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.

Keywords: ADA, anti-drug antibody; CDR, complementarity-determining region; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumor necrosis factor; VH, variable heavy; VL, variable light; allotype; anti-drug antibodies (ADA); glycan; idiotype; immunogenicity; pre-existing antibodies; rheumatoid factor.

Figure 1.

Potentially immunogenic determinants of antibodies. (A) An IgG antibody consists of variable domains (orange/red) and constant domains (gray). Chimeric, humanized and human therapeutic antibodies all contain human constant domains that may carry allotypic determinants. The variable domains can be subdivided in complementarity determining regions (CDRs) that are primarily involved in antigen binding and are highly variable, and framework regions (FRs) that are much less variable. The variation is partially germ-line encoded, partially the result of junctional variation and partially the result of somatic hypermutation. In chimeric antibodies the framework regions are of murine origin, whereas in humanized and human antibodies the framework regions will be largely human. Both CDRs and FRs can contain clone-specific determinants (idiotopes). Furthermore, in case of chimeric antibodies, the FRs may also contain murine-specific determinants (xenotopes). The variable domains may also express N-glycosylation sites that can contain non-human glycans depending on the expression system used to produce the therapeutic antibody. (B) Antibody fragments such as Fab (left) or single VH domains (right) will have regions exposed that are not exposed in an intact IgG antibody that can serve as neo-epitopes. In particular, anti-hinge antibodies can bind to a truncated hinge but will not bind intact IgG. (C) The antigenic trigger for rheumatoid factors is not known, but they might form in response to IgG-containing immune complexes.