Lec 22- Biomolecular drugs Flashcards
1
Q
Cancer treatments
A
- Radiation therapy
- Chemotherapy
- Immunotherapy
- Hormonal therapy (including proteins)
2
Q
Biological Therapeutics
A
- Vaccines
- Abs
- Proteins (cytokines, interleukins, Colony-stimulating factors)
- Oligonucleotides (Antisense, Gene therapy)
3
Q
Angiostatin- prevent angiogenesis
A
- Internal fragment of plasminogen approximately 38kDa
- Inhibits endothelial cell proliferation
- Well tolerated
- High efficacy
- In phase III clinical trials
4
Q
Endostatin- prevent angiogenesis
A
- 20 kDa fragment of c-terminus of collagen XVII
- Blocks mitogen activated protein kinase (MAPK) in endothelial cell proliferation
- 30 times more potent than angiostatin
- Phase I clinical trial few side effects and tolerated well, now in phase III
- Patients with sarcoma, melanoma and neuroendocrine tumours
- These proteins are not stable enough and do not have the required efficacy to be worth it in the clinic
5
Q
Avastin
A
- Bevacizumab- anti-VEGF mAb
- Sequesters VEGF preventing receptor activation
- The first clinically approved angiogenic inhibitor
- Colo-rectal, lung, breast, glioblastoma, kidney and ovarian
- Side effects may include heightened risk bleeding, HTN, Exacerbation CAD, other artery disease
6
Q
Immunotherapy
A
- Exploit the body’s own immune system
- Vaccination
- Therapeutic Abs/Targeting of therapies
- Activation of the immune system (NK, LAK, CTL, DC)
- Bone marrow transplantation
7
Q
Vaccination
A
- Both therapeutic and prophylactic vaccines licensed
- Vaccines to viruses can prevent virus-induced cancers (HPV, hepB) and are available for some bacteria believed to be linked to cancer (e.g. H.Pylori)
- Therapeutic requires identification of cancer-specific immunogenic proteins
- Identification of proteins
- Preferably on the cell surface
- Usually unique to one cancer, but some common
- The difficulty is to find tumour specific Ag rather than tumour associated Ag’s- e.g. EBV, HPV, Glycoproteins, Glycolipids, a-fetoprotein
8
Q
Vaccines based on cells
Modify normal cells to carry Ag
A
- Proving- hormone-refractory metastatic prostate cancer
- Patients Ag-presenting cells (DCs) extracted and activated (with prostatic acid phosphate found on a very high proportion of prostate cancer cells) and granulocyte-macrophage colony stimulating factor then returned to the patient
- Results in longer average survival in clinical trials
- Take immune cells from the patient- manipulate the cells outside of the body stimulated with something that cancer will produce in large quantities so they are reactive to that molecule and put them back in
9
Q
Therapeutic Antibodies (mAbs)
A
- 2 main classes
- Ab’s that rely on host immune system
- Ab’s conjugated to the anti-cancer agent (drug, radioactivity or toxin)
- Ab bind to cancer drug and take the drug specifically to the cancer
- Abs are raised to proteins that are uniquely presented on the surface of cancer cells, for example, CD-52 in leukaemia
- Usually, mAbs produced from mice- 1986
- First for cancer was Rituximab (1997) raised to CD20 for Non-Hodgkins lymphoma
- Most well known is Trastuzumab (Herceptin) to Erb2 in breast cancer
- Require ‘Humanization- just take the part of the mouse Ab that binds specifically- then bind this to a human Ab
- Can have significant side effects (TG1412- TeoGenero- severe anaphylactic response 11 out of 20 died in the trial)
10
Q
Naked Abs act in 2 ways
A
- Bind to cell protein and activate host immune response resulting in killing cells
- Alemtuzumab (CD52- CLL), Rituximab (CD33)
- Prevent ligand binding to or activation of cell surface receptor to modulate cellular signalling
- Often is not the receptor that is responsible for upregulation of cell growth it is often downstream (kinases- RAS)- therefore not effective for all cancers (up to 70%)
- Cetuximab (EGFR) prevents ligand binding
- Bevacizumab (Avastin)- VEGF-A prevents activation
11
Q
Ab how they work and side effects
A
- Acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAb
- Serum sickness
- Tumour lysis syndrome (TIS)
- Cytokine release syndrome (CRS)- Th
- Clinical manifestation range from local skin reactions at the injection site, pyrexia and influenza-like syndrome, to acute anaphylaxis and systematic inflammatory response syndrome
12
Q
Conjugated Abs- where something has been added to the Ab
A
- Carry a toxic cargo to the cell
- Radioisotope (Radioimmunotherapy) e.g. Ibritumab
- Enzyme prodrug therapy (ADEPT) and others
- Immunoconstructs- targeted drugs (brentuximab)
- Immunoliposomes-
- The drug itself when conjugated to the Ab it struggles travel/ release from the Ab to then enter the cell- Ab can’t enter the cell due to size and charge
13
Q
An ADEPT
A
- This is the conjugation of an enzyme to an Ab
- This converts pro-drugs
- If we can use a pro-drug that is not activated by enzymes in our body then you can come up with a selective anticancer agent
- We enzyme Ab complex into the body and binds to a tumour Ag
- Flush the system- get rid of other Ab that hasn’t stuck to the tumour
- Then put pro-drug into the system- won’t have any toxic effects as not active until it reaches the tumour with an Ab on it
- When being released by the cancer cell it will act mostly on the cancer cell- especially when using a very reactive species that can’t diffuse very far
14
Q
Different Ab mechannisms
A
15
Q
Other proteins
A
-
Growth factors
- Colony stimulating factors (e.g. granulocyte colony stimulating factor, G-CSF) often used to combat side effects
- Bone marrow
- Erythrocyte
- Platelets
- Colony stimulating factors (e.g. granulocyte colony stimulating factor, G-CSF) often used to combat side effects
-
Interleukins and Interferons (cytokines)
- IL-2- growth and activity of immune cells e.g. lymphocytes (melanoma and kidney)
- INF-a- stimulate the immune system and slow cancer growth
-
Other immunostimulatory agents
- BCG vaccine (TB), Levamisole
- Always used in combination with other anti-cancer agents
17
Q
Oncos therapeutics
A
