Drug discover (5)- Biologic drugs

Question 1

Biologics

Answer 1

• Monoclonal Abs
• Recombinant proteins
• Vaccines

Question 2

Proteins

Answer 2

• 20 biogenic amino acids =>
• Folds =>
• Protein-protein interaction

Question 3

Biologics drugs are the greatest success of modern pharmaceutical industry

Answer 3

• 7 of top 20 drugs are biologics
• 901 Biologic drugs are being developed
• Including 353 cancer treatments
• 300 are monoclonal Abs
• Biologic market should be worth $239 Billion by 2015

Question 4

Monoclonal Abs

Answer 4

• Monoclonal Abs (mAbs) comprised 32% of the 2009 market or $43 billion
• The mAb segment is expected to increase at the fastest rate within the total biologics market
• Worth $86 million by 2015
• Up from $48 billion in 2010
• A compound annual growth (CAGR) of 12.4%

Question 5

mAbs

Answer 5

• Tuneable and optimazable like small molecules
• Highly specific and highly selective
• High affinity
• Abs undergo affinity maturation during the immune response
• Natural ab affinity seldom exceed 0.1nM
• Artificially optimised Ab have much higher Kd in the pM range

Question 6

mAb- Adalimumab

Answer 6

• Humira
• Abbott
• 9th best selling drug $5.9 billion
• Treatment of heumatoid artheritis, Psoriatic arthritis, Ankylosing spondylitis, Crohn’s disease
• Moderate to severe psoriasis and juvenile idiopathic arthritis
• Whole Ab
• Targets TNF-a
• Human Ab

Question 7

Recombinant proteins

Answer 7

• Therapeutic proteins were nearly half the 2009 market (48.8%) with sales of $66 billion
• The therapeutic protein market value at $72 billion
• Expected to increase at an 8.2% a compound annual growth rate to reach $107 billion by 2015
• More diverse structurally
• Often natural or mutated human proteins- mainly used to address deficiency
• Most often cytokines, chemokines and growth factors

Question 8

RTPs- Intercept

Answer 8

• Developed by American academics
• Marketed by Amgen and Pfizer
• 7th best selling drug in the world with global sales of $6.2 billion
• Treats a series of autoimmune diseases: Rheumatoid Arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, plaque psoriasis and psoriatic arthritis
• Recombinant fusion protein soluble TNF receptor 2 fused to human immunoglobulin G1 Fc

Question 9

Immunogenicity

Answer 9

• TGN1412 was a humanised Ab
• Superagonist of CD28, a receptor on a T cell
• Mediates signal 2 activing regulatory T cells and many other cells
• Proposed treatment for B cell chronic lymphocytic leukaemia and rheumatoid arthritis
• Developed by TeGenero immuno therapies
• Phase I clinical trials in 2006: Cytokine storm led to life threatening multiple organ failure in 6 healthy volenteers

Question 10

Immunogenicity

Answer 10

• Major problem in biological development
• Immunogenicity difficult to define
  
  • B and T cell mediated
  • Complex phenomena
• Immunogenicity identified experimentally using a battery of methods
• Computational techniques can also predict aspects of immunogenicity
• So calledhumanised Abs try to prevent immune response to mAbs

Question 11

Biologics are optimisable

Answer 11

• Using SBDD techniques mediated by protein engineering the affinity and specificity of individual biologics can be modulated
• Reduce or abrogate immunogenicity by identifying computationally and mutating experimentally B cell and T cell epitopes

Question 12

Mutation in sequence

Answer 12

• Use the techniques of protein engineering rather than organism synthesis to optimise biologic drugs