Immunogenicity and Anti-Drug Antibodies

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Questions and Answers

What is the definition of immunogenicity?

The immune response generated by the host against a therapeutic protein (correct)

The effectiveness of a therapeutic protein in treating diseases

The level of toxicity in therapeutic proteins

The ability of a therapeutic protein to bind to its target

Which section of the FDA-approved label contains information about immunogenicity?

Section 3.1: Drug Interactions

Section 5.4: Clinical Pharmacology

Section 6.2: Adverse Reactions (correct)

Section 6.2: Immunogenicity

What is a characteristic of binding anti-drug antibodies (ADA)?

They can affect the pharmacokinetics of the drug. (correct)

They are responsible for a complete loss of drug efficacy.

They exclusively enhance the drug's effectiveness.

They block the drug's interaction with the target.

What is one of the consequences of neutralizing anti-drug antibodies?

Loss of efficacy of the drug Signup and view all the answers

Why is the study of immunogenicity important in biotherapeutics?

It helps predict adverse reactions and efficacy related to the immune response. Signup and view all the answers

What are immune-privileged sites primarily designed to protect?

Specific organs from immune responses Signup and view all the answers

Why is immune privilege in the testis crucial for male fertility?

It limits inflammation that could harm fertility Signup and view all the answers

How does the mother typically tolerate the presence of fetal antigens during pregnancy?

Through immunosuppression mechanisms Signup and view all the answers

What role do self antigens play in the context of immune privilege in the testis?

They are expressed after the immune system is developed Signup and view all the answers

Which of the following factors contributes to immune privilege in the placenta?

Presence of specialized barriers and immunosuppression Signup and view all the answers

What are examples of 'clearing' ADA based on their effects?

Both binding and neutralizing ADA Signup and view all the answers

What is indicated by the development of ADA in terms of plasma drug concentration?

A rapid decrease in plasma drug concentration Signup and view all the answers

How are non-clearing ADA commonly described?

As sustaining ADA Signup and view all the answers

Which type of T cells promote ADA generation?

Thelper cells Signup and view all the answers

What is considered a driver of immunogenic response in T cells?

Context of presentation to T cells Signup and view all the answers

What is the role of Treg cells in relation to ADA?

They limit ADA generation Signup and view all the answers

What are T cell epitopes and Tregitopes related to?

Immunogenic response Signup and view all the answers

What is a typical expectation concerning plasma drug concentrations with multiple dosing?

Decreased plasma concentrations Signup and view all the answers

What role do dendritic cells (DCs) play in the lamina propria?

Take up and process protein antigens from microbes. Signup and view all the answers

Which cytokines are important for the differentiation of bacterial antigen-specific Th17 cells?

IL-6 and IL-23 Signup and view all the answers

What promotes the differentiation of bacterial antigen-specific regulatory T cells (Tregs)?

TGF-β and retinoic acid Signup and view all the answers

How do keratinocytes contribute to the immune response in the epidermis?

They produce antimicrobial peptides and various cytokines. Signup and view all the answers

Where do the skin-homing properties of effector lymphocytes develop?

In skin-draining lymph nodes Signup and view all the answers

Which signaling factors are involved in the migration of effector T cells into the skin?

Homing molecules such as CCR4, CCR8, and CCR10 Signup and view all the answers

What is the primary function of the epidermis in relation to microbes?

Provide a physical barrier to microbial invasion. Signup and view all the answers

What initiates the expression of CCR10 in the skin?

Ultraviolet rays in sunlight (UVB) Signup and view all the answers

What is the role of intestinal epithelial cells in the gastrointestinal immune system?

They are involved in responses to pathogens and antigen sampling. Signup and view all the answers

Where are M cells primarily located within the gut?

In the regions overlying Peyer’s patches. Signup and view all the answers

What distinguishes M cells from absorptive epithelial cells?

M cells exhibit large fenestrations in their membranes. Signup and view all the answers

What characteristic role do the lymphocytes play following their differentiation in lymphoid tissues?

They acquire gut-homing properties. Signup and view all the answers

What type of tissues induce dendritic cells in the gut?

Gut-associated lymphoid tissues (GALT). Signup and view all the answers

What is the primary composition of the gastrointestinal system's structure?

A tube-like structure lined by epithelial cells. Signup and view all the answers

Which of the following statements about M cells is true?

M cells are fewer in number compared to absorptive epithelial cells. Signup and view all the answers

What function does the lamina propria serve in relation to the epithelial layer?

It contains blood and lymphatic vessels. Signup and view all the answers

Study Notes

Immunogenicity

Immunogenicity is the host immune response against a therapeutic protein
Typically, immunogenicity is studied in the context of anti-drug antibody (ADA) formation
All FDA-approved biotherapeutics include a section on immunogenicity in their label (section 6.2) under Adverse Reactions

Anti-Drug Antibodies

There are two main classes of ADAs: binding and neutralizing
Binding ADAs interact with the drug molecule but do not inhibit its binding to the pharmacologic target
- Binding ADAs may impact pharmacokinetics and safety

Neutralizing ADAs

Neutralizing ADAs directly block the interaction of a drug with its pharmacologic target
- Neutralizing ADAs result in loss of efficacy, impact pharmacokinetics, and may impact safety

'Clearing' ADAs

Both binding and neutralizing ADAs can be categorized as 'clearing'
'Clearing' ADAs are detected based on their effects on pharmacokinetics
Non-clearing ADAs are also referred to as 'sustaining' ADAs
- A typical expectation is a rapid decrease in plasma drug concentrations upon ADA development
- Decreased plasma concentrations following multiple dosing (typical expectation is accumulation)

Physiologic Drivers of Immunogenicity

Immunogenicity is largely thought to be a T-cell dependent phenomenon
- The context of presentation to T cells is likely a driver of the ultimate response
- Presentation to T helper cells leads to ADA generation
- Presentation to Treg cells limits ADA generation

The Gastrointestinal Immune System

Intestinal epithelial cells lining the small and large bowel are part of the gastrointestinal innate immune system involved in responses to pathogens and antigen sampling
- The gastrointestinal system is a tube-like structure lined by a continuous epithelial cell layer that serves as a physical barrier
- The lamina propria underlies the epithelium, containing blood vessels, lymphatic vessels, and MALTs

M Cells

M cells are located in regions of the gut epithelium called follicle-associated (or dome) epithelium
Antigen may be delivered from the lumen to the GALT through specialized cells called M cells
M cells have a thin glycocalyx, short irregular microvilli, and large fenestrations in their membranes, enhancing antigen uptake from the gut lumen

Homing Properties of Intestinal Lymphocytes

The gut-homing properties of effector lymphocytes are imprinted in lymphoid tissues
- DCs in GALT are induced by cytokines
- DCs in the lamina propria take up and process protein antigens from microbes and transport them to mesenteric lymph nodes

Effector and Regulatory T Cells in the Intestinal Mucosa

Different subsets of effector CD4+ T cells in the gastrointestinal tract are induced by and protect against different microbial species
Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa
- Bacterial antigen-specific Th17 cells differentiate from naive CD4+ T cells in GALT in response to antigens presented by DCs
- Differentiation of bacterial antigen-specific regulatory T cells is promoted by TGF-β and retinoic acid
- Thymic Tregs that migrate to the intestine expand under the influence of bacterial metabolites

The Cutaneous Immune System

The epidermis provides a physical barrier to microbial invasion
- The epidermis is made up of keratinocytes
Keratinocytes actively respond to pathogens by producing antimicrobial peptides and cytokines

Homing Properties of Cutaneous Lymphocytes

The skin-homing properties of effector lymphocytes are imprinted in skin-draining lymph nodes
Ultraviolet rays in sunlight stimulate vitamin D production
IL-12 induces the expression of E-selectin ligand CLA, and other signals induce CCR4, CCR8, and CCR10 expression

Immune-Privileged Tissues

Immune responses and associated inflammation in certain parts of the body, including brain, eye, testes, placenta, and fetus, carry a high risk for lethal organ dysfunction
These tissues are called immune-privileged sites

Immune Privilege in the Testis

Immune privilege in the testes limits inflammation that may impair male fertility
- Many self-antigens in the testes are first expressed at puberty, so it is unlikely lymphocytes specific for these antigens are deleted during development
Immune privilege in the testes may also prevent autoimmunity

Immune Privilege and the Fetus

The fetus expresses paternally inherited genes that are foreign to the mother
The mother is exposed to fetal antigens during pregnancy, and maternal antibodies against paternal MHC molecules are detectable
- Different molecular and barrier features of the placenta contribute to immune privilege in the fetus

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Description

This quiz explores the concepts of immunogenicity, focusing on the immune responses to therapeutic proteins. It covers the different classes of anti-drug antibodies, including binding and neutralizing antibodies, as well as their implications on pharmacokinetics and drug efficacy. Understanding these mechanisms is crucial for evaluating the safety and effectiveness of biotherapeutics.