6. Biologics Flashcards
(24 cards)
What are biologics?
Biological molecules used as therapeutic agents. Biologic drugs are derived from living organisms used to treat ocular disease. They are large complex molecules often produced using biotechnology.
Used particularly for chronic and severe eye conditions.
What are the differences between biologics and small molecular entities?
SMEs:
* Generally low molecular weight
*Usually chemical synthesis
*Few critical process steps
*Well characterised
*Known strucutre
*Homogenous drug substance
*Usually non immunogenic
Biologics:
*High molecular weight
*Made with or from live cells/organisms
*Many critical process steps
*Less easily characterised
*Structure may or may not be completely defined
*May be heterogeneous mixtures
*Often immunogenic
Why do we use biologics?
They allow us to target specific, hard to get pathways. This expands upon mechanisms available using SMEs.
They may allow treatment of disease that are otherwise untreatable.
What can biologics be used as treatment for?
- AMD
- Diabetic retinopathy
- Uveitis (Non infectious type)
- Glaucoma
- Retinal vein occlusion
- Serious inflammatory conditions like cancer and crohn’s disease
How do biologics work?
They block the activity of mediators of physiological responses by binding to and isolate the mediator or its receptor.
They must have high specificity and affinity for the intended target.
Pathways targeted:
1. Vascular endothelial growth factor (VEGF)
2. Tumor Necrosis factor alpha TNF-a
3. Interleukins (ILs)
How are biologics delivered?
- Intravitreal injections - they are quite large so cant really pass through eye barriers if given topically. So this is the most common way
- Topically
- Implantable devices - this ensures high local concentrations with minimal systemic exposure
What are some types of biologics?
- Monoclonal antibodies
- Modified soluble receptors / fusion proteins
- Aptamers
- Gene therapies
- Cell-based therapies
What are the biochemical and biophysical properties of biologics?
- Relatively unstable in solution
- High viscosity, low solubility at high conc
- Sensitive to environment (light, temperature etc)
- Prone to enzymatic degradation (proteolysis)
- Susceptible to absorption, unfolding, aggregation, inactivation
- Needs special care during fill finish, storage and shipping
- Difficult and expensive to manufacture, ship and store. (For example, Bevacizumab needs to be kept at 2-8 degs, protected from light, not frozen and not shaken.)
Describe the pharmacokinetics of Biologics.
- Usually have to be injected
- Bioavailability of 50-80%
- Long half lives of 3-4 weeks
- Clearance is determined by size and type
- Excretion via kidneys
- Mostly degraded by lysosomes
- Fc mediated elimination - (Many Biologics have a Fc region which can be engineered to modulate their half life and other pharmacokinetic properties)
What is immunogenicity of biologics?
The Px’s immune system recognises and destroys the biologic.
Degree of humanisation:
Trying to change the structure of biologics to be more human like so immune response is less likely to attack. Chimeric antibodies may require co administration of immunosuppressive drug methotrexate to limit immune response.
Subcutaneous route is more likely to be attacked due to phagocytes and other immune system cells under the skin. So IV is better as it needs to be injected less frequently.
The longer the Px is exposed, the greater the likelihood of immune response.
When should biologics not be used?
- Pxs with tuberculosis or other active infection
- Pregnancy or breast feeding
- Demyelinating disease such as multiple sclerosis
- Malignancy must be ruled out as some biologics can cause cancer
- Blood cell counts need to monitored closely
How are biologics named?
*Therapeutic monoclonal antibodies end in -mab
*Chimeric antibody end in -ximab
*humanised antibody end in -zumab
*Fusion proteins containing part of a receptor end in -cept.
What is Dry AMD?
*Characterised by drusen accumulation and retinal pigment epithelium and photoreceptor atrophy
*Gradual breakdown of light sensitive cells in the macula, and supporting tissue beneath macula
*About 90% of AMD cases
What is Wet AMD?
*Abnormal growth of new blood vessels under the retina.
These vessels are fragile so leak fluid or blood causing swelling and damage to macula.
*Severe damage may occur rapidly
*Driven by VEGF-A
*About 10% of AMD cases but 90% of associated vision loss
What is neovascularisation?
Growth of new blood vessels but in AMD this growth is abnormal. It is associated with increased vascular endothelial growth factor A.
VEGF-A is essential for normal ocular development and has a role in ocular homeostasis. This is what stimulates angiogenesis.
It results in leaky vessels and macrophages invade the retina leading to degeneration of photoreceptors.
Describe VEGF-A.
There are 6 different forms with VEGF 165 being the most commonly linked to the eye. Each one has different lengths which means different functions and properties such that smaller ones are diffusible and larger ones are bound in extracellular matrix.
VEGF-A binds to VEGFR-1 and VEGFR-2 receptors.
Receptors work in pairs. So once a ligand binds to one of them, they have to come together, then they can exert their effects. Otherwise nothing happens, it needs to be homodimer.
Activation causes cell proliferation, migration and alteration of gene expression.
Placental growth factor also binds to VEGFR-1
How does VEGF-A lead to pathogenesis of wet AMD?
VEGF 165 is responsible. When it is overexpressed this leads to neovascularisation. Its associated with inflammation, increased vascular permeability resulting in oedema and leakage and damage to macula.
How does anti VEGF work?
Anti VEGF drug binds to VEGF-A and prevents its interation with receptor. This prevents neovascularisation as it is anti angiogenesis.
Anti VEGF can reduce visual loss and improve visual acuity but it is not a cure, rather a life long treatment.
There are 4 anti VEGF drugs targeting VEGF-A currently in the UK:
2 are mAbs (monoclonal antibodies)
1 receptor-based and 1aptamer.
3 are licensed
They are administered by intravitreal injection, this limits systemic effects
Local side effects:
*floaters
*Opacities
*Raised IOP
*Haemorrhage
*Inflammation
*Retinal detachment
*Infection
Systemic side effects:
*risk of serious bleeding
*hypertension and proteinuria (as VEGF helps to control vascular tone and glomerular capillary fucntion)
*infertility
*inhibition of bone growth
*inhibition of skeletal muscle regeneration
*impairment in wound healing
Describe the available anti-VEGF drugs
- Bevacizumab -
Recombinant full length humanised mAb (monoclonal antibody).
Binds to all forms of VEGF
IV injection stabilises visual acuity and prevents decline in vision.
Long half life of up to 3 weeks
Problems:
It was developed for cancer so ocular use require dilution which reduces stability so can only be stored for up to 8h. Due to dilution can risk contamination and risk of protein aggregation. - Ranibizumab -
Derived from same mAb as bevacizumab but has higher affinity.
This is most common anti-VEGF drug.
Specifically designed for ocular use.
It has fewer side effects as it has shorter half life and lacks Fc domain so doesn’t initiate inflammation and immune system activation.
Increased incidence of ischaemic events however not necessarily caused by the drugs and is only found in a small number of Pxs.
Resistance:
51.5% of eyes treated with ranibizumab and 67.4% treated with bevacizumab still have persistent fluid after 2 years.
- Aflibercept -
Recombinant fusion protein (soluble receptor).
VEGF binding sites are fused with the Fc domain of human IgG, to make the soluble VEGF binding protein.
3 loading doses monthely, then 2 monthly injections.
It has similar effects to ranibizumab, with fewer adverse effects and fewer injection than with the mAbs. - Pegaptanib -
PEG-ylated oligonucleotide aptamer (single stranded DNA molecule attached to polyethyleneglycol)
This specifically binds to VEGF-A 165
6 weekly intra vitreous injection, improvement seen after 6 weeks but visual decline still occurs.
NICE no longer recommends this for Wet AMD.
What is diabetic retinopathy
Damage caused to retinal microvasculature by hyperglycaemia. Blood vessels swell, leak and localised hypoxia (lack of O2). This stimulates abnormal new blood vessels to form, neovascularisation. Scarring and retinal detachment may result.
There are two types:
1. NPDR - non proliferative diabetic retinopathy. This is early stage of swelling and leaking of vessles.
2. PDR - proliferative diabetic retinopathy. This is later stage where there is an abnormal growth of leaky new vessels (neovascularisation).
How is diabetic retinopathy treated?
DR is seen as a chronic low grade inflammatory disorder.
PPAR alpha agonists can be used to combat inflammation.
Inhibitors of the renin-angiotensin system can be used to protect against angiogenesis.
Anti VEGF treatments are used to stabilise PDR (Ranibizumab and Aflibercept)
What is Uveitis?
Uveitis is the inflammation of the middle layer of the eye called the Uvea.
It is caused by infection, post trauma/surgery , or autoimmune conditions like Crohn’s disease or rheumatoid arthritis.
If untreated can lead to cystoid macular oedema, cataracts, secondary glaucoma, vitreous opacities, retinal scars.
First line treatment = corticosteroids, if this doesn’t work then biologics may be used.
Which biologics can be used to treat Uveitis?
They all aim to reduce inflammation by regulating inflammatory immune responses.
- Abatacept (targets T-cell activation)
- Rituximab (targets B cells)
- Alemtuzumab (targets B cells)
- Canakinumab (binds and isolates cytokine IL-1Beta)
- Anakinra (recombinant for of naturally occurring IL-1 receptor antagonist)
- Tocilizumab (binds and blocks IL-6 receptor - currently in clinical trial)
- Interferon alpha (recombinant form of naturally occurring cytokine which regulates immune responses)
How can the biologics TNF inhibitors treat Uveitis?
Tumour necrosis factors are a family of cytokines.
Very high levels of TNF, particularly TNFa activates TNF receptors 1 and 2 which cause pathological inflammatory conditions such as Crohn’s disease and rheumatoid arthiritis which then results in Uveitis.
TNF inhibitors prevent receptor activation.
- Adalimumab
- Infliximab
- Golimumab
- Certolizumab pegol
- Etanercept (less effective)
Adalimumab is the only FDA licenced biologic for uveitis but can’t be used for those under age of 2.
In UK it can only be used by specialists and is given by subcutaneous injection. Initially given 80mg, then 40mg a week after and then a continuous 40mg every 2 weeks.
