[email protected]. live (virulent) virus disease immune response what happens when you get...
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Live (virulent)virus
Disease
Immune response
What happens when you get infected?
Death Survive (Immune)OR
Live (virulent)virus
Killed oravirulent virus
Disease
Immune response
No Disease
Immune response
Vaccines help you fight infections
Components of an Immune Response
Antibodies
Killer white cells (CTLs)
Immune surveillance
The Immune Response Protects Against Cancer
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
HumanAntibody
Malaria protein
Antibodies are important in cancer
Antibodies are a major class of drugs :
1. Orthoclone: mouse antibody (Ortho Biotech) Transplant anti-rejection
2. ReoPro: chimeric antibody (Centocor) Prevents blood clotting
3. Rituxan: chimeric antibody (Genetech) Cancer therapy/ anti arthritis $1.9billion
4. Zenapax: humanized antibody (Hoffman-La Roche) Transplant immune suppression
5. Simulect: chimeric antibody (Novartis) Transplant anti-rejection
6. Synagis: humanized antibody (Medimmune) Anti-respiratory syncytial virus
7. Remicade: chimeric antibody (Centocor) Anti-arthritis treatment
8. Herceptin: humanized antibody (Genetech) Cancer therapy $1.45billion
9. Mylotarg: humanized antibody and calechiamycin (Wyeth) Cancer therapy
10. Campath-1H: humanized antibody (Genzyme) Cancer therapy
11. Humira: human antibody (Abbott/CAT) Anti-arthritis treatment $883million
12. Xolair: humanized antibody (Genetech) Treatment of allergic asthma
13. Raptiva: humanized antibody (Genetech) Treatment of psoriasis
14. Erbitux: chimeric antibody (Imclone systems) Cancer therapy
15. Avastin: humanized antibody (Genetech) Cancer therapy $1.3billion
16. Tysabri: humanized antibody (Biogen Idec) Multiple sclerosis treatment
17. Lucentis: humanized antibody (Genetech) Macular degeneration
18. Vectibix: human antibody (Amgen) Cancer therapy
19. Zevalin: mouse antibody and Yttrium 90 (Biogen Idec) Cancer therapy
20. Bexxar: mouse antibody and Iodine 131 (Corixa) Cancer therapy
FDA approved antibodies:
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 Roche (Switzerland) April 2, 2007 $56.5 million
Polyclonals (USA)
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
Shark antibodies are 1/10 the size of human antibodies
SharkMab
Why Shark Antibodies?
Tailored half lifeIn humans
Low cost of manufacture in
microbesExtreme stability
Address targets inaccessible to
conventional antibodies
Why Shark Antibodies?
IgG
Shark Antibodies
VH
Greenberg, Flajnik et al. Nature 374 (1995)
What if you could capture these shark antibodies in a test tube ?
IgNAR
Generation of shark antibody library
BLOOD SAMPLE TAKEN FROM SHARK
LYMPHOCYTE FRACTION ISOLATED
mRNA PREPARATION MADE FROM
LYMPHOCYTES
WOBBEGONG SHARK
cDNA COPIES CORRESPONDING TO
mRNA FROM ANTIBODY PRODUCING CELLS
Sfi1
Not1
CDR1 CDR3
Degenerate primer for mutagenesis
Making a shark antibody library
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
Shark antibody
Malaria protein
Shark antibodies can block key sites on malaria
OR can we make antibodies bind better ?
Better shark antibodies block malaria invasion
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
Sharklibrary
CXCR4
Sharkantibody
CXCR4Shark antibody
complex
Binding to Cancer cells
21H5
114
Block HIV infection
anti-CXCR4 i-bodies do many things
Bind to rat fibrocytes
DAPI CD45
i-body Merge
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
