Lecture 6- Monoclonal antibodies Flashcards
What are monoclonal antibodies?
Monoclonal antibodies are monovalent antibodies which bind to the same epitope of an antigen and are produced from a single B-lymphocyte clone
antibodies are produced by
plasma cells (mature B cells)
which part of the antibody recongises antigen
-
Fab (fragment antigen binding) part of antibody recognises antigen
- Hypervariable regions meaning that antibody can recognise an infinite number of antigens
- Paratope region on antibody reacts with epitope (antibody binding site) of antigen
- Hypervariable regions meaning that antibody can recognise an infinite number of antigens
which part of the antibody interacts with the cell surface receptors on other cells
-
Fc (fragment crystallizable region) region
- Interacts with cell surface receptors on other cells
Monoclonal antibodies in clinical practice
-
Diagnostics
- E.g. immunohistochemistry (ELISA)
- Therapeutics
Production of monoclonal antibodies
e.g. Hybridoma technology
- 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
Types of monoclonal antibodies drugs
- Naked monoclonal antibodies
- Conjugated monoclonal antibodies
- Bispecific monoclonal antibodies
Naked monoclonal antibodies
- Derived from mice (murine)
- Recognised as foreign- rapidly cleared and destroyed
- Chimeric (65% human)
- Humanised (>90% human)
- Fully human (100% human)
- Significant immunogenicity
Conjugated monoclonal antibodies
- Monoclonal antibody is linked to a potent drug to allow targeted delivery to cancer cell
- Tumour specific antigen is targeted by monoclonal antibodies
- Drug (cytotoxic agents) internalised 9receptor mediated endocytosis) by cancer cell and killed
- E.g. lysosomal degradation: ADCC and induction of apoptosis
- Limits systemic exposure
- ADCs (antibody-drug conjugates) are designed to allow for the use of highly potent, normally intolerable, anticancer cytotoxic agents
e.g. B/T cell lymphoma
Bispecific monoclonal antibodies e.g. Mosunetuzumab
- Utilise 2 binding domains of antibody structure
- Bind onto 2 different cell populations–> bringing the two populations into close proximity e.g. T cell and malignant B cell (enhanced cell mediated cytotoxicity)
- In clinical trials
How do they work in cancer?
Binding with cell surface receptors to either activate or inhibit signalling within the cell
-
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
Monoclonal antibodies in haemtology
- Understanding what antigens are present on cancer cells and on normal tissue we could try to develop specific targeted treatments.
- Cluster of differentiation (CD) classification.
What type of cancer is 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
- weight loss .. But some have none of these symptoms
lymphoma b cells express
CD20 - therefore creation of mAb which binds to CD20 e.g. Rituximab
types of B cell lymphoma
- follicular lymphoma
- diffuse large B cell lymphoma
clinical examples of lymohoma
Lymphoma treatment
- Chemotherapy
- Radiotherapy
- Monoclonal antibody therapy
- Emerging new targeted therapy
- Stem cell transplantation
mAbs in Lymphoma
Side effects of monoclonal antibodies in treatment of lymphoma
- 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
monoclonal antibodies in solid cancer
monoclonal antibodies in autoimmune disease
monoclonal antibodies in cardiology
monoclonal antibodies in endocrine disorders
