Biologics

Question 1

Aims for antibody based biologics for chronic inflammatory conditions

Answer 1

• Designed to have immunosuppressant activity
• Prevent cell to cell interactions
• Prevent cytokine / receptor association
○ By blocking the ability of the cytokine to bind to its receptor or
○ Blocking the ability of the receptor to bind the cytokine

Question 2

Aims for antibody based biologics for cancer

Answer 2

• Designed to prevent proliferation / enhance apoptosis

* Reveal the cancer to the immune system

Question 3

Strategy 1 for biologics used to treat inflammatory conditions

Answer 3

Prevent cell- cell interactions
• Cell to cell interactions are important in the immune response. Physical contact is required for:
• Recruitment of immune cells to the site of the response
• Activation of immune cells

Question 4

Targeting T-cells: ABATACEPT

Answer 4

• Fusion protein (immunoadhesin) linking the extracellular domain of CTLA-4 to Fc region of IgG1
• Binds to CD80/86 on the APC and prevents the co-stimulatory signal between the T cell and APC (i.e. the CD28 - CD80/CD86 interaction)
• Prevents full activation of the T cell

Question 5

Targeting T-cells : RITUXIMAB

Answer 5

• Chimeric monoclonal antibody against the CD20 surface protein found on mature B cells
• Binds to CD20
• Inhibits B-cell proliferation and differentiation
• Reduces CD40 and CD80 expression on the B cell
• Inhibits the release of TNF-α from macrophages
• Increases the release of IL-10

Question 6

Targeting T-cells: VEDOLIZUMAB

Answer 6

• A humanised IgG1 monoclonal antibody that targets an intergrin – the α4b7 cell adhesion molecule important for immune cell migration to the site of the inflammation / injury / infection
Prevents activation, adhesion and migration of immune cells

Question 7

Targeting T-cells: OMALIZUMAB

Answer 7

• A humanised IgG1 monoclonal antibody that targets the constant region of circulating IgE.
  
  • Prevents binding of circulating IgE to the FcεR1 on mast cells, and basophils
  • Reduces FcεR1 expression on effector cells
• N.B. does not block IgE already bound to its cell surface receptor and does not bind to FcεR1

Question 8

what is Strategy 2 for biologics to treat inflammatory conditions?

Answer 8

Block cytokine/receptor association

• Cytokines provide co-stimulatory inflammatory signals that help to initiate and maintain the immune response that leads to inflammation
• TNF-α has a central role as pro-inflammatory cytokine
• Synthesised by a range of tissues and cells including Macrophages, other lymphocytes, adipose tissue, endothelium cells and fibroblasts
• Activation of its receptor leads to
  
  • production of other inflammatory cytokines by activating NFkB (e.g. IL-1, IL-6 which it works in concert with)
  • Expression of adhesion molecules on endothelial cells etc (e.g. ICAM-1)

Question 9

monoclonal antibodies targeting TNF-alpha

Answer 9

Infliximab:
• chimeric IgG1 mAb against TNF-α

Adalimumab and Golimumab:
• human IgG1 mAb for TNF-α
Bind to TNF-α preventing it from binding to their receptors

Question 10

targeting interkeukin IL-5

Answer 10

Mepolizumab
• Humanised IgG1 monoclonal antibody against cytokine IL-5
• Prevents IL-5 binding to its receptor
• N.B. IL-5 receptors are particularly abundant on eosinophils
• Effects of blockade of IL-5 binding to eosinophils
• Reduced proliferation
• Reduced maturation
Reduced activation

Question 11

Targeting interleukin IL-6 receptor

Answer 11

Tocilizumab
• Humanised IgG1mAb against the interleukin-6 receptor (IL-6R).
• Binds to the soluble and transmembrane bound form of the IL-6 receptor preventing IL-6 from binding (i.e. acts a receptor antagonist) therefore blocking its activation and signalling via the JAK-STAT pathway.

• Effect of blockade:

1. No IL-2 synthesis
2. Inhibition of helper T cell differentiation and proliferation 
3. Inhibition of cytotoxic T cell differentiation and proliferation 
4. Reduced macrophage differentiation

Question 12

targeting interleukin IL-17A

Answer 12

Secukinumab
• Human IgG1 monoclonal antibody against interleukin IL-17A
• IL-17A is released from cells as a homodimer or as a heterodimer with IL-17F.
• Both bind to a heterodimer receptor consisting of IL-17RA and IL-17RC
• Secukinumab prevents IL-17A containing dimers from binding to their receptor
Inhibits the release of pro-inflammatory cytokines, chemokines and mediators of cellular damage

Question 13

biologics used in the treatment of cancer: CETUXIMAB

Answer 13

• Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR (HER1) blocking its signalling pathway
Used for the treatment of cancers that overexpress this receptor subtype

Question 14

biologics used in the treatment of cancer: TRANSTUZUMAB

Answer 14

• Trastuzumab binds to and inhibits Her2 blocking its signalling pathway
• Her2 is an epidermal growth factor receptor (EGFR) subtype that forms a dimer with other EGFRs
Trastuzumab is used for the treatment of cancers that overexpress HER2

Question 15

Biologics used in the treatment of cancer: BEVACIZUMAB

Answer 15

Bevacizumab
• Vascular endothelial growth factor (VEGF) promotes vasculogenesis and angiogenesis by binding to its receptors VEGFR-1 and VEGFR-2, on the surface of endothelial cells.

• Bevacizumab is a recombinant humanized IgG Mab
• It binds to VEGF inhibiting it binding to its receptors and inhibits tumour growth by:
  
  • regressing the vascularisation of tumours
  • inhibiting the formation of new tumour vasculature

Question 16

Biologics in the treatment of cancer: NIVOLUMAB

Answer 16

Nivolumab
An immunoregulatory antibody

• PD-1 is expressed by activated CD4+ and CD8+ T cells
• It belongs to the same family as CD28 and CTLA-4
• The ligand of PD-1 (PD-L1) promotes apoptosis of the T cell when it binds to PD-1.
  • PD-L1 is overexpressed by cancerous cells
  • Nivolumab binds to PD-1 preventing downregulation of cytotoxic T cell function