Clinical immunotoxicity of therapeutic proteins

Abstract

Therapeutic proteins are proteins engineered in the laboratory for pharmaceutical use. Although they tend to offer a better safety margin than most synthetic small molecules because they are processed by the same pathways as natural proteins in the human body, or mimic or replace natural proteins that are missing or defective, they can induce a variety of adverse effects in human patients among which immunotoxic effects deserve particular attention. Infectious complications and virus-induced neoplasias are the main consequences of intended or unexpected immunosuppression. They have been primarily described with anti-TNF-α drugs and anticancer monoclonal antibodies (mAbs) whose immunosuppressive effects can be largely anticipated from their mechanism of action. Cytokine release-associated adverse reactions ranging from mild-to-moderate flu-like reactions to severe cytokine release syndromes, or exceptionally cytokine storm, are now an issue of chief concern. They have been observed with most of the therapeutic proteins in current use. Acute infusion reactions whose clinical features are somewhat similar have been variably described with many mAbs. Immunostimulatory properties are suspected to account for the occurrence of more frequent autoimmune diseases as seen in patients treated with recombinant cytokines such as the IFNs-α and rIL-2. The risk of more frequent hypersensitivity reactions to unrelated allergens is also suspected to be a potential consequence of immunostimulation but compelling evidence is limited to radiocontrast media-induced hypersensitivity reactions in IL-2 treated cancer patients. In addition, recombinant cytokines can inhibit cytochrome P450 dependent biotransformation pathways with resulting alterations in the pharmacokinetics of the combined drugs at therapeutic dose. Because of their structure and origin, therapeutic proteins are intrinsically immunogenic. Despite extensive laboratory and clinical studies that were instrumental in delineating general concepts about key factors involved in immunogenicity, it is impossible nowadays to anticipate to what extent a novel therapeutic protein will be immunogenic in human patients. Specific antibodies are frequently detected in the sera of treated patients. They are often inconsequential but can also be neutralizing and result in decreased efficacy. Anaphylactic reactions induced by human therapeutic proteins have been rarely reported and true serum sickness extremely rarely. Because the immunotoxic effects of therapeutic proteins are frequent, sometimes severe and even potentially life-threatening, there is an urgent need to improve our capacity to anticipate the immunotoxic risks of novel therapeutic proteins and this could be achieved by the development of clinical immunotoxicology.

Keywords::

• anti-TNF-α
• drugs
• autoimmunity
• clinical immunotoxicology
• cytokines
• hypersensitivity
• immunogenicity
• immunostimulation
• immunosuppression
• monoclonal antibodies
• therapeutic proteins