Lecture 17: THERAPEUTIC ANTIBODIES, BIOLOGICAL THERAPIES, NEW DIRECTIONS Flashcards
What are requirements for humanised antibody use?
Antigens need to be overexpressed in tumours
Antigens expressed need to be accessible to antibodies
How do humanised antibodies work?
Prevent interaction of growth factor with cell surface receptor ir recuit components of the immune system to kill antibody-bound cancer cells
OR conjugation of a toxin/radioisotope to antibody
In most cases the MOA is not known
What is a hybridoma cell line?
cell line originating from the combination of spleen and cancer cells
What is a single chain variable region fragments (scFv)?
Smaller version of humanised antibodies
Synthesised by bacteriophages
Advantageous as smaller and therefore able to penetrate the tissue more effectively
Explain herceptins mechanism of action
Targets extracellular domain of HER2
Mechanism unclear
What is the clinical use of herceptin?
Breast cancers that do not respond to oestrogen or progesterone
Effective in metastatic breast cancer but less clear in early stage
What is the main adverse effect of herceptin?
Heart failure
What new development is being tried with herceptin?
linking emtansine (a tubulin inhibitor normally too toxic for cells to Herceptin to kill HER2+ metastatic breast cancer cells
Explain the mechanism of action of Bevacizumab
Binds to vascular endothelial growth factor (VEGF)
Prevents angiogenesis
What is the clinical use of Bevacizumab?
Colorectal cancer - extends life expectancy
What are the adverse effects of Bevacizumab?
Hypertension
Intestinal bleeding
What is the mechanism of action of Rituximab?
Binds to CD20 which is expressed on all B cells in non-Hodgkins lymphoma
What is the clinical use of Rituximab?
Therapy for non-Hodgkins lymphoma and other lymphomas and leukaemias
What are the side effects of Rituximab?
fever and hypotension
cardiac problems
What is the mechanism of action of Cetuximab?
Targets EGF receptor
May interfere with cancer cell growth by preventing EGF binding
What are the clinical uses of Cetuximab?
Colorectal cancer treatment
What are the side effects of Cetuximab?
Fever
Hypotension
What is the mechanism of action of L-Asparaginase
Inhibits aspiraginase
Part of the pathway which converts exogenous asparigine into aspartate
Therefore aspartate is not formed and able to be used for protein synthesis/cell growth
What are the clinical uses of L-asparagine?
childhood acute lymphocytic leukaemia with vincristine and prednisone
What are the 2 major types of interferons?
Type I (IFN- alpha and beta) Type II (IFN-gamma)
What are the functions of IFNs?
Promote apoptosis in cancer cells
Stimulate immune cells to recognise and kill cancer cells
What are the clinical uses of IFN-alpha2a and b?
AIDS related Kaposi’s sarcomas
Hairy cell leukaemia
Promising results in extending disease free survival in melenoma
In what form are interferon alphas given?
IM
SC
IV
What are some of the associated side effects of interferon alpha?
high dose = depression and loss of energy
What are the clinical uses of interleukin 2?
renal cell carcinoma
melanoma
What are the side effects of interleukin 2?
Hypotension
Liver damage etc.
Note: they are all reversible
What are the max no of doses in which tolerance is reached?
14
What is the use of granulocyte-monocyte colony stimulating factor?
Used to reconstitute myeloid blood cells after stem cell and bone marrow transplantation
In cancer patients, may stimulate the cellular immune system
Which cells does IL-12 stimulate?
B cells
T cells
NK cells
Explain the racial variation that occurs in response to Iressa
Japanese 3x more likely to respond than Americans
May be due to particular mutations of the Iressa binding site on EGFR
Need for personalised medicine - done via large scale DNA sequence profiling of individuals and populations
