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
Outline the benefits of biologic drugs
- Decrease disease activity by 20-70%
- Decrease blood markers of inflammation
- Improves strength and patient vitality
- May induce complete disease remission – 15%
- Prevents progression and permits healing of radiographic bone damage
Outline the adverse effects of biologic therapy
- Local site reactions/allergic reactions
- Infection-unusual organisms-tuberculosis, fungi, listeria-monitor regularly
- Blood disorders-low WBC, platelets
- Liver toxicity
- Induced auto-immune diseases – SLE, MS
- Malignancy-lymphomas
What are the major safety issues with biologic therapies?
- Infections
- Infusion/injection-site reactions
- Autoimmune diseases
- Malignancy
- Immunogenicity, blocking antibodies
- Use in pregnancy
- Use in patients with congestive heart failure
- Use in patients with cardiovascular diseases
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
- What infection can be linked to anti-TNF-a therapy?
- What is the median time to diagnosis?
- What are the risks of TB when using mabs ?
- TB - screened BEFORE
10712 anti-TNF α vs 3232 DMARD cohort
- Median time to diagnosis (mos)
- 5 (INF), 11-13(ETN), 15-18.5 (ADA)
- ↑↑3-4 -fold among INF, ADA users vs ETA
–62% extrapulmonary, 28% disseminated
–10/39 deaths within 12 months of diagnosis
Malignancy risk with Biologics
13001 subjects, 49000 p yrs (1998-2005)
- For what was there no increased risk?
- For what is there an increased risk?
- No increased risk for lymphoma, lung, breast, and colon cancer
- Increased risk for skin cancer
Non melanotic skin cancer
OR1.5 (95%CI 1.2-1.8) 623 incident cases
Melanoma - OR 2.3 (95% CI 0.9-5.4)
Give examples of autoimmune diseased induced by biologics
- SLE or lupus-like syndromes
- Vasculitis
- Psoriasis
- Sarcoidosis
- Demyelinating CNS Disease
- Demyelinating peripheral neuropathies
- Antiphospholipid syndrome or APS-like features
- Interstitial lung diseases
- Ocular Autoimmune Diseases
- Autoimmune Hepatitis
- Inflammatory myopathies
Conclusion
- Biologics have revolutionised the treatment of autoimmune diseases due to their efficacy, speed of onset and tolerability
- Not a panacea as serious adverse effects reported and long term safety data lacking
- Some patients have a poor response indicating our understanding of immune-mediated inflammatory diseases as incomplete
Take-Home Points
- Vigilant monitoring is needed for infections, malignancy, infusion/injection reactions, and other safety issues
- Vaccination early into RA treatment should be considered
- TB screening
- Risk - benefit should be considered on an individual basis
- Biologics are relatively safe, however long-term studies especially for recently approved drugs are needed
- Use of biologics in pregnancy/lactation – needs further study
