AR - Pre-clinical models

Question 1

Q1: What are the main phases in drug development and their bottlenecks? (4)

Answer 1

1. Drug Discovery (6.5 years) – Identify hits, leads, optimize compounds.
2. Preclinical (1.5 years) – Animal studies and in vitro screening for PK, toxicity, and efficacy.
3. Clinical Trials (7 years) – Phases I–III in humans; costly and time-consuming.
4. FDA Review – Regulatory approval process (NDA submission).

Common failure reasons: Poor PK, toxicity, lack of efficacy, synthetic complexity, ambiguous toxicity, and market issues.

Question 2

Q2: What preclinical models are used in drug development and why? (4)

Answer 2

• In vitro cell cultures – 2D or organoid systems for rapid screening.
• In vivo animal models – Wild-type, knockout, or transgenic mice; non-human primates (NHPs).
• Humanised mice – Engineered to express human proteins or cells, improving translational relevance.
• These models test efficacy, pharmacodynamics, and safety before human trials.

Question 3

Q3: What is Rituximab and what are its primary uses? (4)

Answer 3

• First monoclonal antibody (mAb) approved for cancer treatment.
• Targets human CD20 on B cells.
• Used to treat B cell malignancies (e.g., lymphomas) and autoimmune diseases.
• Despite success, some patients show resistance due to immune microenvironment factors.

Question 4

Q4: How does Rituximab eliminate B cells in cancer therapy? (3)

Answer 4

• Binds to CD20 on B cells, marking them for destruction.
• Engages Fcγ receptors (FcγRs) on immune cells (e.g., macrophages).
• Leads to ADCC (antibody-dependent cellular cytotoxicity) and phagocytosis.

Question 5

Q5: What causes resistance to Rituximab therapy in some patients? (4)

Answer 5

• Immunosuppressive tumour microenvironments (TME).
• Upregulation of inhibitory Fcγ receptors, especially CD32B (FcγRIIB) on macrophages.
• Reduced macrophage activation and impaired ADCC.
• Tumour cells evade immune-mediated clearance.

Question 6

Q6: What is the difference between CD32A and CD32B in immune regulation? (3)

Answer 6

• Both are FcγRII receptors with \~94% homology.
• CD32A is an activating receptor (enhances phagocytosis).
• CD32B is an inhibitory receptor, suppressing macrophage activity and reducing Rituximab efficacy.

Question 7

Q7: How can targeting CD32B improve Rituximab’s therapeutic effect? (4)

Answer 7

• Combination of Rituximab + anti-CD32B mAb blocks the inhibitory signal.
• In vivo: Extended B cell depletion (\~15 days longer).
• Enhances macrophage-mediated killing of tumour B cells.
• Provides a synergistic therapeutic effect in transgenic mice expressing hCD32B and hCD20.

Question 8

Q8: What were the PK and safety findings for anti-CD32B mAbs? (3)

Answer 8

• Good PK profile with appropriate half-life and tissue distribution.
• No severe adverse effects observed in mouse models.
• Supported progression into clinical trials (Phase I/II).

Question 9

Q9: How do PDX models support preclinical immunotherapy evaluation? (4)

Answer 9

• CLL patient PBMCs (\~80% cancer cells) are isolated.
• Injected into irradiated immunodeficient mice.
• Human CLL cells home to lymphoid organs and proliferate.
• Used to test efficacy of anti-CD32B and Rituximab combinations in a more human-relevant context.

Question 10

Q10: What is BI-1206 and its current clinical status? (3)

Answer 10

• BI-1206 is a human anti-CD32B monoclonal antibody.
• Currently in Phase I/II trials in the UK and USA.
• Aims to restore macrophage-mediated killing in rituximab-resistant cancers

Question 11

Q11: What are the key translational insights from the Rituximab + CD32B study? (4)

Answer 11

• Shows the need to understand Fc receptor regulation in human-like models.
• Highlights how humanised mouse models help predict clinical outcomes.
• Demonstrates that combination therapy can overcome immune resistance.
• Validates CD32B as a novel immunotherapeutic target in B cell malignancies.