Antidrug Antibodies: B Cell Immunity Against Therapy

Abstract

Chronic inflammatory diseases are now treated with a range of different biopharmaceuticals, often requiring lifelong parenteral administrations. This exposure to drugs is unnatural and can trigger the immune system and result in the formation of antidrug antibodies. Drug-specific antibodies will, if of sufficiently high titre and affinity, block the intended effect of the drug, increase its clearance and make continued treatment worthless. We expect the immune system to react towards therapies against which tolerance has never been established, which is the case for factor VIII treatment in patients with haemophilia A. However, even biopharmaceutical molecules that we should be tolerant against can elicit antidrug antibodies, for instance in treatment of multiple sclerosis patients with recombinant human interferon-beta. Possible immunological mechanisms behind the breaking of tolerance against drugs, the impact this has on continuous treatment success, clinical practice and drug development, will be discussed in this review.

ACTH4-10 protects the ADR-injuried podocytes by stimulating B lymphocytes to secrete IL-10

“…In addition, according to the different responses of B cells to ACTH 4-10 and PMA, we hypothesized that B cells were not a simple type of inflammatory cells. B cells had a double-sided effect and could react differently to different stimuli, which was consistent with a previous study [29].…”

Immunogenicity to Biotherapeutics – The Role of Anti-drug Immune Complexes

“…Marginal zone splenic B cells or dendritic cells localized within tissue-specific compartments important for surveillance may capture and process aggregated therapeutic or ADA bound complexes of therapeutic leading to antigen presentation to T cells. These pathways illustrate how a seemingly low-affinity T-independent generated ADA from a primary immune response could lead to formation of a drug–ADA IC which in turn through uptake by Class II bearing B cells or APCs could activate T cells and thereby leading to further B cell activation, epitope spreading, clonal expansion, affinity maturation, and generation of higher affinity ADA (Figure 1 ) ( 10 , 16 ). The ICs formed early may also involve preexisting circulating IgM or IgG antibodies that recognize the biotherapeutic.…”

“…Preexisting antibodies that are predominantly IgM with low affinity and broad specificity are secreted by CD5+ B1-b cells ( 16 ). Such antibodies have been described against hinge regions and known to form complexes.…”

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

“…However, in spite of these multiple treatments, there still remains a significant proportion of RA patients who are either de novo poor responsive to biological DMARDs or acquire resistance due to the production of neutralizing anti-drug antibodies (ADAs) [14]. The lack of homogeneous response to treatment might be attributed to the heterogeneity of the disease [15].…”