Lecture 10 - Drug discovery and development 2

Question 1

complexity of small molecules

Answer 1

• low molecular weight
• chemically synthesised
• well defined structure

Question 2

complexity of biological molecules

Answer 2

• high molecular weight
• derived from living organisms
• large and complex structure

Question 3

complexity of monoclonal antibodies

Answer 3

• high molecular weight
• derived from living organisms
• more complex structure

Question 4

what are biopharmaceuticals?

Answer 4

• defined as products where the active substance is produced/ extracted by a biological source

Question 5

what was the first biopharmaceutical produced?

Answer 5

insulin approved by FDA in 1982

Question 6

what are biopharmaceuticals made of?

Answer 6

includes recombinant and monoclonal antibody-based products and recombinant vaccines.

Question 7

biopharmaceutical model

Answer 7

• highly specific for a human target and most used is NHP (e.g. macaque monkey) where it will be used for the whole nonclinical safety program.

Question 8

what is a surrogate molecule?

Answer 8

proteins that recognise the target in an animal model that is analogous to the human target recognised by the clinical products. Allows hazard detection for pharmacological activity

Question 9

Cause of adverse reactions for biopharmaceuticals?

Answer 9

result of exaggerated pharmacology or nonspecific anti-drug antibody (ADA) mediated responses.

Question 10

role of immunogenicity

Answer 10

distinguishes biopharmaceuticals from small-molecule drugs and is a cofounding factor when testing human proteins in animal models

Question 11

what is the effect of ADA’s on biopharmaceuticals?

Answer 11

neutralise their activity, reduce exposure and elicit ADA-mediated toxicities in the animal model

Question 12

what would cause an immune response for biopharmaceuticals?

Answer 12

greater dissimilarity between the human protein sequence and animal protein sequence

Question 13

how does antibody responses affect the outcome of nonclinical toxicology studies?

Answer 13

alters the pK, tissue distribution, pharmacological activity of biopharmaceutical and interpretation of toxicology data

Question 14

why is it important to measure presence of ADA’s?

Answer 14

determines potential correlation with pharmacology, PD, PK, or immune mediated toxicity

Question 15

when are ADA measurement studies conducted?

Answer 15

if there is an altered PD activity, changes in exposure in absence of PD or immune-mediated toxicity

Question 16

what are the antibody responses to biopharmaceuticals?

Answer 16

• accelerated clearance of molecule
  prolonged exposure
  neutralise pharmacological activity
  neutralise the natural, endogenous counterpart protein.

Question 17

what is the maximum dose for the nonclinical animal model?

Answer 17

dose is 10x the maximum exposure in the clinic

Question 18

what does an immunotoxicity study include for small molecules?

Answer 18

• haematological changes
• changes in weight
• histopathology of immune organs

Question 19

what is the inherent risk for adverse immune-mediated drug reactions in humans?

Answer 19

• infusion reactions
• cytokine storm
• immunosuppression
• autoimmunity

Question 20

how to test the clinical risk of adverse immunotoxicological events

Answer 20

select a safe starting dose with immunomodulatory mAbs based on the minimum anticipated biological effect level and its selection of a safe maximum recommended starting dose

Question 21

cause of toxicities arising from use of pharmacologic immunostimulation

Answer 21

caused by imbalances in cytokine signalling

Question 22

what happens in phase 1 of clinical testing for biopharmaceuticals?

Answer 22

aim is to test if drug is safe to humans and performed on small group of normal healthy volunteers (20-80). tests for pharmacodynamic effects in volunteers

Question 23

what does phase 1 clinical testing check signs for?

Answer 23

• dangerous effects on organ systems
• tolerability
• pharmacokinetic properties

Question 24

what is immunotherapy?

Answer 24

form of cancer treatment that uses immune system to attack cancer cells in the same way it would for an immune response against pathogens

Question 25

how does checkpoint inhibitors work?

Answer 25

• works by releasing a natural brake on your immune system so that immune cells (T cells) recognise and attack tumours

Question 26

how does chimeric antigen receptor (CAR) T cell therapy work?

Answer 26

scientists genetically engineer a patients own immune cells to make a new protein. turns them into supercharged cancer fighters

Question 27

how do cancer vaccines work?

Answer 27

strain body to protect itself against own damaged or abnormal cells like cancer cells

Question 28

characteristics of Yearvoy (Ipilimumab)

Answer 28

• monoclonal antibody used to fight malignant melanoma by checkpoint-inhibition. however it is not broadly effective

Question 29

characteristics of MK-3475 (pembrolizumab)

Answer 29

blocks the PD-1 interaction with checkpoint inhibition and shown to get results with lung cancers

Question 30

characteristics of immunotherapies

Answer 30

• may not work at all
• eliminate cancer or cause it to stabilise, or regress
• response to therapy is longer lasting
• only 20% of cancers respond to immunotherapy so far but it is effective against the cancers it does work on

Question 31

how are chimeric antigen receptors (CAR) produced?

Answer 31

by splicing together the gene of an antibody that recognise tumour antigen ad gene for receptor on surface of T cells. this gene is put into T cells

Question 32

what are the two limitations of CAR-T therapy?

Answer 32

1. T-cells programmed to target CD19 is only common to the surface of a few blood cancers.
2. CAR-T has been known to trigger immune reactions that can be fatal

Question 33

fatal immune reactions of CAR-T

Answer 33

• cytokine-release syndrome
• B-cell aplasia
• brain swelling
• neurotoxicities