Monoclonal Antibodies

1. Monoclonal Antibodies BAT: Explain what monoclonal antibodies are and discuss their uses

3. Until 1975 it was not possible to culture lymphocytes outside of an organism because it was not possible to get them to divide. So lymphocytes were only manufactured in the body.

4. In 1975 they devised a new method. It involved fusing mouse cells from the spleen (an organ rich in lymphocytes) with a type of myeloma (cancer cells). Why did they choose cancer cells? Georges Kohler and Cesar Milstein

7. Hybridomas • Some of the resulting hybrids develop into clones called hybridomas. • Some of these combined the antibody-producing capacity of plasma cells with the tumour cells ability to reproduce. • The desired clone is then isolated and used for the industrial production of antibodies.

9. Major setback • Kohler and Milstein were awarded a Nobel prize for their work because of its important impact on medicine. • Problem – it was found that the monoclonal antibodies manufactured from mouse cells provoked an immune response if injected into a patient. • How has this been overcome?

10. Recent techniques use genetic engineering to overcome this problems. Monoclonal antibodies are ‘humanized’ by replacing much of the antibody that triggers the immune response with the corresponding human antibody structure.

11. Transgenic mice • To eliminate the need for humanisation of the antibody, transgenic mice can be used. In this case, a human gene is placed in the mice so that they produce human antibodies rather than mouse antibodies. This raises the whole debate surrounding the ethics of genetic engineering.

12. Uses of Monoclonal Antibodies • Pregnancy test kits • Diagnostic tools for AIDS • Industrial production of interferon (a chemical used to treat cancer and hepatitis) • ADEPT (Antibody-Directed Enzyme Pro-drug therapy).

15. An enzyme is attached to the antibody and the enzyme-antibody conjugate is administered to the patient. In the body the antibody-enzyme complex binds to the tumour antigens ADEPT (Antibody-Directed Enzyme Pro-drug therapy) - Magic bullets

16. 3. A prodrug is now given to the patient This circulates all around the body but is only activated by the enzyme attached to the antibody-enzyme complex at the tumour site. 4. Once activated the prodrug becomes cytotoxic, destroying the cells at the tumour site.

17. ADEPT – Clinical Trial • It is a new therapy that has to go through double blind clinical trials – what is this? • Side effects of ADEPT – flu-like symptoms, nausea, allergic reaction, increased risk of infection.

18. Points to ponder • After their first manufacture, monoclonal antibodies were quickly and widely used in diagnostic kits such as pregnancy tests. Suggest why their use in human therapy has been much slower. • Discuss how the design of a clinical trial has to consider both ethical and scientific factors, and how these might conflict.

19. Check your understanding • Why are monoclonal antibodies so-named? • Why is it not possible to use lymphocytes or plasma cells directly as commercial producers of specific antibodies?