an immunomodulatory member of the gut ... - 4d pharma plc€¦ · 4d pharma plc “developing...
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4D Pharma PLC “Developing Science, Delivering Therapies”
Results
Introduction Study Designi
4D Pharma PLC is a pharmaceutical company focussed on developing live biotherapeutic products (LBPs) from the human gut microbiome. LBPs represent a new class of drugs that contain live organisms for the prevention, treatment or cure of disease. 4D Pharma currently has two clinical stage programmes (in IBS and IBD) and a strong pipeline of pre-clinical programmes in autoimmunity, inflammation, oncology and CNS disease.
MRx0006 shows efficacy in CII-induced arthritis model, indicating potential therapeutic value in the treatment of RA
Reduced severity of clinical scores
Protection from histopathological joint damage
Suppression of systemic inflammatory cascades
Future DirectionKey Findings
Rheumatoid arthritis (RA) is an autoimmune disease of the synovial tissuesaround the joints which affects over 3 million people in the US and EU.Microbiota alterations have been associated with many autoimmunedisorders1. For instance, Prevotella copri abundance correlates stronglywith RA onset2. Identification of bacterial strains which can ameliorateinflammation and clinical symptoms of arthritis may lead to thedevelopment of new therapeutics.
MRx0006 is a bacterial strain isolated from the intestinal tract of a healthyhuman donor. Data generated by the MicroRxTM discovery platformshowed that MRx0006 can modulate inflammatory responses in human-derived immune cells. MRx0006 was tested for its therapeutic effects invivo in a type II collagen (CII) -induced arthritis model.1Kamada et al 2013. Nature Reviews Immunology 13, 321-3352Scher et al 2013. Elife. 5;2:e01202
Aim: To test the effects of MRx0006 on clinical disease andimmunological markers in a type II collagen (CII)-induced arthritis model.
Daily dose of vehicle or 1x108 CFU MRx0006
Fig. 5: Cytokine levels in tissue culture supernatantsafter CII stimulation. Data are presented as Mean ± SD.* p<0.05 compared to vehicle.
Further studies are underway to determine the mechanism through which MRx00006 mediates a therapeutic effect on the immune system.
MRx0006 is in development for future FiM clinical trials
Splenocyte Cytokine Response
Fig. 4: The CII-specific proliferative recall response insplenocytes was significantly reduced by MRx0006treatment. Data are presented as Mean ± SEM (mediabackground subtracted). * p<0.05 compared to vehicle.
Splenocyte Proliferation Response
Body weight: 3 x per week
Clinical scores: 3 x per week
Sacrifice
Disease Induction100 mg type II collagen + CFA+ 4 mg/ml M. tuberculosis H37Ra
Disease Booster100 mg type II collagen + CFA
Day -14 Day 42Day 0 Day 21
Disease Onset
Histopathology
Fig. 3: Representative H&E stained saggital sections of arthritic mouse hind limbs.Cartilage destruction, bone erosion and infiltration of inflammatory cellsincluding macrophages (M) and neutrophils (N), were visible in vehicle-treatedanimals (Fig.3A, B & C) bu,
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Fig. 1: MRx0006 significantly reduced clinical scores(swelling of paws and joints). Data are presented asMean ± SEM. **** p<0.0001 compared to Day 21 invehicle. ♦, p<0.05 compared to vehicle on given day.
Clinical Scores
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Total Histopathology Scores
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Fig. 2: MRx0006 significantly reduced all hind limbhistopathological scores, including joint inflammationand cartilage/bone damage. Data are presented asMean ±SEM. *** p<0.001 compared to vehicle.
Vehicle MRx0006
An immunomodulatory member of the gut microbiota reduces clinical signs and inflammatory joint damage in an animal model of rheumatoid arthritis
Emma Raftis, Margaret Delday, Imke Mulder4D Pharma PLC, UK