Recombinant Protein Therapeutics

Question 1

What are biotherapeutics?

Answer 1

Therapies derived from living organisms used to treat chronic diseases

Question 2

What’s a crucial incentive for innovation into new medicines?

Answer 2

Strong intellectual property rights

Question 3

What is the central tenet of Biotherapeutics?

Answer 3

Patient need = disease pathology + treatment agent + MoA + treatment development + treatment manufacture = Performance in Pts

Question 4

What is diabetes mellitus?

Answer 4

Chronic hyperglycemia due to insulin deficiency, resistance or both

Question 5

What is a late stage complication of DM?

Answer 5

Macrovascular disease - CAD, peripheral vascular disease & stroke

Question 6

What can microvascular damage lead to?

Answer 6

Diabetic nephropathy & retinopathy

Question 7

What is insulin secreted by?

Answer 7

Beta cells of pancreatic islets

Question 8

What is insulin required for?

Answer 8

Storage & controlled release of chemical energy available from food

Question 9

What is insulin’s primary target organ?

Answer 9

Liver >50%

Question 10

What does liver store glucose as?

Answer 10

Glycogen
maintains blood glucose at 3.5 - 8.0 mmol/L

Question 11

What chains make up the insulin monomer?

Answer 11

B - 30aa
A -21aa

Question 12

Why does the monomer have to stay in its specific shape?

Answer 12

Has to have this shape in order for it to be recognisable to insulin receptors on hepatocytes

Question 13

How many aa does the insulin molecule contain?

Answer 13

51

Question 14

When does the insulin molecule assemble into hexamers?

Answer 14

In the presence of zinc
Amitosole rings arise from side chains from histadines and circles around sphere of zinc

Question 15

What is the hexamer?

Answer 15

Inactive form with long - term stability - keeps it protected

Question 16

What is the hexamer-monomer conversion?

Answer 16

The central aspects of insulin formulations for injection

Question 17

Where is prepro insulin cleaved into proinsulin?

Answer 17

Golgi

Question 18

What does proinsulin travel as?

Answer 18

Exosomes

Question 19

How many insulin pathways are there?

Answer 19

2

Question 20

What happens when insulin binds to the receptor?

Answer 20

hyperphosphorylation of cytoplasmic domains (serine & thyrine) - intermediate signalling proteins activated

Question 21

Is glucose membrane permeable?

Answer 21

No

Question 22

How does insulin act in a fasting state?

Answer 22

Regulate glucose release by liver

Question 23

How does insulin act in a postprandial state?

Answer 23

Facilitates glucose uptake by fat & muscle

Question 24

What is type 1 caused by?

Answer 24

Autoantibodies against pancreatic islet proteins

Question 25

What is Type 2 caused by?

Answer 25

Age obesity ethnicity family history

Question 26

What diseases are type 2 associated with?

Answer 26

Obesity hypertension decreased HDL hypertriglycerideameia insulin resistance

Question 27

What are 3 therapeutic modalities for T2DM?

Answer 27

Incretins short acting insulin long acting insulin

Question 28

What is the MoA of short acting?

Answer 28

Pre-meal injection (sub cutaneous) absorbed slowly (peak at 60-90 mins after) May last too long leading to hypoglycaemia

Question 29

What are 3 sort acting insulins?

Answer 29

Insulin lispro insulin aspart insulin glulisine

Question 30

What is the change in insulin aspart?

Answer 30

Switched proline for an aspartic acid (-vely charged) poor hexamer structure = rapid dissociation

Question 31

What is the change in insulin lispro?

Answer 31

Switched position of 2 aa - instability created

Question 32

What is insulin structure modified to in long lasting?

Answer 32

Delay absorption to prolong duration of action eg. insulin glargine

Question 33

What is insulin glargine soluble as?

Answer 33

In a vial at pH 4 but precipitates when SC injected

Question 34

How is insulin glargine engineered?

Answer 34

Replace Asp at 21 of A chain with glycine & adds 2 asparg. to end of B chain

Question 35

What does insulin detemir have?

Answer 35

fatty acid tail - binds to serum albumin - slow dissociation kinetics from bound state - prolonged action

Question 36

What can lysine form?

Answer 36

Lysine has an amino side chain - can form an ionic bond with another moiety - as long as there is no other lysines in the chain

Question 37

What is combination therapy?

Answer 37

Multiple injection regiment with short acting insulin longer lasting at night

Question 38

What has Oramed POD technology been designed to?

Answer 38

Protect orally delivered proteins from unwanted enzymatic activity within GIT Enhance absorption across intestinal wall

Question 39

What are incretins?

Answer 39

Insulin response due to release of 2 peptide hormones from L cells in the intestine

Question 40

What are 2 types of incretins?

Answer 40

GLP-1 Glucose dependent insulinotropic peptide

Question 41

What are 2 peptide analogues of GLP-1?

Answer 41

Exenatide Liguratide

Question 42

What is the Moa of exenatide?

Answer 42

Promotes insulin release & inhibits glucagon - reduce appetite & gastric emptying & slows postprandial increase in glucose

Question 43

How long is glucagon?

Answer 43

180aa ~21kDA

Question 44

What is semaglutide?

Answer 44

Potent, long-acting GLP-1 administered SC once weekly 94% homology with native GLP-1

Question 45

What are 3 structuraly changes in semaglutide?

Answer 45

1. substitution of Ala with Ab at position 8 increases enzymatic stability (protects from DPP-4 degradation) 2. attachment of linker & C18 dl-acid at position 26 ( strong albumin binding) 3. substitution of Lys with Arg at position 34 prevents C18 fatty acid binding at wrong site

Question 46

What is GLP-1 RAs to be the 1st line therapy for?

Answer 46

CV risk reduction in patients with T2DM with very high/high risk

Question 47

Which insulin strains were produced in e.coli?

Answer 47

Humulin exubera isulin lispro insulin glusine insulin glargin