AR - Drug Discovery & Development II

Question 1

Q1: What are human-derived alternatives to traditional preclinical models? (3)

Answer 1

• Human mammary epithelial organoids replicate the histological and genetic features of original tumours.
• Organoids enable high-throughput drug screening, improving speed and accuracy.
• They hold promise for personalised medicine, reducing reliance on animal models.

Question 2

Q2: What is the role of CD28 in T cell activation? (3)

Answer 2

• CD28 is a co-stimulatory molecule on T cells.
• Binds B7 molecules (CD80/CD86) on APCs to promote full T cell activation.
• Enhances cytokine release and T cell proliferation, critical for effective immune responses.

Question 3

Q3: What was TGN1412 and what happened in the 2006 trial? (4)

Answer 3

• TGN1412 was a superagonist monoclonal antibody targeting CD28.
• Aimed to activate T cells non-specifically, especially for treating cancer and autoimmune disease.
• In a Phase I trial (March 2006), all six healthy volunteers suffered severe cytokine storms.
• Led to multiple organ failure, ICU admission, and sparked global re-evaluation of preclinical testing.

Question 4

Q4: What is cytokine release syndrome and how did it relate to TGN1412? (3)

Answer 4

• CRS is a systemic inflammatory response caused by over-activation of immune cells.
• Triggered in this case by massive T cell activation from CD28 stimulation.
• Symptoms include fever, hypotension, organ failure, and can be life-threatening.

Question 5

Q5: Why did animal testing fail to predict the toxic effects of TGN1412? (5)

Answer 5

• CD28 expression patterns differ between species – especially on effector memory T cells.
• Cynomolgus monkeys used in preclinical testing had incomplete representation of human immune subsets.
• The dose escalation protocol lacked safeguards for first-in-human trials.
• Animals showed no cytokine release, but humans responded dramatically.
• Highlighted the need for more predictive, human-relevant in vitro models.

Question 6

Q6: What improvements were made to in vitro models following the TGN1412 disaster? (4)

Answer 6

• Development of human effector memory T cell assays (CD4+CD45RO+CCR7–CD28+).
• Comparison to monkey T cells revealed key phenotypic differences.
• Reinforced the need for using human PBMCs and immune subset-specific assays.
• Validated the idea that even subtle immunological differences can cause dramatic translational failures.

Question 7

Q7: What systemic changes followed the TGN1412 trial failure? (5)

Answer 7

• Regulatory protocols were revised for first-in-human dosing.
• New emphasis on staggered dosing and starting at ultra-low doses.
• Improved risk assessment tools for biologics and immunotherapies.
• Humanised models and in vitro testing gained greater regulatory support.
• Case became a milestone example in translational medicine education and policy.

Question 8

Q8: What are the key takeaways from the TGN1412 case study? (4)

Answer 8

• Importance of relevant and predictive preclinical models.
• Animal data must be interpreted cautiously when immunological differences exist.
• Translational failures can have devastating human consequences.
• Preclinical models must include human immune parameters for immunotherapy candidates.