Immunogenicity and Anti-Drug Antibodies

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

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.