Immunogenicity of Biotherapeutics

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Questions and Answers

What is the primary reason the host immune system may recognize a drug as 'non-self'?

The drug's immunogenicity is recognized by T-cells (correct)

The drug contains human proteins

The drug is presented to T-helper cells

The drug has a similar structure to self-antigens

Which factor does NOT contribute to the development of immunogenicity?

Molecular factors

Nutritional factors (correct)

Product factors

Patient factors

What role do Treg cells play in the context of immunogenicity?

They are responsible for presenting T-cell epitopes

They increase the likelihood of ADA generation

They limit ADA generation (correct)

They have no effect on immunogenicity

Which of the following is believed to drive whether an immunogenic response occurs?

Amino acid sequences known as T cell epitopes and Tregitopes Signup and view all the answers

What is a key aspect of immunogenicity development?

It is multi-factorial in nature Signup and view all the answers

What is the primary difference between binding and neutralizing anti-drug antibodies (ADA)?

Binding ADA interacts with drugs without inhibiting target binding. Signup and view all the answers

Which of the following impacts can both binding and neutralizing ADA have?

Impact on pharmacokinetics. Signup and view all the answers

What term is used to describe anti-drug antibodies that can be detected based on their effects on pharmacokinetics?

Clearing ADA Signup and view all the answers

What is typically expected regarding plasma drug concentrations when clearing ADA develop?

Rapid decrease in plasma drug concentrations. Signup and view all the answers

In terms of immunogenicity, what effect does neutralizing ADA have on drug efficacy?

It blocks the drug's interaction with its target. Signup and view all the answers

What are non-clearing ADA commonly referred to as?

Sustaining ADA Signup and view all the answers

What aspect of pharmacokinetics can be impacted by both types of anti-drug antibodies?

Drug elimination rates. Signup and view all the answers

Which statement accurately describes the impact of binding ADA on safety?

It may impact safety negatively. Signup and view all the answers

What defines immunogenicity in the context of therapeutic proteins?

The host immune response against a therapeutic protein Signup and view all the answers

How variable is the incidence of immunogenicity in biotherapeutics?

It ranges from 0% to nearly 50% of subjects Signup and view all the answers

What is typically included in the FDA-approved label of biotherapeutics concerning immunogenicity?

A section on adverse reactions Signup and view all the answers

What is pegloticase primarily used for?

Treating gout patients who do not respond to other treatments Signup and view all the answers

What usually affects the impact of immunogenicity on a biotherapeutic's safety and efficacy?

Stratification by ADA status Signup and view all the answers

What major effect did the nanoparticle show in clinical trials regarding pegloticase?

Reduced ADA development against pegloticase Signup and view all the answers

What is one mechanism by which anti-drug antibodies (ADA) affect drug safety and efficacy?

Neutralizing drug activity Signup and view all the answers

What are the two main types of anti-drug antibodies (ADA)?

Neutralizing and binding Signup and view all the answers

What may accelerate drug elimination due to immunogenicity?

Formation of immune complexes Signup and view all the answers

In what way can immunogenicity data be presented in the labeling of biotherapeutics?

In a graphical presentation with pharmacokinetics Signup and view all the answers

Which factor is NOT mentioned as influencing immunogenicity?

Intensity of physical exercise Signup and view all the answers

What approach is suggested to potentially restore tolerance to immunogenic biologics?

Antigen-specific mechanistic approaches with immune components Signup and view all the answers

Which factor does NOT contribute to the variability in the incidence of immunogenicity?

Type of insurance coverage Signup and view all the answers

What is the primary benefit of low dose methotrexate in combination with adalimumab?

Reduces ADA development and increases serum adalimumab concentrations Signup and view all the answers

Which of the following medications can reduce ADA development alongside adalimumab?

Rituximab Signup and view all the answers

What is a potential downside of long-term treatment with immunosuppressives?

Increased risk of infection and other side effects Signup and view all the answers

What are T cell epitopes responsible for in the body?

Binding to T-cell receptors and triggering immune responses Signup and view all the answers

How does the content of T cell epitopes affect immunogenicity?

More content generally leads to a higher risk of immunogenicity Signup and view all the answers

What type of tools are available to help predict immunogenicity?

In silico tools Signup and view all the answers

Which is NOT a recognized method to reduce ADA development?

Increased doses of adalimumab Signup and view all the answers

What role do in silico tools focus on when assessing immunogenicity?

Identifying T-cell and B-cell epitopes Signup and view all the answers

Study Notes

Immunogenicity

Immunogenicity is the host's immune response to a therapeutic protein.
All biotherapeutics address immunogenicity in the FDA-approved label (Section 6.2).
Immunogenicity is highly variable in occurrence.
Incidence can range from 0% to almost 50% of studied subjects.

Reporting Immunogenicity

Immunogenicity data is typically included in the label of biotherapeutics, though the amount of information varies.
Data is often visually displayed with pharmacokinetics and efficacy to illustrate the impact of immunogenicity.
Data is stratified by ADA status to quickly identify the impact of immunogenicity.

Effects of Immunogenicity

ADA can affect safety and efficacy in a variety of ways.
Typically, the presence of ADA reduces both efficacy and safety.
Impact arises through these key mechanisms:
- Neutralizing drug activity
- Accelerating drug elimination
- Formation of immune complexes

Anti-Drug Antibody Types

Binding ADA: Interacts with the drug molecule, but does not inhibit its binding to the target.
- May influence pharmacokinetics.
- May impact safety.
Neutralizing ADA: Directly blocks interaction of the drug with its target.
- Loss of efficacy.
- May impact pharmacokinetics.
- May impact safety.

Clearing ADA

Binding and neutralizing ADA can be categorized as ‘clearing’ based on their effect on pharmacokinetics.
Non-clearing ADA are also referred to as ‘sustaining’ ADA
Typically seen with clearing ADA:
- Rapid decrease in plasma drug concentrations after ADA development.
- Decreased plasma concentration after multiple doses even though accumulation is expected.

Immunogenicity Causes

The host immune response to the drug as ‘non-self’ is the core cause.
This is influenced by numerous factors such as molecular, product, antigen, and patient factors.

Physiologic Drivers of Immunogenicity

Immunogenicity is thought to be primarily T-cell dependent.
The context of presentation to T-cells is a key driver of response.
- Presentation to Thelper cells promotes ADA generation.
- Presentation to Treg cells limits ADA generation.
Amino acid sequences known as ‘T cell epitopes’ and ‘Tregitopes’ influence the type of immune response.

Anti-Inflammatory Drugs and Immunogenicity

Low dose methotrexate reduces ADA development to adalimumab in patients.
Methotrexate is commonly used as an anti-inflammatory in rheumatoid arthritis treatment.
In combination with adalimumab, methotrexate reduces ADA incidence in a dose-dependent manner and increases serum adalimumab concentrations.
Other immunosuppressive agents, including corticosteroids and B-cell depleting agents, have also been shown to reduce ADA development.

A Priori Prediction of Immunogenicity

T-cell epitopes are presented by MHC and bind to the T-cell Receptor.
A higher content of T cell epitopes generally leads to a higher risk of immunogenicity.
In silico tools are available to predict potential immunogenicity.

Clinical Trial of NP Co-Delivery of Antigen/Rapamycin

Pegloticase, a PEGylated uricase used to treat gout, is highly immunogenic.
Clinical trials showed that nanoparticle delivery reduced ADA development against pegloticase.
This allowed for sustained improvement in disease severity.

Summary

Immunogenicity can negatively impact the pharmacokinetics, safety, and efficacy of biologics.
The primary types of ADA are ‘neutralizing’ and 'binding'.
Immunogenicity is a complex interplay between drug, formulation, patient, and disease factors, which makes prediction challenging.
Antigen-specific approaches that involve cellular components of the immune system are being developed to restore tolerance.

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Description

This quiz explores the concept of immunogenicity, focusing on the immune response to therapeutic proteins. It examines the reporting of immunogenicity data, its effects on drug safety and efficacy, and the types of anti-drug antibodies involved. Enhance your understanding of how immunogenicity impacts biotherapeutic treatments.