m.foley@latrobe.edu.au. live (virulent) virus disease immune response what happens when you get...

M.Foley@latrobe.edu.au

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