Biologics Flashcards
What’a GALT?
Gut-associated lymphoid tissue
- it is a mucosal immune system
- in GIT
Innate immunity vs Adaptive immunity
What cells are affected by cytokines?
- immune cells
- fibroblasts
- endothelial cells
The role of macrophages a cancerous cell that is over-producing itself?
- Macrophages ‘collect’ the sample from a cell that is over-producing itself
- some of the collected cells - would be normal cells - if these are presented to antigen presenting cells/T cell -> then nothing would be done
- If abnormal proteins are presented -> then we can fight the cancer
* Check-Point inhibitors -> will block the pathway of cancer development
What are check-point inhibitors?
They block the pathway of a body not being able to fight cancer (due to ‘normal’ cellular antigens being presented to T cells)
Example of a key cytokine that initiates the pathway in responder cell that is specific to that cell?
RA -> TNF alpha
What are (2) regions on immunoglobulin?
- Fab -> fragment antigen binding
- Fc -> determines the type of immune response
What would the variable regions of immunoglobulin protein mean/result in?
Genetic variability of immunoglobulins - able to match different antigens
What are antigens?
Antigens - proteins on a cell/ micro-organism that are able to activate B cells (and production of antibodies)
How dos elimination of antigen occur? (2)
- directly -> by neutralisation
- indirectly -> by promoting phagocytosis or complement activation (lysis)
IgM vs IgG
- IgM - early stage
- IgG - late
What’s the role of IgE in allergic reaction?
IgE triggers the release of histamine from basophils
What antibody is linked with mucosal immunity?
IgA
What is the function of IgD
cellular regulatory function
What most biologics are?
Antibodies
How are monoclonal antibodies produced?
- Antigens are injected into the mouse -> mouse will produce antibodies in spleen
- Antibody-producing cells from the spleen - but they do not have long lives - as cells die
- We want to make the cells immortal -> so we fuse them with tumour cells (immortal) -> hybridomas are formed
- Hybridomas produce antibodies -> these can be injected into patient and block specific pathways
*we combine human and mouse immunoglobulins - to reduce allergic reaction to animal antibody (chimeric antibody)
* most recent technologies -> human antibodies only are produced
What are biologics?
Medications with near-identity to the original biologic agents (e.g. protein or antibody
What are the problems with biologics?
We are not able to monitor entirely how the antibodies circulate and move around the body - not predictable pharmacokinetics and pharmacodynamics
What are biosimilars?
Type of biologics
Infliximab
What does it do? (MoA)
Infliximab
It binds to TNF-alpha
*TNF-alpha is a cytokine secreted during intial steps of inflammatory response that triggers the enhancement of inflammatory response by other cells (cellular proliferation, differentiation and apoptosis)
Indications for Infliximab
Crohn’s and UC, RA, psoriasis, ankylosing spondylitis
Side effects of Infliximab
Same side effects with any other biologics
- injection site reactions
- infusion reactions
- infections (as TNFalpha cannot get involved -> pathway that induces immunity is lost)
- malignancy
- neutropenia
- demyelinating disease (<0.1%)
- heart failure
Route of administration of biologics
- IV infusions
- SC
*no other route due to big molecular mass
Side effects of biologics
Same side effects with any other biologics
- injection site reactions
- infusion reactions
- infections
- malignancy
- neutropenia
- demyelinating disease (<0.1%)
- heart failure
What so we need Ix for if a patient on biologics comes with unclear symptoms?
Ix for malignancy and infections
- as being on biologics will suppress immune system
What’s the mechanism of action of Adalimumab?
Adalimumab
Works against TNFalpha
What’s the difference between Infliximab and Adalimumab?
*Adalimumab very similar to Infliximab (side effects and indications same for Adalimumab and Infliximab) -> they are bothTNF-alpha inhibitors
Adalimumab is first fully human monoclonal antibody (Infliximab is partially human partially mouse)
*less allergic reactions with Adalimumab (as fully human antibody) - but anti-drug antibodies may develop (resistance)
Mechanism of action of Etanercept
Etanercept
MoA: TNF-alpha and TNF-beta inhibitor
What are the benefits of giving Etanercept?
Etanercept is a combination of TNF-receptr and IgG (blocks TNF alpha, TNF beta pathways)
- less resistance will develop
Rituximab - mechanism of action
Rituximab blocks CD20 receptor on B cells and: (destruction of B cells)
a) activation of complement cascade -> apoptosis of B cell
b) Natular Killer cells are attracted -> killing of B cell
c) activation of intracellular pathways -> apoptosis of B cells
*useful where (ie. blood malignancies) where B cells produce antibodies against our own tissues -> so we want to reduce B cells
Indications of Rituximab
*useful where (ie. blood malignancies) where B cells produce antibodies against our own tissues -> so we want to reduce B cells
In general: autoimmune conditions and blood cancers
Side effects of Rituximab
- reactions at the side of infection
- being prone for opportunistic and latent infection reactivation (Hep B,CMB, Herpes)
Latent infections and biologics
Biologics will remove immune action on the latent infections (infections not active but present in the body) -> activated infections
So always check for EBV, CMG, Hep before e.g. bone marrow transplant (in donor and recipient)
What’s Acute Cytokine Release Syndrome?
It is a side effect of any biologics (but particular Rituximab)
- Administration of big molecules of biologics -> immune system will pick up the antigens from biologics -> presentation to the T cells -> massive response of immune system -> massive amount of cytokines released
- response like for an infective antigen (but to biologics antigen) -> massive exacerbation of fever, headache, chills, myalgia, bronchospasm, hypotension etc
*it may cause angioedema and anaphylaxis
Why do we administer anti-histamines of steroids with Rituximab?
To prevent angioedema and anaphylaxis (Acute Cytokine Release Syndrome)
What’s MoA of Alemtuzumab?
Alemtuzumab = Campath
MoA:
- Alemtuzumab is directed against CD52
- CD52 is found only on B and T lymphocytes
- CD52 blocked -> production of cytokines inducing cellular apoptosis
End effect: we try to kill B and T cells
What is the danger of Alemtuzumab?
Malignancy and infection (immunosuppression as T cells and B cells are ‘killed)
Uses of Alemtuzumab
Uses: CLL, relapsing MS (remains effective long after the drug itself is undetectable), transplantation (off-label)
*MoA of Alemtuzumab: B and T cells are killed
Side effects of Alemtuzumab
Similar to other biologics
- Infusion reactions (>90%)
- Secondary autoimmunity (20-30%) up to 5 years after treatment
- thyroid autoimmunity (Graves’ disease)
- glomerulonephritis
- Infections
- Malignancies
Secondary autoimmunity as a side effect of biologics - what’s that?
As biologic is an antibody that is introduced to the body -> detected by immune system -> possible immune response against it -> cytokine production and T/B cells against own tissues
Possible consequences:
*antibodies against lung -> pneumonitis
* kidneys -> glomerulonephritis
* colitis -> against GIT
* antibodies against thyroid
What are the examples of other ‘biologics’ (apart from Infliximab etc)>
- blood products (RBC, FFP)
- insulin and other hormones
- growth factors (EPO) and immunoglobulins
- enzymes
- human tissues/organs
- vaccines
- other monoclonal antibodies
Kinase Inhibitors
- class name
- MoA
Kinase inhibitors
Class: small molecules -> end in ‘-nib’
MoA: regulators of cell cycle progress and cell proliferation
Kinase Inhibitors
- use
- MoA
Use: targeted anti-cancer therapy
Advantage: promising selective therapeutics (very targeted - target specific pathways; low toxicities)
D. All of the above
*immune imbalance may be blamed for miscarriages
F. RA, Crohn’s, Lymphoma
*C Diff is an infection - we do not want to suppress the immune system here
B. Most common: Injection/infusion reactions & infections
* Serum sickness - rale
*Acute Cytokine release syndrome - are not as common as we administer steroids and anti-histamines with biologics
Secondary autoimmunity - potentially with all biologics
* the most frequent with Adaliumab
What’s the general name of biologics?
To suppress immune over-activity and restore balance
