What’s been Hapten-ing over the last 88 years?

Abstract

Definition of the relationship between drug protein adduct formation (haptenation) and development of immunological adverse drug reactions (drug hypersensitivity) has been an area of active research for over 80 years. The hapten hypothesis which states that “immunogenicity of low molecular weight organic chemicals is dependent on modification of self-proteins,” evolved from Landsteiner and Jacob’s discovery of a correlation between the reactivity of dinitro-halogenated benzenes and their sensitization potential. The hypothesis rapidly evolved to encompass drugs that often require metabolic activation to generate electrophilic, protein-reactive intermediates. As tissue culture methods advanced, the importance of drug hapten-specific T-cells in the disease pathogenesis was defined. This led to a plethora of studies describing the uptake and processing of drug(metabolite) protein adducts by antigen presenting cells, and the subsequent surface display of hapten-modified peptides in the context of MHC molecules. Although the pathway of hapten-specific T-cell activation is now well established, several questions need to be addressed: first, what is the nature of the hapten-modified peptides displayed by MHC? Second, how many of these peptides stimulate T-cells?; third, what are the critical protein modifications involved in T-cell activation; and finally, what is the role of hapten-specific T-cells in the iatrogenic disease? These questions will become increasingly important as more and more targeted covalent binding inhibitor drugs are approved for human use. In this review, we provide a brief synopsis of hapten research and then describe the approaches used by Pharma and academia to study hapten covalent binding and the role of drug protein adducts in the activation of human T-cells.

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM

“…1,2,4 Exposure to very low levels of a certain RM might even, in fortunate cases, lead to tolerance development and no or minor IADRs. 3 As has been reported many times, RMs can react with biomolecules to cause other unfortunate consequences than IADRs. Most noted are other nonidiosyncratic reactions such as carcinogenicity, mutagenicity, and drug−drug interactions caused by time-dependent inhibition (TDI/MBI) of cytochrome P450 enzymes.…”

“…Intrinsic reactivity, in contrast, is usually easier to recognize and is sometimes part of the mechanism of action, for example in the beta-lactams and covalent kinase inhibitors. Like for other types of immune response, there is no fixed level of RM formation/concentration that can be considered safe even when a crude dose–response relation exists; low-dose drugs have a better track record in this regard and it is always desirable to minimize the “body burden” of covalent bonding. ,, Exposure to very low levels of a certain RM might even, in fortunate cases, lead to tolerance development and no or minor IADRs …”