SM 227a - Biologics and Therapeutics Flashcards
Which biologic inhibits T cell activation?
Which patients benefit from this therapy?
Abatacept
- Binds CD80/86, thus displacing CD28
- Without CD28, the 2nd the 2nd signal for activation is blocked
- Used in patinets who have failed anti-TNF + MTX therapy
Why is infliximab combined with methotrexate?
Without methotrexate, human anti-chimeric antibodies (HACAs) build up to target the murine portion of infliximab
Giving methotrexate with infliximab can slow/inhibit the production of HACAs
In RA pathogenesis, which cells produce TNF-alpha, IL-1, IL-6, and MMPs?
Macrophages
Activated by anti-CCP antibodies (ACPAs) producced by B-cells
Which biologics target IL-6 signaling?
Which disease can be treated by targeting this pathway?
tocilizumab, sarilumab
Both are monoclonal antibodies against the IL-6 receptor
Used to treat rheumatoid arthritis
Describe the basic pathway that is activated by cytokine signaling
- Cytokine binds to its cell surface receptor
- -> Receptor polymeraziation
- Activation of associated JAKs
- Activated JAKs phosphorylate receptors that dock STATs
- Activated JAKs phosphorylate STATs
- Phosphorylated STATs dimerize and move to the nucleus to activate new gene transcription
What cytokines are targeted in RA therapy?
IL-1, IL-6, TNF-alpha
Describe the structure and mechanism of action of adalimumab
- Fully human IgG1 monoclonal antibody
- Less antigenic than infliximab
- Targets TNF-alpha
- Binds soluble TNF-alpha before it can bind to its receptor on a target cell
Describe the structure and mechanism of etanercept
- Soluble fusion protein
- 2 copies of soluble TNF-alpha receptor + Fc fragment of human IgG2
- Can bind and inactivate soluble and cell-bound TNF-alpha
- Prevents soluble TNF-alpha from reaching its target cell
- Prevents signal probagation when TNF-alpha is bound to the target cell because it prevents TNF receptors from cross-linking
- Used in combination with methotrexate to treat RA
Describe the progression of RA - what drives disability at each stage?
- Early
- Disability is driven by inflammation
- Treating inflammation can reverse disability
- Later
- Disability is driven by bone erosion
- Treating inflammation will no longer reverse disability
The treatment goal is to reduce inflammation early before it can lead to permanent joint damage
Describe the structure and mechanism of infliximab
- Chimeric IgG1 monoclonal antibody
- Targets TNF-alpha
- Binds soluble TNF-alpha before it can bind to its receptor on the target cell
- Used in combination with methotrexate to treat RA
What are the major safety issues with DMARDs and biologic agents?
Opportunistic infections and/or serious infections
Theoretically, malignancies may come up but has not yet been an issue (except non-melanoma skin cancer)
Biologic therapies have been shown to reduce mortality risk, even wtih increased risk of infection
Which biologic targets the TNF-alpha receptor?
Etanercept
Which drug targets B cells to treat RA?
Which patients will receive this treatment?
Rituximab
- Chimeric anti-CD20 monoconal antibody
- Transiently depleats pre-B and Mature B cells only
- Try in patinets who have failed Anti-TNF + MTX therapy
Describe the mechanism of tofacitinib
Inhibits JAKs
-> Blocks signal transduction after cytokine binds to its receptor
Describe the mechanism of rituximab
Chimeric anti-CD20 monoclonal antibody
- Depletes pre-B and mature B cels
- No effect on progenitor and plasma cells
- Used to treat RA
- B cells differentiate into plasma cells and release RF and ACPA
- Targeting B cells for destruction prevents them from becoming plasma cells
What are the differences between biologic therapies and targeted small-molecule therapies?
- Biologics
- Extracellular mechanism
- Most must be administered parenterally
- Targeted small-molecules
- Intracellular mechanism
- Can be taken orally
Which drugs used to treat RA are “targeted small molecule inhibitors?”
Tofacitinib and Baracitinib (-tinib drugs)
JAK inhibitors - prevent signal transduction after cytokines bind to their receptors
What is the mechanism of action of methotrexate?
Inhibits dihydrofolate reductase to limit DNA synthesis
- Inhibits IL-1 and IL-8 production by mononuclear cells
- Inhibits TNF production by T cells
- Inhibits neutrophil activation and adherance
- Inhibits vascular proliferation
First line agent in the management of RA
Used in combination with biologics to prevent antibody HACA production
Why is it important to treat RA early and aggressively?
Failing to adequately treat RA ->
- Increasing joint destruction and deformity
- Progressive physical disability
- Reduced QOL
Goal is to treat early enough to prevent radiographic changes
