What is Carpa
The potential for hypersensitivity reactions increases with the growing number of nanotechnology-enhanced (liposomal, micellar, polymer-conjugated) and protein-based (antibodies, enzymes) drugs being developed today.
The molecular mechanism of mild to severe allergy symptoms may differ from case to case and is mostly not known, however, in many cases a major cause or contributing factor is activation of the complement (C) system.
The clinical significance of complement activation-related pseudo allergy (CARPA), a non-immunoglobulin E (IgE)-mediated pseudo allergy, is underscored by its unpredictable nature and potential for fatal outcomes.
What is the difference between CARPA and IgE-mediated (Type I allergy)?
The molecular mechanism of mild to severe allergy symptoms may differ from case to case and is mostly not known, however, in many cases a major cause or contributing factor is activation of the complement (C) system.
The clinical significance of complement activation-related pseudo allergy (CARPA), a non-immunoglobulin E (IgE)-mediated pseudo allergy, is underscored by its unpredictable nature and potential for fatal outcomes.
What is the difference between CARPA and IgE-mediated (Type I allergy)?
In order to develop an IgE-mediated hypersensitivity, the experimental drug needs to bind to an antigen, i.e., anti-drug antibodies. These would not normally be present when administering the first doses of a new agent.
However, several medications have shown that hypersensitivity reactions that occur with the first administration are due to cross-reactivity with environmental allergens like in the case of cetuximab ( a type of targeted cancer drug.)
It has been Endovascular Grafts. In the case of CARPA, the reactions occurred mostly at the first exposure to the drug. In some cases, this is believed to be due to previous exposure to polyethylene glycol (PEG), which is present in many medications and ‘everyday’ products such as toothpaste.
CARPA can also be induced by medical devices such as endovascular grafts, heart valves, and dialysis membranes.
What are the symptoms of CARPA?
Numerous symptoms of CARPA relate to the cardiovascular, bronchopulmonary, hematological, mucocutaneous, and gastrointestinal systems (Szebeni 2005).
Symptoms of flushing due to histamine release may be part of CARPA. Still, they could also be mediated via the MrgprX2 receptor present on peripheral blood basophils and eosinophils, another mechanism that bypasses the antibody-mediated pathway and directly triggers mast cell degranulation by activating the mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MrgprX2). Urticaria might also be confused with IgE mediated mast cell activation. Thus, CARPA can be difficult to diagnose.
CARPA patients have reported the unusual symptom of a metallic taste that occurred within seconds of the infusion starting.
Complement activation
There are three pathways of complement activation: the classical pathway, the mannan-binding lectin (MBL) pathway, and the alternative pathway.
The classical pathway of complement activation is activated by C1, which binds either directly to bacterial surfaces or to antibodies, flagging the bacteria as foreign.
The MBL, also known as mannose-binding protein, is an acute-phase protein that binds to mannose residues. It can opsonize pathogens bearing mannose on their surfaces and activate the complement system via this pathway, an important part of innate immunity.
The alternative pathway of complement activation is not triggered by antibodies but by the binding of complement protein C3b to the surface of a pathogen; it is,, therefore,, a feature of innate immunity. The alternative pathway also amplifies the classical pathway of complement activation.
Irrespective of the pathway, complement activation always leads to the cleavage of C3, forming C3a and C3b. Increased levels of C3b result in the generation of the C5-convertase, which cleaves C5 into C5a, a powerful anaphylatoxin and chemoattractant, and C5b.
Finally, C5b binds and interacts with C6–C9, forming the membrane attack complex (MAC/C5b-9) (Poppelaars et al. 2018).
CARPA can be particularly dangerous as there is an amplification of the initial complement activation trigger that transforms the initial drug effect into a massive, vicious cycle of abnormal physiological changes that include pulmonary hypertension, systemic hypotension, myocardial hypoxia, bronchospasm, and more.
How can you avoid/mitigate the risks of CARPA?In essence, you first need to consider that CARPA could occur and then ensure that all the appropriate preclinical tests are performed, the medication is administered appropriately, and the patient is under observation at a hospital.
It’s important to note that premedication, such as acetaminophen, antihistamines, and corticosteroids, may not be effective in preventing CARPA. This unpredictability underscores the need for thorough preclinical testing and careful medication administration.
Preclinical Testing
The test compound should be screened for complement activation by incubating with normal human serum (samples taken from around 10 subjects) and measuring sC5b-9 concentrations after 20-30 minutes of incubation.
A 5-to-10-fold rise in sC5b-9 may be a realistic predictor of a clinical reaction. Increases in sC5b-9 of this magnitude were shown to correlate with clinical symptoms in patients treated with Doxil (PEGylated liposomal doxorubicin), which is known to induce this kind of reaction.
If this test is negative, it is recommended that a much larger number of normal human serum samples (10 to 100) be tested (Szebeni 2005).
In addition, advice should be sought on appropriate preclinical tests as susceptibility to CARPA varies considerably across different animal species and humans.
Another point to consider is if the disease target is associated with the presence of autoantibodies or pre-sensitisation to PEG for PEGylated compounds e.g., PEGylated liposomal doxorubicin.
It’s important to note that the candidate drug may only exhibit complement activation in the presence of the autoantibodies/antibodies to PEG. Therefore, testing with normal human serum may lead to a “reassuring” but potentially misleading result. Specific testing conditions are crucial to avoid such errors.
Drug administration
It’s important to note that the candidate drug may only exhibit complement activation in the presence of the autoantibodies/antibodies to PEG. Therefore, testing with normal human serum may lead to a “reassuring” but potentially misleading result. Specific testing conditions are crucial to avoid such errors.
Drug administration
Learning from the Tegenero experience, it’s clear that investigations into avoiding serious infusion reactions are crucial. This underscores the necessity of sentinel dosing in drug development based on past incidents and the lessons learned from them.
Initial infusions should be given slowly, e.g., over 4-8 hours, and investigators should have a very low threshold for discontinuing the infusion should the subject develop any relevant symptoms.
If the drug has been shown to induce CARPA and the development of the compound is to continue. Sponsors should determine a ‘safe infusion protocol’ in pigs and use this to determine the dosages and infusion rates for patients.
Perhaps the best industrial and regulatory proof of the model’s utility is that the safe human administration protocol for double-stranded small interfering RNA (siRNA) delivering solid lipid nanoparticles was developed in the pig model.
Patisiran (Onpattro R) was the first Federal Drug Administration (FDA) approved gene therapy using (phospho) lipid-based nano-delivery vehicles (Bedőcs and Szebeni 2020).
Samples to be taken in the event of an infusion reaction
As mentioned previously, determining the cause of the infusion reaction can be clinically challenging. Therefore, multiple blood samples should be taken to help understand the mechanism.
Blood samples include mast cell tryptase (elevated in IgE-mediated reactions), histamine, IgE, a panel of cytokines including IL-6, IL-8, TNF, and complement (C3, C3a, C5a, and sC5b-9).
It is important to obtain a sample at the peak of the reaction, which is often around 30 minutes after the initial onset.
Histamine can also be measured using a urine collection. In addition, a ‘reference’ sample should be taken 48–72 hours after the anaphylaxis episode to allow a comparison between the peak and the ’reference’ values (Doessegger and Banholzer 2015).
Ensure the samples are taken and processed correctly as histamine, for example, is particularly unstable.
Finally, it’s always advisable to take an extra sample so when an expert says, ‘Did you measure serum rhubarb concentrations?’
You can reply, ‘No but there is a sample in the freezer, so we can measure this if you think it would be useful’.
References
Finally, it’s always advisable to take an extra sample so when an expert says, ‘Did you measure serum rhubarb concentrations?’
You can reply, ‘No but there is a sample in the freezer, so we can measure this if you think it would be useful’.
