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

Abstract

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.

Peptides, Antibodies, Peptide Antibodies and More

“…Rhesus-D Ig/rhesus syndrome prophylaxis PAb (Sp IVIG) [69] Anti-toxins/botulism PAb (Sp IVIG) [70,71] Rituximab/lymphoma, Ocrelizumab/multiple sclerosis MAb (recombinant), chimeric [72,73] Infliximab/rheumatoid arthritis MAb (recombinant), chimeric [74] Nivolumab/malignant melanoma MAb (recombinant), human [75] Panitumumab/EGFR metastatic colorectal carcinoma MAb (recombinant), human [76] Daclizumab/allograft rejection Mab (recombinant), humanized [77] HpHbR Ab-PBD conjugate/African trypanosomiasis treatment (mouse model) MAb-drug conjugate [78] Vaccines MMR live attenuated viruses vaccine/measles, mumps, rubella prophylaxis PAb in vivo [79] DiTePePolHiB SU vaccine/diphtheria-tetanus-pertussis-polio-hemophilus prophylaxis PAb in vivo [80][81][82] HPV SU vaccine/cervix cancer prophylaxis PAb in vivo [83,84] CD: cluster of differentiation. DiTePePolHiB SU: Diphteria-Tetanus-Pertussis-Polio-Hemophilus influenzae B subunit vaccine.…”

How are Trypanosoma brucei receptors protected from host antibody‐mediated attack?

“…[72,85] However, the combined strategies are not sufficient to prevent antibody binding as HpHbR monoclonal antibodies readily gained access to the T. brucei endosomal system both in vitro and in the mouse infection model. [86] HpHbR and human innate immunity Some primates including humans exploit the expression of HpHbR by T. brucei. There are primate specific innate immune complexes, Trypanolytic Factors (TLF1 and TLF2), [87,88] that can act as a second ligand for the HpHbR.…”

The Use of Antibody-Antibiotic Conjugates to Fight Bacterial Infections

“…Since it remains unmodified during the parasite antigen variation, it represents an attractive target for target-selective therapies. In an attempt to explore this pathway, researchers developed a recombinant human anti-trypanosome-HpHbR conjugated to a pyrrolobenzodiazepine (PBD) toxin ( MacGregor et al, 2019 ). The antibody-PBD conjugate was effective at killing trypanosomes in vitro at picomolar concentrations.…”