Lecture 7: Drug Development I

Flashcards covering the drug development of biopharmaceuticals, immunotoxicology, immunotherapy history (PD-1/PD-L1), and CAR-T cell therapy challenges and engineering strategies.

What are the three defining characteristics of a small molecule drug?

Low molecular weight, chemically synthesised, and a well defined structure.

Biologics accounted for more than what portion of new medicine approvals in the past decade?

More than one-third.

Which specific therapy is used for Duchenne Muscular Dystrophy (DMD) as mentioned in the growing trend for biologics?

RNAi.

What gene therapy approach is used for haemophilia?

Adeno-associated virus ($AAV$) delivery of Factor IX.

What are three potential adverse reactions from Anti-drug antibody ($ADA$) responses?

Accelerated clearance, prolongation of exposure, and neutralisation of pharmacological activity.

How is the maximum dose for assessing human protein toxicity calculated?

$10\times$ maximum exposure in clinic.

What is the criteria for the Phase 1 dose of a biopharmaceutical drug?

Minimum anticipated biological effect.

What was the target antigen of the drug TGN1412, and what severe reaction did it cause in health volunteers?

CD28-SuperMAB; it caused cytokine release syndrome.

How much lower was the volunteer dose of TGN1412 compared to the preclinical profile?

$500$ times lower.

What is the mechanism of Checkpoint Inhibitors in immunotherapy?

They release a natural brake on the immune system so that $T$ cells recognize and attack tumors.

Which scientist discovered that blocking Cytotoxic T-lymphocyte-associated protein 4 ($CTLA-4$) caused tumors to vanish?

James Allison.

What proteins identified by Tasuku Honjo in 1999 are involved in tamping down the immune system and protecting cancers?

Programmed Cell Death Protein 1 ($PD1$) and Programmed death-ligand 1 ($PD-L1$).

What company originally invented Pembrolizumab (Keytruda) in 2006?

Organon.

What are the recorded response rates for $PD\text{-}1$ therapy in Hodgkins lymphoma versus Pancreatic cancer?

$90\times$ for Hodgkins lymphoma and $0\times$ for Pancreatic cancer.

Which patient was the first pediatric recipient of CAR-T therapy in 2012?

Emily Whitehead.

What are the two specific antigens targeted by current approved CAR-T therapies listed in the transcript?

CD19 and BCMA.

Which company is the manufacturer of the CAR-T therapy Kymriah?

Novartis.

What is the indication for the approved therapies Abecma and Carvykti?

Multiple myeloma.

What was the approximate cost of ImmunoACT, India’s first cut-price CAR-T therapy?

$\$40,000$.

What causes $T$ cell-mediated rejection in allogeneic cell therapies?

The host’s $T$ cells recognize allogeneic cell surface markers such as HLA mismatches.

Why do Natural Killer ($NK$) cells activate and eliminate introduced allogeneic cells?

They detect the lack of self-MHC molecules on the introduced cells.

In HLA engineering, how is cloaking from $T$ cells achieved?

By knocking out HLA class I and II molecules.

How does the overexpression of HLA-E or HLA-G protect engineered cells?

It protects them from $NK$-mediated killing.

What is the advantage of using Virus-Specific T Cells ($VSTs$) for CAR-T therapy?

Longer persistence due to stimulation from latent viral antigens, which prevents exhaustion and rejection.

How many total Cell Therapy trials were recorded on ClinicalTrials.gov as of 5 March 2025?

$2707$.