

Single Domain ◽

Soluble Form ◽

Therapeutic Window ◽

Single Domain Antibody ◽

Pseudomonas Exotoxin A ◽

Simple Strategy ◽

Domain Antibody ◽

Recombinant Immunotoxin

Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.

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Over expression of anti-MUC1 single-domain antibody fragments in the yeast Pichia pastoris

Molecular Immunology ◽

10.1016/j.molimm.2005.03.003 ◽

2006 ◽

Vol 43 (5) ◽

pp. 426-435 ◽

Cited By ~ 49

Author(s):

Fatemeh Rahbarizadeh ◽

Mohammad J. Rasaee ◽

Mehdi Forouzandeh ◽

Abdol-Amir Allameh

Keyword(s):

Pichia Pastoris ◽

Antibody Fragments ◽

Single Domain ◽

Single Domain Antibody ◽

Yeast Pichia Pastoris ◽

Over Expression ◽

Domain Antibody

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Toward chaperone-assisted crystallography: Protein engineering enhancement of crystal packing and X-ray phasing capabilities of a camelid single-domain antibody (VHH) scaffold

Protein Science ◽

10.1110/ps.034892.108 ◽

2008 ◽

Vol 17 (7) ◽

pp. 1175-1187 ◽

Cited By ~ 47

Author(s):

Valentina Tereshko ◽

Serdar Uysal ◽

Akiko Koide ◽

Katrina Margalef ◽

Shohei Koide ◽

...

Keyword(s):

Protein Engineering ◽

Crystal Packing ◽

Single Domain ◽

Single Domain Antibody ◽

X Ray ◽

Domain Antibody

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Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217316641704 ◽

2016 ◽

Vol 2 ◽

pp. 205521731664170 ◽

Cited By ~ 1

Author(s):

Melissa M Gresle ◽

Yaou Liu ◽

Trevor J Kilpatrick ◽

Dennis Kemper ◽

Qi-Zhu Wu ◽

...

Keyword(s):

Optic Nerve ◽

Axonal Regeneration ◽

Antibody Therapy ◽

Experimental Models ◽

Therapeutic Effects ◽

Axonal Loss ◽

Nerve Crush ◽

Acute Optic Neuritis ◽

Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

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