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

Abstract

Biological molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However, by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. In the context of immune-mediated adverse effects that have been documented to biological drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biological drugs in instances where there have been immune-mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs) elicited in vivo to a biotherapeutic; alongside with the structural, biophysical, and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However, many of the immune-mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex (IC) intermediate that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing ICs, risk factors that are intrinsic either to the therapeutic molecule or to the host that might predispose to IC-mediated effects, and review the recent literature on prevalence and intensity of established examples of type II and III hypersensitivity reactions that follow the administration of a biotherapeutic. Additionally, we propose methods for the study of immune parameters specific to the biology of ICs that could be of use in conjunction with the detection of ADAs in circulation.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

“…56 Measurement of ADA in animal models is undertaken within the PK/PD studies to inform the relevant PK and IgG data (unaffected by ADA) that could be used to guide dose selection in the first in human study, and to ensure that a sufficient number of animals are adequately exposed to the test item, to enable derivation of toxicological effects; the frequency of ADA is not representative or translatable into humans. The ADAs identified in rozanolixizumab-treated cynomolgus monkeys possibly contributed to the gradual loss of PD observed in some repeat-dosed animals after an initial period of efficacy of ~ 10 days or longer during which the ADA response was mounted.…”

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

“…Immunogenic responses can lead to the production of anti-drug antibodies that can mediate rapid clearance or neutralization of the drug's activity [74]. Such immunogenic reactions not only lead to loss of drug efficacy, but also can cause severe adverse reactions.…”

Murinization and H Chain Isotype Matching of the Anti-GITR Antibody DTA-1 Reduces Immunogenicity-Mediated Anaphylaxis in C57BL/6 Mice

“…Strategies to mitigate risk factors from the clinical use of human protein therapeutics (i.e., humanization, CDR modification, formulation, biophysical characteristics, routes of delivery, etc.) should also be applied to anti-mouse Abs (56)(57)(58)(59)(60)(61). Currently, no serious immune-related adverse events have been reported in phase I clinical trials of humanized anti-GITR agonistic Abs (62,63).…”