SPR L8 Biologic Drugs Flashcards
Biologics
- What are they derived from?
- What are they based on?
- What are they used for?
- living material (plant, animal or microorganism)
- usually based on protein and/or nucleic acid
- used for the treatment of diseases in humans
How are Biologics Different from Small Molecule Drugs?
What are the steps to making Recombinant Biological Products?
- Develop Host
- Establish a Cell Bank
- Protein Production System
- Purification
- Analysis
- Formulation: Therapeutic protein is then formulated
As with all of the steps, the components of the formulation and the process used can significantly affect the product and its behavior in patients
What are the special concerns with Biologics?
- Species specificity limits standard pre-clinical models for safety testing
- Usually injected
- Immunogenicity
- Macromolecules (proteins) like biologic drugs are capable of triggering an immune response with varying but unpredictable consequences:
- Antibodies may have no clinical effect
- Antibodies may neutralize the molecule making it therapeutically ineffective
- Rare but serious autoimmune responses can be life-threatening
- Small changes in a macromolecule can completely shift its immunogenicity profile
Understanding Cytokines
- What are cytokines?
- What are their three primary functions that cytokine-receptor interactions give specificity to?
- first picture
- Autocrine, Paracrine, Endocrine
Understanding Cytokines
What are the main groups of cytokines?
Interferons – 3 main classes
Interleukins (IL)
Tumour necrosis factor (TNF) cytokines
Haematopoietins
Understanding Cytokines
Give examples of the following
- Interferons – 3 main classes
- Interleukins (IL)
- Tumour necrosis factor (TNF) cytokines
- Haematopoietins
- interferon alpha & beta (type 1 interferons) antiviral activity, interferon gamma (type 2 interferon) – immuno-stimulatory actions
- 35 interleukins 1L-1, 1L-2 etc
- Primary member TNF alpha – broad range of activities
- Granulocyte – colony stimulating factor (G-CSF)
Granulocyte monocyte – colony stimulating factor (GM-CSF)
What do cytokines do?
- Inflammatory effects (e.g. IL-1, TNF)
- T and B cell regulation ( e.g. IL-2, interferon gamma)
- Anti-inflammatory effects ( e.g. IL-4)
- Haematopoietic effects ( G-CSF)
- Chemo attractant activity (> 50 cytokines termed chemokines due to ability to influence movement of immune cells
Exhibit pleitrophism (more than 1 biological effect) and act in cascades or networks
Cytokines in Disease
- Which diseases are cytokines implicated in?
- What is critical in the pathogenesis of rheumatoid arhtiritis?
- multiple sclerosis, Alzheimer’s disease, Myocardial infarct, stroke, asthma, COPD, psoriasis, inflammatory bowel disease, rheumatoid arthritis etc.
- TNF critical in pathogenesis of rheumatoid arthritis - Produced by macrophages in inflamed synovial membranes.
Cytokines as Medicines
Give examples of how INTERFERONS can be used in treatment of diseases
Alpha - Rx of hepatitis B and C
Beta - Rx of multiple sclerosis
Gamma - Rx chronic granulomatous disease
Colony Stimulatory Factors - chemotherapy induced
neutropenia e.g. filgrastim
Medicines that Affect Cytokines
Give examples of specific medicines that affect cytokines
- TNF antagonists
- Interleukin antagonists
- Monoclonal antibodies (mab) when used as medications given generic name ending in - mab
- Antecedent u (-umab) = human antibody
- Antecedent xi (- ximab) = mixed human/murine (chimeric) Antibody
- Fusion proteins end in - cept
Outline the pathogenesis of rheumatoid arthritis (don’t learn)
- Upregulation of both pro-inflammatory and anti-inflammatory cytokines
- Pro-inflammatory cytokines overwhelming the anti-inflammatory cytokines
- Resulting imbalance/tilt
Activated T-cells release cytokines including IL-2 IFN-g, TNF-b, IL-3 and TNF-a. TNF-a, plays a key role in the pathology of rheumatoid arthritis. TNF-a stimulates the macrophages, which produce TNF-a, IL-1 and IL-6. TNF-a is also a potent stimulator of IL-1, IL-6, and IL-8, which stimulate chondrocytes, osteoclasts and fibroblasts that release metalloproteinases (e.g., MMP-1 and MMP-3), ultimately leading to the erosion of bone and cartilage. 1-3. TNF-a is at the apex of the inflammatory cascade promoting downstream mediators that lead to bone erosion and inflammation in RA.1,4 Blocking TNF-a inhibits the production of IL-1, IL-6, and IL-8 and may have a more global effect versus blocking other cytokines further down the cascade
Outline the spectrum of RA treatment
Biologic Treatment of RA
Give examples of the following types of drug
- Anti-TNF
- Anti-B Cell
- Anti-T Cell
- Anti- IL-6
- Infliximab, Adalimumab, Etanercept
- Rituximab
- Abatacept
- Tocilizumab
Adalimumab: Recombinant human anti-TNF monoclonal antibody - s.c. once every 2 weeks
Outline how the new biologic drugs are used
- Must be given by injection - they are proteins
- Must be monitored closely - potential side effects
- Must be used long term – NOT a cure-stopping therapy can cause disease flare
- Initiate after non-biologic DMARDs have failed to work
What are the predictive factors of serious infections in RA?
(Serious Infections (Definition)
Life-threatening, fatal, requiring hospitalization, intravenous antibiotics, or resulting in persistent of significant disability)
- ↑Age
- +RF
- Nodules
- ↑ESR
- ↓WBC
- Extraarticular Features
- Corticosteroid use
- Diabetes mellitus
- Alcoholism
- Chronic Lung Disease
- Organic Brain Disease
