INNOVATIVE CELL BIOLOGY AND
IMMUNOLOGY
LECTURES
1A: INTRODUCTION TO ANIMAL FREE INNOVATIONS
MAIN AIM AND LEARNING GOALS
→ Introduce you to the concept of the international “Transition towards animal free innovations”
• Know the separate phases leading from drug discovery to market approval
• Understand the necessity for improvement and the challenges this involves
• Have insight into the international transition to animal free innovations
TRANSITION TO ANIMAL FREE INNOVATIONS
Clinicians → new drugs, medical devices needed
Clinical problems: no optimal solution = new drugs and medical devices needed
Problems
- Potential drugs not reaching Phase 1 testing
- Only 1 out of 10 drugs entering Phase 1 is finally approved
= Improvement preclinical testing needed
→ challenges scientists for development alternative methods
DRUG DEVELOPMENT PIPELINE
Test throughput: number of tests running in a certain phase
- Animals
- In vitro assays
1. Discovery
o Academic scientists → find mechanism of disease (e.g. melanoma)
= understanding why one patient gets disease, other doesn’t
o Understand pathways = block pathways = stop progression
, o In hundreds of animals
= target found
2. Lead optimization
o Tens of thousands of in vitro assays
o Hundreds of animals
3. Phase I
o Not in animals or in vitro
o Very small group with 10-20 patients
o Testing of safety of drug
4. Phase II
o When Phase I has proven safety
o Expansion of group
o Testing of efficacy – does the drug work?
5. Phase III
o Thousands of patients
6. Submission
o Approval = accepted for use in certain disease in certain patient group
7. Post-marketing approval
o Testing for usefulness in other type of diseases
Where are improvements needed and why?
→ need physiologically relevant human models
1) Prior to entering Phase I clinical study
o Use of hundreds of animals in
discovery phase to find
potential hit
▪ Small rodents mostly
o Optimization
▪ Useful drugs failing
▪ Safety in animals, but
not in humans
= Optimization pre-clinical phase
necessary
→ “Pre-phase 1 in vitro”
o Determine whether substance safe for human exposure
▪ Prediction adverse event
o Identification of mode of action of new drugs – working mechanism of drug
o Identification of target group of patients
▪ Patient variation
▪ Personalized medicine
→ Each clinical trial focuses on specific disease and patient inclusion criteria
→ Different organoid models from different donors = better look into patient
variation
2) Personalized medicine and post-approval extension
→ “Post market approval in vitro”
o Determine whether substance with proven safety and efficacy for certain disease
useful for treatment different disease
▪ Drug for treating hypertrophic scar suitable for treating keloid fibrosis
o Identification target group of patients
▪ Patient variation
▪ Personalized medicine
,TRANSITION TO ANIMAL FREE METHODS
→ Transition to animal free methods
- Anything that comes in contact with humans have to be tested for safety and efficacy →
transition to not using animals
o TPI – Transitie Proefdiervrije Innovatie
- Variation in between all the different topics in which animals are used
o In cosmetics: no animals used; in vitro models available
o Brain models: animal models used extensively; in vitro models hard to create
COLLABORATION
Scientific challenge = collaboration
- Cell biologist - Computational modeling/big data
- Immunologist (correlating in vitro-animal-human
- Technical engineer data)
- Clinician - Patient organizations
- Industry
= working together to solve a problem
SKINLAB
Development different organotypic models by SkinLab: organotypic skin/mucosa models
- Useful in:
1) Barrier function
2) Chronic toxicity
3) Systemic toxicity (acute)
4) Immunotoxicity
5) Allergy vs. tolerance
6) Fibrosis
▪ Scar models used for testing new
therapeutic strategies for burn
wounds
7) Melanoma
▪ Able to recreate melanoma (SK-Mel-
28 cell line-derived tumors) in human
skin equivalent
▪ Future: static culture – try to achieve
metastasis into other tissues, with
organ-on-chip
, 8) Safety and efficacy dental medical devices
▪ Host-microbiome interactions
• Interaction of microbiome with individual
• Multi-species biofilm cultured from healthy human saliva
o Community composition
o Average OTUs > 70
• Reconstructed human Gingiva
o Healthy and suppression of immune response shown
▪ Animal alternative dental implant: Gingiva model
1. Introduction microbiome, saliva and immune cells
2. Investigation biological seal around implants
3. Introduce underlying bone in vitro
o All related to Adverse Outcome Pathways and
- Ideal test requirements
a) Long term, stable culture
▪ >28 days
• Needed to see how drugs affects organ + recovery of organ
b) Tissue complexity
▪ Organotypic – look and feel like real organ
▪ Microenvironment – mini organ in microenvironment that the real organ is in
c) Bio-distribution
▪ Organs linked via vasculature → not stand-alone organs
- Eventually skin-on-chip and mucosa-on-chip lead to multi organ-on-chip
1. Biopsy, blood sample
2. Tissue equivalent, endothelial cells, immune cells
3. Organ-on-chip
4. Visualization circulating immune cells: medium flow through vasculature to different
organs
5. Multi-organ-on-chip
= future perspective
More information:
IMMUNOLOGY
LECTURES
1A: INTRODUCTION TO ANIMAL FREE INNOVATIONS
MAIN AIM AND LEARNING GOALS
→ Introduce you to the concept of the international “Transition towards animal free innovations”
• Know the separate phases leading from drug discovery to market approval
• Understand the necessity for improvement and the challenges this involves
• Have insight into the international transition to animal free innovations
TRANSITION TO ANIMAL FREE INNOVATIONS
Clinicians → new drugs, medical devices needed
Clinical problems: no optimal solution = new drugs and medical devices needed
Problems
- Potential drugs not reaching Phase 1 testing
- Only 1 out of 10 drugs entering Phase 1 is finally approved
= Improvement preclinical testing needed
→ challenges scientists for development alternative methods
DRUG DEVELOPMENT PIPELINE
Test throughput: number of tests running in a certain phase
- Animals
- In vitro assays
1. Discovery
o Academic scientists → find mechanism of disease (e.g. melanoma)
= understanding why one patient gets disease, other doesn’t
o Understand pathways = block pathways = stop progression
, o In hundreds of animals
= target found
2. Lead optimization
o Tens of thousands of in vitro assays
o Hundreds of animals
3. Phase I
o Not in animals or in vitro
o Very small group with 10-20 patients
o Testing of safety of drug
4. Phase II
o When Phase I has proven safety
o Expansion of group
o Testing of efficacy – does the drug work?
5. Phase III
o Thousands of patients
6. Submission
o Approval = accepted for use in certain disease in certain patient group
7. Post-marketing approval
o Testing for usefulness in other type of diseases
Where are improvements needed and why?
→ need physiologically relevant human models
1) Prior to entering Phase I clinical study
o Use of hundreds of animals in
discovery phase to find
potential hit
▪ Small rodents mostly
o Optimization
▪ Useful drugs failing
▪ Safety in animals, but
not in humans
= Optimization pre-clinical phase
necessary
→ “Pre-phase 1 in vitro”
o Determine whether substance safe for human exposure
▪ Prediction adverse event
o Identification of mode of action of new drugs – working mechanism of drug
o Identification of target group of patients
▪ Patient variation
▪ Personalized medicine
→ Each clinical trial focuses on specific disease and patient inclusion criteria
→ Different organoid models from different donors = better look into patient
variation
2) Personalized medicine and post-approval extension
→ “Post market approval in vitro”
o Determine whether substance with proven safety and efficacy for certain disease
useful for treatment different disease
▪ Drug for treating hypertrophic scar suitable for treating keloid fibrosis
o Identification target group of patients
▪ Patient variation
▪ Personalized medicine
,TRANSITION TO ANIMAL FREE METHODS
→ Transition to animal free methods
- Anything that comes in contact with humans have to be tested for safety and efficacy →
transition to not using animals
o TPI – Transitie Proefdiervrije Innovatie
- Variation in between all the different topics in which animals are used
o In cosmetics: no animals used; in vitro models available
o Brain models: animal models used extensively; in vitro models hard to create
COLLABORATION
Scientific challenge = collaboration
- Cell biologist - Computational modeling/big data
- Immunologist (correlating in vitro-animal-human
- Technical engineer data)
- Clinician - Patient organizations
- Industry
= working together to solve a problem
SKINLAB
Development different organotypic models by SkinLab: organotypic skin/mucosa models
- Useful in:
1) Barrier function
2) Chronic toxicity
3) Systemic toxicity (acute)
4) Immunotoxicity
5) Allergy vs. tolerance
6) Fibrosis
▪ Scar models used for testing new
therapeutic strategies for burn
wounds
7) Melanoma
▪ Able to recreate melanoma (SK-Mel-
28 cell line-derived tumors) in human
skin equivalent
▪ Future: static culture – try to achieve
metastasis into other tissues, with
organ-on-chip
, 8) Safety and efficacy dental medical devices
▪ Host-microbiome interactions
• Interaction of microbiome with individual
• Multi-species biofilm cultured from healthy human saliva
o Community composition
o Average OTUs > 70
• Reconstructed human Gingiva
o Healthy and suppression of immune response shown
▪ Animal alternative dental implant: Gingiva model
1. Introduction microbiome, saliva and immune cells
2. Investigation biological seal around implants
3. Introduce underlying bone in vitro
o All related to Adverse Outcome Pathways and
- Ideal test requirements
a) Long term, stable culture
▪ >28 days
• Needed to see how drugs affects organ + recovery of organ
b) Tissue complexity
▪ Organotypic – look and feel like real organ
▪ Microenvironment – mini organ in microenvironment that the real organ is in
c) Bio-distribution
▪ Organs linked via vasculature → not stand-alone organs
- Eventually skin-on-chip and mucosa-on-chip lead to multi organ-on-chip
1. Biopsy, blood sample
2. Tissue equivalent, endothelial cells, immune cells
3. Organ-on-chip
4. Visualization circulating immune cells: medium flow through vasculature to different
organs
5. Multi-organ-on-chip
= future perspective
More information:
