In vivo pharmacology

 

Evotec has developed considerable in vivo pharmacology expertise in all key therapeutic areas including neurosciences, metabolic diseases and complications, oncology, immuno-oncology, infectious disease, inflammation and immunology.

Our in vivo pharmacology team (> 80 staff), consists of highly experienced scientists with extensive biopharmaceutical and drug hunting expertise. The team supports in vivo studies from early target validation through to candidate selection. Furthermore, we have the flexibility to support defined stand-alone studies as well as in vivo work conducted as part of larger integrated drug discovery programmes.

All experimental procedures involving animals are carried out to the highest standards of animal welfare in state-of-the-art facilities and approved according to European Union and national regulations.

Evotec will work with you to identify the most appropriate in vivo pharmacology solution for your drug discovery programme; whether that’s an off-the-shelf standard protocol or developing bespoke assays/read-outs for your specific requirements. We utilise a plethora of acute, mechanistic, pharmacodynamic models relevant to the target biology to assess target engagement and establish PK/ PD relationships. Our efficacy models are used to assess biological effects on pathophysiologies relevant to the disease of interest and are validated with appropriate standards of care and supported by rigorous statistical methods.

At Evotec we are continually striving to develop in vivo models and endpoints with greater translational relevance to the clinic, with a strong focus on understanding drug MoA. All our models can be supported by relevant pharmacokinetic measurements to determine exposure to effect relationship. Importantly, Evotec’s in vivo pharmacology functions are typically co-localised with our in vitro pharmacology units and this complementarity leads to biology platforms with a deeper disease focus and breadth of expertise. 

In vivo Pharmacology for Anti-infectives

Evotec is expert in assessing the efficacy of lead and candidate compounds in highly relevant and validated models of infection. Our extensive range of established models are well-suited to the development of multiple classes of agent including small molecules, natural products, peptides, antibodies, other biologics and vaccines. We provide a highly bespoke service, customising studies to meet the exact requirements based on programme needs and parameters/endpoints of interest.

Models of infection

For efficacy assessment against bacterial and fungal infections, our models address different sites of infection (localised and systemic) and pathogens by

  • Gram-positive (including Staphylococcus aureus, Streptococcus pneumoniae, and others)
  • Gram-negative (including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumanii and others), anaerobes (including Clostridium difficile)
  • Fungal species (including Candida sp., Aspergillus sp., Mucorales, Malassezia sp.)

Evotec also specialises in PK/PD profiling and modelling of antimicrobial agents in multiple disease models in order to understand the key drivers for efficacy and translation of data into clinical trial design.

Key read-outs

  • Burden at site of infection and in multiple biological matrices including quantitative culture, QPCR and biomarkers
  • Microbiome analysis and sequencing
  • Bioluminescence (IVIS Spectrum) imaging
  • Host response endpoints including ELISA, Western Blotting, dot-blotting, histology, immunohistochemistry, cytokine profiling and cytometry
  • Bioanalysis for associated pharmacokinetic studies (PK/PD) and pathogen-associated biomarkers

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Our capabilities in anti-infectives In vitro biology for anti-infectives

In vivo Pharmacology for Inflammation and Immunology

Evotec’s experienced immunology & inflammation in vivo team has an established and proven track record. The team has contributed to the discovery and development of multiple pre-clinical and clinical candidates and is currently working on >12 immunology and inflammation programmes in the areas of inflammation, autoimmune disorders, inflammatory pain, endometriosis and cancer immunotherapy. Evotec’s core expertise in small molecule drug discovery in immunology and inflammation is complemented by a growing state-of-the-art know-how in the development of therapeutic antibodies.

Histopathology (H&E-stained sections) of mouse knee joints 31 days after intra-articular injection of mono-iodoacetate (MIA) inducing chronic arthritis

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Inflammation and immunology models

  • Joint disease (e.g. CIA, MIA)
  • Inflammatory pain (e.g. CFA, NGF)
  • Neuro-inflammation (e.g. Q175, BACHD)
  • Anemia (peptidoglycan-polysaccharide-induce Anemia)
  • Endometriosis
  • Pharmacodynamic/target engagement assays including: LPS/TLR induced cytokine release, IL-1b/desArg9 Bradykinin paw oedema, anti-CD induced T-cell activation and expansion, plus a range of bespoke target/project specific models

Key read-outs

  • In life clinical measurements: pain, swelling/paw volume, disease activity scoring, automated behavioural analysis (Laboras)
  • Imaging: high-content histology, Bioseb dynamic weight bearing
  • Differential cell counts, full blood chemistry profiling and FACS analysis
  • Quantitative mRNA analysis by RT-qPCR, RNAseq
  • Multi-analyte protein determination in fluids/tissues by MSD and Singulex technology

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Our capabilities in immunology and inflammation In vitro biology for immunology and inflammation

In vivo Pharmacology for Metabolic Diseases and Diabetic Complications

Evotec’s in vivo pharmacology team has a strong expertise in supporting drug discovery in the area of metabolic diseases and complications.
Evotec offers a range of developed and well characterised in vivo models of Type 1 and 2 Diabetes, obesity, liver, renal and chronic kidney disease, with a particular focus on NASH and fibrosis respectively. In addition our team routinely develop bespoke models to fit our collaborator’s specific projects’ needs.

Metabolic disease models

  • Genetic models (e.g. ZDF and ZSF1 rats, db/db and ob/ob mice)
  • Chemically-induced diabetes models with Streptozotocin (STZ) or Alloxan
  • A humanised beta-cell model where human islets are transplanted into STZ-treated diabetic NOD-SCID mice
  • Diet-induced models (e.g. for Typ 2 Diabetes, obesity and NASH)

Histopathological features in a mouse model of chronic kidney disease secondary to ischemia and reperfusion injury

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Acute and chronic kidney disease models

  • Acute and chronic renal ischemia reperfusion injury models (aIRI, cIRI)
  • Unilateral ureter obstruction model (UUO)
  • Genetic, dietary and surgical models of diabetic nephropathy and combinations thereof (e.g. uninephrectomised db/db mice)
  • Chemically induced Diabetes mellitus models
  • Chronic renal failure model

 

Animal models of eye disease for proliferative and diabetic retinopathy

  • Chemically induced diabetes
  • Oxygen Induced Retinopathy (OIR)

Key read-outs

  • Standard clinical and metabolic read-outs:
    • Functional glucose/insulin tolerance test
    • Ex vivo read-outs including RT-PCR
    • Biochemical assays
    • Hormonal status and histology

Sirius red staining showing collagen deposition in the liver of a diet-induced mouse model of NASH

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  • Advanced read-outs:
    • Hyperinsulinemic euglycemic clamp
    • Food intake profiles
    • Pairfeeding
    • Body composition analysis by Nuclear Magnetic Resonance (NMR) spectroscopy
    • Morphometric analysis with customised algorithms e.g. with pancreas and adipose tissue
    • Quantitative analysis of fibrosis (Sirius Red, alpha-SMA)
    • Histopathologic staging of fibrosis
    • Blood pressure analysis
    • Assessment of Glomerular Filtration Rate (GFR)

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Our capabilities in metabolic diseases and complications In vitro biology for metabolic diseases and complications

In vivo Pharmacology for Neurosciences

Evotec´s scientists have in-depth knowledge and expertise in a wide range of rodent models of CNS diseases including neurodegeneration, psychiatry and pain. Utilisation of our Adeno-Associated Virus (AAV) platform provides essential target validation for novel targets; development of tailor-made assays allow us to demonstrate target engagement/modulation using acute behavioural, biomarker and ex vivo receptor occupancy read-outs. Importantly, our scientists are fully blinded to reduce the potential for operator bias.

Acute / Chronic pain models

Evotec offers a range of acute and chronic pain models in rodents with different readouts including dynamic weight-bearing deficits for mono-iodoacetate (MIA) arthritis, von Frey for spinal nerve ligation (SNL), visceromotor reflex-EMG activity for visceral pain to automated quantification using Laboras for formalin paw and a Paclitaxel-induced peripheral neuropathy model to assess neuroprotective and analgesic agents.

Key read-outs:
  • Thermal sensitivity: Hargreaves test, hot plate, tail flick
  • Mechanical sensitivity: Von Frey test, pressure application measurement device, dynamic weight bearing
  • Laboras automated recording for formalin paw and locomotor activity
  • Visceral motor reflex-EMG activity
  • Nerve conduction (SNAPs and CMAPs)

Neurodegenerative disease models

Phenotypic screening of models of neurodegeneration, primarily in transgenic animals for Huntington Chorea (e.g. Q175) and for Alzheimer’s disease (e.g. ARTE10).

Key read-outs:
  • Locomotor activity (rotarod)
  • Emotion (Elevated Zero Maze, fear conditioning)
  • Cognition (Novel Object Recognition, spatial memory)
  • Irwin test Pre-Pulse Inhibition
  • Gait analysis

Bilateral injection of monoclonal antibody TrkB agonist staining in mouse brain

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AAV target validation platform

Neonatal and adult (stereotaxic) injections into specific brain regions in rodents using AAV-vectors designed for knock down or overexpression of specific proteins.

Key read-outs:
  • Behavioral assays, histology and immuno-histochemistry (IHC), morphometric analysis
  • High-content IHC analysis
  • Biomarkers (e.g. cytokines using Mesoscale)

Ex vivo radioligand binding autoradiography platform

State-of-the-art imaging technologies (Beta Imager & Phosphoimager) to determine protein localisation, functional responses using GTPγS radioligand binding and ex vivo receptor occupancy.

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Our capabilities in neurosciences In vitro biology for neurosciences

In vivo Pharmacology for Oncology and Immuno-Oncology

Evotec has a long-standing expertise in oncology, including contributing to multiple clinical candidates and one marketed drug. Evotec offers a range of mouse, syngeneic and orthotopic xenograft models, coupled with the possibility of a broad range of efficacy and biomarker read-outs. Access to a humanised mouse platform expands the evaluation of drug effects with species specificity or on specific patient populations.

CD3 (T-lymphocytes) and hypoxyprobe (hypoxia zones) dual staining in 4T1 tumour

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Evotec also has access to a range of human tumour tissues via the Institut Universitaire du Cancer Toulouse which can be utilised for biomarker studies or ex vivo evaluations including compound treatment.

Oncology and immuno-oncology models

  • Orthotopic (and subcutaneous) xenograft models in multiple organs
  • Syngeneic models suitable for the evaluation of immuno-oncology therapies (alone or in combination with ICT)
  • Humanised mouse, carcinogen-induced and metastasis models
  • Laser Doppler and X-ray imaging for blood flow and anatomical evaluations

Target staining in patient tumour material

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Key read-outs

  • Efficacy evaluation by tumour volume, bioluminescence imaging or surrogate markers
  • Full haematological analysis including FACS and ELISpot
  • Bioanalysis and formulation for associated PK/PD studies
  • Clinically translatable read-outs on tissues (both human and mouse):
    • Ventana-based IHC and histology supported by quantitative image analysis (Definiens)
    • Genomics studies including RT-qPCR, TLDA
    • Proteomics and immunoassays
    • Metabolomics and quantification of lactate, glucose, glutamine, glutamate
  • Microdialysis applied to in life monitoring of metabolites and/or drug levels in tissue or biological fluids

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Our capabilities in oncology In vitro biology for oncology

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