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
