Lecture 6- Monoclonal antibodies Flashcards Preview

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Flashcards in Lecture 6- Monoclonal antibodies Deck (24)
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1

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

2

antibodies are produced by

plasma cells (mature B cells)

3

​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

4

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

5

Monoclonal antibodies in clinical practice

 

  • Diagnostics
    • E.g. immunohistochemistry (ELISA)

 

  • Therapeutics

6

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

7

Types of monoclonal antibodies drugs

 

  • Naked monoclonal antibodies
  • Conjugated monoclonal antibodies
  • Bispecific monoclonal antibodies

8

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

9

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

10

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

11

How do they work in cancer?

 

Binding with cell surface receptors to either activate or inhibit signalling within the cell

  1. Binding with cell surface receptors to activate:
    • antibody-dependent cell-mediated cytotoxicity (ADCC) or
    • complement-dependent cytotoxicity (CDC)
  2. Internalization (ie being taken in by the cell through the membrane) for antibodies delivering toxins into the cancer cell
  3. Blocking inhibitory effects on T cells (checkpoints). Thus activating T cells to help ‘kill’ the cancer cells

12

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.

13

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

14

People with lymphoma often complain of

 

 

  • drenching night sweats
  • fevers
  • weight loss .. But some have none of these symptoms

15

lymphoma b cells express

CD20 - therefore creation of mAb which binds to CD20 e.g. Rituximab 

16

types of B cell lymphoma

  • follicular lymphoma
  • diffuse large B cell lymphoma

17

clinical examples of lymohoma

18

Lymphoma treatment

 

  • Chemotherapy
  • Radiotherapy
  • Monoclonal antibody therapy
  • Emerging new targeted therapy
  • Stem cell transplantation

19

mAbs in Lymphoma

20

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

21

monoclonal antibodies in solid cancer

22

monoclonal antibodies in autoimmune disease

23

monoclonal antibodies in cardiology 

24

monoclonal antibodies in endocrine disorders