A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-dr...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2019-05, Vol.13 (5), p.e0007373-e0007373
Main Authors: MacGregor, Paula, Gonzalez-Munoz, Andrea L, Jobe, Fatoumatta, Taylor, Martin C, Rust, Steven, Sandercock, Alan M, Macleod, Olivia J S, Van Bocxlaer, Katrien, Francisco, Amanda F, D'Hooge, Francois, Tiberghien, Arnaud, Barry, Conor S, Howard, Philip, Higgins, Matthew K, Vaughan, Tristan J, Minter, Ralph, Carrington, Mark
Format: Article
Language:English
Subjects:
African trypanosomiasis
Animals
Antibodies
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - chemistry
Antibody-drug conjugates
Antiprotozoal Agents - administration & dosage
Antiprotozoal Agents - chemistry
Benzodiazepines - administration & dosage
Benzodiazepines - chemistry
Biochemistry
Biological products
Biology and Life Sciences
Biopharmaceuticals
Blood-brain barrier
Care and treatment
Conjugates
Cures
Development and progression
Drug dosages
Drugs
Engineering
Exploitation
Female
Funding
Haptoglobin
Hemoglobin
Hemoglobins
Humans
Hygiene
Immunoglobulins
Infection
Infections
Livestock
Medical research
Medicine and Health Sciences
Mice
Mice, Inbred BALB C
Monoclonal antibodies
Parasites
Patient outcomes
Pentamidine
Proteins
Proteomics
Protozoal infections
Pyrroles - administration & dosage
Pyrroles - chemistry
Receptors
Recombinants
Research and Analysis Methods
Side effects
Therapeutics
Toxins
Tropical diseases
Trypanosoma brucei brucei - drug effects
Trypanosome
Trypanosomiasis
Trypanosomiasis, African - drug therapy
Trypanosomiasis, African - parasitology
Uptake
Vector-borne diseases
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Description
Summary:Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0007373