Clinical Use Of Monoclonal Antibodies Flashcards
What is a monoclonal antibody Add. Antibody drug conjugates. Mab, linker, potent cytotoxic. Kill cancer but minimise effect on normal tissues. Mabs used in adrs tag antigens mostly on cancer cells. Someme of such mabs have their own anticancer activity (AC/DC,, induce apoptosis) and can retain this. Linkers link mabs and cytotoxic. Cytotoxics can be more 1000 fold more potent than chemo. Have multiple proposed mechs of action. Can be internalised - endocytosis, lysosomal degradation - release o cytotoxic. Then interacts to illicit cell death.
• Monoclonal antibodies are monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone
What is an epitope
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What is an antigen
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How are abs generated
- First generated in mice in 1975 using a hybridoma technique
- The generation of hybridomas involves immunising a certain species against a specific epitope on an antigen and then harvesting the B-lymphocytes from the spleen of the mouse
- The B-lymphocytes are then fused with an immortal myeloma cell line not containing any other immunoglobulin-producing cells
- The resulting hybridoma cells are then cultured in vitro so only the hybridomas (i.e. the fusion between the primary B-lymphocytes and myeloma cells) survive
- Selected hybridomas are found making a specific desired clonal antibody
Descrbe the immunogenicity of chimeric mabs
Combine with humaan to human immune system less stimulated by them. Mouse antibodies short half life, human antibodies longer half lives.
What are adcs
Add. Antibody drug conjugates. Mab, linker, potent cytotoxic. Kill cancer but minimise effect on normal tissues. Mabs used in adrs tag antigens mostly on cancer cells. Someme of such mabs have their own anticancer activity (AC/DC,, induce apoptosis) and can retain this. Linkers link mabs and cytotoxic. Cytotoxics can be more 1000 fold more potent than chemo. Have multiple proposed mechs of action. Can be internalised - endocytosis, lysosomal degradation - release o cytotoxic. Then interacts to illicit cell death.
What are bispeciic mabs
Only 1 approved. 2 parts of the antibody bind ifferent targets, bring different ells together. When both rams engarges, T cell engaged and directed to kill B cell. Binds to cd20 on B cells an cd3 - on T cells. Performing created transmembrane pores in B cell allowing granzymes to enter it. These make reactions resulting in apoptosis o the B cell
Potent. Risk if T cells activated.
Briefly how do monoclonal antibodies work
- Binding with cell surface receptors to either activate or inhibit signalling within the cell
- Binding to induce cell death
- Binding with cell surface receptors to activate:
- antibody-dependent cell-mediated cytotoxicity (ADCC) or • complement-dependent cytotoxicity (CDC)
- Internalization (ie being taken in by the cell through the membrane) for antibodies delivering toxins into the cancer cell
- Blocking inhibitory effects on T cells (checkpoints). Thus activating T cells to help ‘kill’ the cancer cells
What type of cancer s lymphoma
- Lymphoma divided into B and T cell neoplasms – clonal proliferations of lymphoid cells
- It typically causes enlargement of lymph nodes
- The spleen, bone marrow and other areas of the body such as liver, skin, testes and bowel (‘extra-nodal’) may also be involved
- People with lymphoma often complain of drenching night sweats, fevers and weight loss .. But some have none of these symptoms
What are types of lymphoma
The lymph node can be taken over by small clonal B lymphocytes which retain the follicular pattern Follicular lymphoma
or by larger clonal B lymphocytes which take over the node in a diffuse pattern. Diffuse large B cell lymphoma
What are treatment strategy in lymphoma
- Chemotherapy - combination chemo used to be used in 90s
- Radiotherapy
- Monoclonal antibody therapy
- Emerging newtargetedtherapy
- Stem cell transplantation - Only in ppl who probs wont survive without it.take stem cells it, heavy chemo, - wipe out bone marrow. Very vulnerable bc no immune system. put stem cells back in/ OR can use someone else’s bm but risky.
• The 2 cases shown both received chemotherapy, steroids and Rituximab (a monoclonal antibody against CD20)
What are teh side effects of mabs
• Some have no or mild symptoms eg mild fatigue • Many have a mild reaction to the 1st infusion and then
tolerate subsequent treatments well
• A few people will have severe infusion related reactions as their immune system reacts to the presence of a ’foreign’ protein
Bp drops, bradycardia, chest pain
What info should be given to a patient in terms o infusion reaction
• Patient education:
• Explain to the patient that even though they have received
premedication, they may still experience some side effects.
• Explain that they should inform staff the moment of any change, so that staff can take immediate action
• Instruct patient to omit their anti-hypertension medication for 12 hours prior to their infusion.
What steps should be taken to manage irrs
- Prevention with Pre-medication: steroid, anti-histamine, paracetamol
- Start at a slow infusion rate, slowly increase if tolerated
- Drugs required to treat IRRs should be prescribed prior to starting patients treatment
What are some examples of uses o mabs
- Solid cancer
- Trastuzumab – inhibition of HER-2 signalling
- Bevacizumab – inhibition of VEG-F signalling
- Nivolumumab – inhibition of CTLA-4 signalling
- Autoimmune
- Infliximab and Adalimumab – inhibition of TNF-alpha
- Cardiology
- Abciximab – inhibition of platelet glycoprotein IIb/IIIa
- Endocrine
- Denosumuab – inhibition of RANK ligand on osteoclasts
