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Cross-reactive and pre-existing antibodies to therapeutic antibodies--Effects on treatment and immunogenicity.

ABSTRACT: The potential for immunogenicity is an ever-present concern during the development of biopharmaceuticals. Therapeutic antibodies occasionally elicit an antibody response in patients, which can result in loss of response or adverse effects. However, antibodies that bind a drug are sometimes found in pre-treatment serum samples, with the amount depending on drug, assay, and patient population. This review summarizes published data on pre-existing antibodies to therapeutic antibodies, including rheumatoid factors, anti-allotype antibodies, anti-hinge antibodies, and anti-glycan antibodies. Unlike anti-idiotype antibodies elicited by the drug, pre-formed antibodies in general appear to have little consequences during treatment. In the few cases where (potential) clinical consequences were encountered, antibodies were characterized and found to bind a distinct, unusual epitope of the therapeutic. Immunogenicity testing strategies should therefore always include a proper level of antibody characterization, especially when pre-formed antibodies are present. This minimizes false-positives, particularly due to rheumatoid factors, and helps to judge the potential threat in case a genuine pre-dose antibody reactivity is identified.

SUBMITTER: van Schie KA

PROVIDER: S-EPMC4623040 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:BackgroundEpidemic viral diseases have become more prevalent.. Among the various strategies to prevent such epidemics, vaccination is the most cost-effective. However, populations that are immunized are typically already exposed to multiple previous vaccinations or natural infections. Studies from this and other laboratories have revealed that pre-existing dengue antibodies can either inhibit or enhance subsequent dengue infection depending on the pre-existing antibody levels. While cross-reactive antibody is potentially pathogenic in dengue, how it impacts immune response to vaccination is unclear. Aggregated at the site of vaccination and the respective draining lymph nodes are antigen-presenting and immune regulatory cells that express Fc receptors and play pivotal roles in determining the magnitude and polarity of the immune response. Vaccine uptake by these antigen-presenting cells may thus be either inhibited or enhanced when vaccines are opsonized with cross-reactive antibodies.DesignIn view of the limited knowledge on how cross-reactive antibodies affect vaccination outcome, we propose a study that exploits the known cross reactivity between Japanese encephalitis (JE) virus antibody and yellow fever (YF) vaccine. We hypothesize that cross-reactive antibodies impact antibody response to YF at the point vaccination in a concentration-dependent manner by altering both vaccine uptake and the innate immune response by antigen presenting cells. We will structure an open-label clinical trial on sequential vaccination with JE and YF vaccines, with different time intervals between vaccinations. This would test immune response to YF vaccination in subjects with different titer of cross-reactive JE vaccine-derived antibodies. The clinical materials obtained in the trial will drive basic laboratory investigations directed at elucidating how heterologous antibody affect vaccination at the molecular level. YF neutralizing antibody titer will be measured using plaque reduction neutralization test against the vaccine strain YF17D. Innate immune response will be characterized genetically using either microarray or digital PCR (or both). The innate immune response will also be characterized at the protein and metabolite level using Luminex bead technology and lipidomic/metabolomic approaches.DiscussionThis proposed study represents one of the first to examine the role of cross-reactive antibodies in modulating immune responses to vaccines, the findings of which may re-shape vaccination strategy.Trial registrationClinical Trials.gov registration number: NCT01943305 (3 September 2013).

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Cross-reactive and pre-existing antibodies to therapeutic antibodies--Effects on treatment and immunogenicity.

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