Part 2
In the previous article in this series on ADAs, we discussed the historical background of antibody discovery and research. We also discussed the significance of ADAs in modern drug development.
In this instalment, we will be getting into the weeds of immunology and how ADAs play a role in it. So, tighten your belts.
FUNDAMENTAL IMMUNOLOGICAL CONCEPTS
Basic Principles of Immune Response
- Humoral Immunity
The development of anti-drug antibodies (ADAs) is fundamentally rooted in humoral immunity, representing a specific arm of the adaptive immune response. This process involves the recognition of therapeutic substances (mostly proteins) as potential harmful, foreign invaders (antigens), triggering a series of immunological events (Murphy & Weaver, 2022). The humoral immune response primarily operates through the production of antibodies (defensive proteins) by cells known as plasma cells. Plasma cells are produced when B-Cells recognise antigens (Goodnow et al., 2019).
- B-cell Response
B-cells activation can be in response to therapeutic substances in the body. The process begins with the B-Cell recognising specific portions of the therapeutic substance as foreign (Kumar et al., 2021). In response to this, the B-Cell absorbs the substance and processes it. In doing this, the therapeutic substance is recognised as a foreign substance and then marked for destruction. Another effect of the internal processing of therapeutic substances as antigens is that the body keeps a record of the structure of these substances to enable a quick response to them in future invasions. This is known as immunological memory.
- Immunological Memory
The development of immunological memory against therapeutic proteins represents a critical challenge in managing ADA responses. Memory B cells, generated during the initial exposure to the therapeutic protein, can persist for extended periods and rapidly reactivate upon subsequent exposures (Tangye & Tarlinton, 2021). This phenomenon explains the accelerated secondary immune responses observed in some patients receiving repeated doses of biologic therapies.
Mechanisms of ADA Formation
T-cell Dependent Response: The classical pathway of ADA formation typically involves specific cells known as T-cells, especially for large protein therapeutics. This process requires antigen presentation by cells known as Antigen Presenting Cells (APCs), followed by T-cell recognition of processed proteins. The process is facilitated by other molecules like cytokines that assist in the stimulation of ADA formations. The quality and magnitude of the T-cell help significantly influence the characteristics of the resulting ADA.
Independent Response: Some therapeutic proteins can antibody responses without T-Cells, particularly those that can directly activate B cells. This pathway typically results in the production of antibodies with low affinity for antigens and limited immunological memory (Zhang et al., 2019). However, recent studies have shown that some T-cell independent responses can lead to more robust and persistent ADA formation than previously recognized (Wilson & Baker, 2023).
Factors Influencing Immunogenicity
Product-related Factors: Several intrinsic properties of therapeutic proteins influence their potential for causing immune reactions. These properties include variations of the genetic sequence, variations in protein sequence, the presence of contaminating proteins and structural stability (Johnson et al., 2021).
Treatment-related Factors: The administration protocol significantly impacts ADA development through various factors including the route of administration, dose frequency, duration of treatment, concomitant medications, and storage and handling conditions (Smith & Thompson, 2022).
Patient-related Factors: Individual patient characteristics play crucial roles in determining ADA risk. These characteristics encompass genetic background (HLA haplotypes), immune status, concurrent diseases, previous exposure to similar proteins, and age and gender (Anderson & Lee, 2023).
ADA CHARACTERIZATION AND CLASSIFICATION
Types of Anti-Drug Antibodies
Neutralizing Antibodies: Neutralizing antibodies (NAbs) directly interfere with the therapeutic protein’s mechanism of action through binding to active sites, blocking receptor interaction, and preventing substrate access. These antibodies typically have the most significant impact on treatment efficacy (Williams et al., 2022).
Non-neutralizing Antibodies: Non-neutralizing antibodies (non-NAbs) bind to regions of the therapeutic protein without directly affecting its function. However, they can alter drug pharmacokinetics, form immune complexes, and influence drug biodistribution. Recent evidence suggests that non-NAbs may have more significant clinical implications than previously thought (Martinez & Cooper, 2023).
Cross-reactive Antibodies: Cross-reactive antibodies can recognize epitopes shared between the therapeutic protein and endogenous proteins, potentially leading to autoimmune responses, interference with natural biological processes, and unexpected adverse events (Peterson et al., 2022).
Structural Properties of ADA
Antibody Isotypes: ADA responses can involve multiple antibody types, each with distinct functional implications. These include IgM for early response with lower affinity, IgG which predominates in mature responses, IgE associated with hypersensitivity reactions, and IgA which is relevant for mucosal administration (Taylor & Brown, 2023).
Epitope Recognition: An epitope is a molecular region on an antigen that can cause an immune reaction. Understanding epitope recognition patterns is crucial for predicting immunogenicity, designing therapeutic alternatives and developing mitigation strategies. Modern epitope mapping techniques have revealed complex patterns of recognition that can evolve during treatment (Richardson et al., 2022).
Affinity and Avidity: The strength of ADA-drug interactions, determined by: Individual binding site affinity, multiple binding site avidity and maturation over time These parameters significantly influence the clinical impact of ADAs (Hughes & Parker, 2023)
Temporal Development Patterns of ADA
Early-onset Response: This is characterized by rapid development within the first month, often dominated by IgM, and may indicate pre-existing immunity. Early detection can guide treatment modification strategies (Chen et al., 2023).
Late-onset Response: This features delayed development occurring after 6 months, usually presenting as a more mature response, and is often more difficult to manage. Understanding the mechanisms of late-onset responses remains an active area of research (Thompson et al., 2023).
Transient vs. Persistent Response: The duration of ADA responses varies significantly, with transient responses potentially resolving spontaneously while persistent responses often require intervention. The factors determining persistence remain poorly understood. Recent longitudinal studies have provided new insights into the determinants of response duration (Watson & Liu, 2023).