Transcript Why Shark Antibodies?

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What happens when you get
infected?
Disease
Immune response
Live (virulent)
virus
Death
OR
Survive (Immune)
Vaccines help you fight infections
Killed or
avirulent virus
Live (virulent)
virus
No Disease
Immune response
Disease
Immune response
Components of an Immune Response
Antibodies
Killer white cells (CTLs)
The Immune Response Protects
Against Cancer
Immune surveillance
Antibodies are a Key Part of our Immune System
Antibodies are important in malaria
The malaria parasite gets into our red blood
cells and multiplies
The malaria parasite invades red blood cells
The malaria parasite surface is a target for
antibodies
Antibodies bind to proteins on the malaria
parasite surface and prevent invasion of RBC
Human
Antibody
Malaria
protein
Antibodies are important in cancer
Antibodies are a major class of drugs :
FDA approved antibodies:
1. Orthoclone: mouse antibody (Ortho Biotech)
2. ReoPro: chimeric antibody (Centocor)
3. Rituxan: chimeric antibody (Genetech)
4. Zenapax: humanized antibody (Hoffman-La Roche)
5. Simulect: chimeric antibody (Novartis)
6. Synagis: humanized antibody (Medimmune)
7. Remicade: chimeric antibody (Centocor)
8. Herceptin: humanized antibody (Genetech)
9. Mylotarg: humanized antibody and calechiamycin (Wyeth)
10. Campath-1H: humanized antibody (Genzyme)
11. Humira: human antibody (Abbott/CAT)
12. Xolair: humanized antibody (Genetech)
13. Raptiva: humanized antibody (Genetech)
14. Erbitux: chimeric antibody (Imclone systems)
15. Avastin: humanized antibody (Genetech)
16. Tysabri: humanized antibody (Biogen Idec)
17. Lucentis: humanized antibody (Genetech)
18. Vectibix: human antibody (Amgen)
19. Zevalin: mouse antibody and Yttrium 90 (Biogen Idec)
20. Bexxar: mouse antibody and Iodine 131 (Corixa)
Transplant anti-rejection
Prevents blood clotting
Cancer therapy/ anti arthritis $1.9billion
Transplant immune suppression
Transplant anti-rejection
Anti-respiratory syncytial virus
Anti-arthritis treatment
Cancer therapy
$1.45billion
Cancer therapy
Cancer therapy
Anti-arthritis treatment
$883million
Treatment of allergic asthma
Treatment of psoriasis
Cancer therapy
Cancer therapy
$1.3billion
Multiple sclerosis treatment
Macular degeneration
Cancer therapy
Cancer therapy
Cancer therapy
Antibodies’ long revenue stream spurs pharma
acquisitions
(Nature Biotechnolgy, Volume 11, November, 2007)
Biotech
Pharma
Date
Amount
Domantis (UK)
GlaxoSmithKine (UK)
Jan 8, 2007
$454million
Therapeutic Human
Polyclonals (USA)
Roche (Switzerland)
April 2, 2007
$56.5 million
Abmaxis (USA)
Merck (USA)
May 9, 2007
$80 million
MedImmune (USA)
AstraZeneca (UK)
June 19, 2007 $15.6 billion
Haptogen (UK)
Wyeth (USA)
Oct 5, 2007
not disclosed
Cost of getting a drug to market
• Clinical trials can cost up to $1 billion. The cost of the research to
discover a new drug, by contrast is less than 10% of this.
• New drugs need Intellectual Property (IP) protection eg patents.
• Big Pharma is mainly interested in huge markets eg obesity,
depression, dementia, cancer, autoimmune disease.
• Amgen’s Magic Bullet, Retuximab against blood cancer, earns
them more than $3 billion per year.
• Amgen’s Erythropoietin (EPO), which stimulates the production of
red blood cells, raises $4 billion per year. This is the drug cyclists
and long distance runners and swimmers use (illegally)!
Shark Antibodies
Why Shark Antibodies?
Shark
Mab
Shark antibodies are 1/10 the size of human antibodies
Why Shark Antibodies?
Address targets
inaccessible to
conventional antibodies
Low cost of
manufacture in
microbes
Extreme stability
Tailored half life
In humans
Shark Antibodies
IgG
IgNAR
VH
Greenberg, Flajnik et al.
Nature 374 (1995)
What if you could capture these shark antibodies in a test tube ?
Making a shark antibody library
Generation of shark antibody library
WOBBEGONG SHARK
BLOOD SAMPLE TAKEN
FROM SHARK
LYMPHOCYTE
FRACTION ISOLATED
mRNA PREPARATION
MADE FROM
LYMPHOCYTES
Sfi1
CDR1
CDR3
Not1
Degenerate primer for
mutagenesis
cDNA COPIES
CORRESPONDING TO
mRNA FROM ANTIBODY
PRODUCING CELLS
Could you use this big library to select antibodies for therapy ?
Selecting shark antibodies against
malaria
Shark library
Shark antibodies bind to key sites on malaria
Malaria protein
Shark antibody
Shark antibodies can block key sites on malaria
OR can we make antibodies bind better ?
Better shark antibodies block malaria
invasion
120
100
Growth Inhibition %
80
60
40
1
10
100
20
0
-20
IgNAR Conc mg/ml
1000
12A9
12Y2
14M8
14M15
14I1
14I1Y2
14I1M15
14I1M8
Fibrosis is a major disease
CXCR4 has been associated with
more than 23 types of cancers
HIV-1 uses CXCR4 as a co-receptor
for viral entry into host cells
Critical player in development of
Fibrosis
Important in maintaining stem cells in
bone marrow
Selecting shark antibodies against
CXCR4
Shark
library
Shark
antibody
CXCR4
CXCR4
Shark antibody
complex
anti-CXCR4 i-bodies do many things
Binding to
Cancer cells
Block HIV infection
Bind to rat fibrocytes
21H5
DAPI
CD45
i-body
Merge
114
Lekocytes (white blood cells) can cause fibrosis
Fibrosis
CXCR4 controls migration of white blood
cells into tissues
Where to next?
Sharks are nice
But we would rather not work with them