Immunogenicity/Hypersensitivity of Biologics

Abstract

This continuing education course was designed to provide an overview of the immunologic mechanisms involved in immunogenicity and hypersensitivity reactions following administration of biologics in nonclinical toxicity studies, the methods used to determine whether such reactions are occurring, and the associated clinical and anatomic pathology findings. Hypersensitivity reactions have classically been divided into type I, II, III, and IV reactions; type I and III reactions are those most often observed following administration of biologics. A variety of methods can be used to detect these reactions. Antemortem methods include hematology; detection of antidrug antibodies, circulating immune complexes and complement fragments, and immunoglobulin E in serum; tests for serum complement activity; and evaluation of complement receptor 1 on erythrocytes. Postmortem methods include routine light microscopy and electron microscopy, which can demonstrate typical findings associated with hypersensitivity reactions, and immunohistochemistry, which can detect the presence of immune complexes in tissues, including the detection of the test article. A final determination of whether findings are related to a hypersensitivity reaction in individual animals or across the entire study should rely on the overall weight of evidence, as findings indicative of these reactions are not necessarily consistent across all affected animals.

Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

“…There are four classes of HSRs generally recognized according to the revised Gell and Coombs' classification (Pichler 2007; reviewed in Leach et al 2014):…”

“…TEM is most informative when glomerular deposits are identified in kidney glomeruli; however, only small numbers of glomeruli can be examined (Leach et al 2014). …”

“…Changes in veins or venules are less frequent but have been observed in infusion reactions (e.g., case 2 monkey 2A) and might be associated with acute, rapid IC formation in animals with high ADA. Vascular/perivascular inflammation also has been associated with sites of turbulent blood flow (e.g., heart valve; Leach et al 2014). Choroid plexus is also a site of 746 ROJKO ET AL.…”

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

“…During research and early development of new therapeutic biologics, animal studies are required to assess their efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) properties, and safety. Since therapeutic biologics are usually human or humanized proteins, they can be perceived as foreign in nonclinical species and elicit an immune response (1). The immune response usually leads to the formation of drug-specific antidrug antibodies (ADA)-the measurable hallmark of immunogenicity.…”

“…The formation of ADA can have impact on safety, efficacy, and PK of a therapeutic protein. ADA-driven effects on safety include hypersensitivity reactions (1,2), whereas the efficacy of the therapeutic protein can be affected in two different ways: either by reducing or eliminating its biological activity or by changing its PK properties and thus altering exposure. The former effect is caused by ADA binding to the epitopes on the therapeutic protein that are essential for biological activity (so-called neutralizing antibodies), while all ADA, both neutralizing and non-neutralizing, may change clearance of the therapeutic protein.…”