4a.) Monoclonal antibodies Flashcards
What is a monoclonal antibody?
Monovalent antibodies (i.e. each only binds to a specific antigen)which bind to the same eptiope and are produced from a single B lymphocyte clone
State some clinical uses of monoclonal antibodies
Diagnostics
- Pregnancy test
- Blood group test
- Location of metastatic tumours
Therapeutics
- Cancer
- Immunosupressive therapies
Describe how monoclonal antibodies are produced
- Immunise miceaginst a specific epitope of an antigen
- Harvet the B lymphocytes from the spleen of the mouse
- Fuse B lymphocytes with an immortal myeloma cell line (not containing any other immunoglobulin-producing cells)
- The resulting hybridoma cells are cultured in vitro so only the hybridomas survive
- Screen hybridomas for those that produce the specific desired clonal antibody
- Clone the antibody producing hybridomas
Briefly summarise the advances we have made in terms of producing monoclonal antibodies which has allowed us to reduce the potential for immunogenicity
State and briefly summarise the 3 types of monoclonal antibodies
- Naked: just as they are
- Conjugated monoclonal antibodies: has antibody, linker and cytotoxic drug attached. Allows us to give highly toxic cancer drugs as we make the antibodies specific to cancer cells and drug only activated once taken up and inside cell by receptor mediated endocytosis followed by lysosomal degradation which releases the toxic drug
- Bispecific monoclonal antibodies: these antibodies recognise and bind to both B and T cells; when both cells are bound the T cell is activated and instructed to kill the B cell
State some potential mechanisms in which monoclonal antibodies work
- Bind with cell surface receptors to either activate or inhibit signalling wihtin the cell
- Binding to induce cell death
- Binding with cell surface receptors to activate:
- Antibody-dependent cell-mediated cytotoxicity (e.g. bind to and mark for phagocytosis)
- Complement dependent cytoxicity (e.g. activates complement system which then attacks cell resulting in cell lysis)
- Internalisation for antibodies delivering toxin into a cancer cell
- Blocking inhibitory effects on T cells (checkpoints) thus activating T cells which can help to kill cancer cells
What information do we need about our target cells to allow us to develop monoclonal antibodies which are specific to those cells hence allowing targetted treatment?
Need to know what antigens are present
e.g. all mature B lymphocytes have CD20
Discuss the very basic classification of lymphoma
Compare the lymph node structure in diffuse large B cell lymphoma and in follicular lymphoma
Discuss some treatments for lymphoma
- Chemotherapy
- Radiotherapy
- Monoclonal antibody therapy
- Stem cell transplantation
Discuss the siefe effects of monoclonal antibodies
- Some have no or mild symptoms e.g. mild fatigue
- Many hav emild reaction to 1st infusion and then tolerate subsequent infusions well
- A few people have sever infusion related reactions as their immune system reacts to the presence of a foreign protein
Briefly discuss how we manage infusion related reactions
- Patient education
- Exlain that they may get side effects
- Explain that they should inform staff as soon as they notice any change so staff can take immediate action
- Instruct patient to omit their anti-hypertension medication for 12 hours prior to infusion
- Prevention with pre-medication: steroid, antihistamine, paracetamol
- Start slow infusion rate and slowly increase if tolerated
- Drugs required to treat IRR should be prescribed to patient prior to starting patients treatment
State 3 examples of monoclonal antibodies and for each state their target
I would pick adalimumab, trastuzumab and abciximab as easy 3 since you already know
Describe the pathophysiology of rheumatoid arthritis
- Autoimmune disease in which there are autoantibodiesagainst to the Fc portion of the immunoglobulin G (rheumatoid factor). Causes persistent synovitis causing chronic symmetrical polyarthritis with systemic inflammation
- Snyovitis occurs when chemoattractants produced in the joint recruit circulating inflammatory cells. Over produciton of TNF-alpha leads to synovitis and joint destruction. Interaction of macrophages and T and B lymphocytes drives this overproduction. TNF-alpha then in turn stimulates production of IL-6 as well as other cytokines
- Patients can also develop a range of non-articular problems affecting many systems of body
State some signs and symptoms of rheumatoid arthritis
- Progressive, symmetrical, peripheral polyarthritis evoloving over weeks or months generally between ages 30-50
- Also get non-articular manifestations: