Detection of Human Antibodies Generated Against Therapeutic Antibodies Used in Tumor Therapy

Jochen Reinsberg Summary

Application of monoclonal antibodies (MAb) for therapeutic purpose may induce the formation of human antibodies directed against the immunogenic epitopes, which are presented on the therapeutic MAb. Formation of such human antibodies mostly is an undesired side effect, but in the case of newly developed immunotherapeutic tumor treatment strategies it represents the underlying therapeutic effect. Especially the formation of so-called "internal image" antibodies, which are directed against the antigen-combining site (paratope) of the therapeutic antibody, is supposed to evoke specific immune responses against tumor antigens mediated via idiotype-anti-idiotype interactions within the immunoregulatory network. For the monitoring of the immune response after antibody application, the newly formed human antibodies can be measured with immunoassay procedures involving the applied therapeutic antibody as test antibody. Because the original antigen is directed against the therapeutic antibody and inhibits the binding of "internal image" antibodies, a special assay design is needed to avoid interferences with samples containing the antigen. We describe an immunoassay procedure that allows the correct quantification of antiidiotypic antibodies including "internal image" antibodies that are not affected by the original antigen or other serum components that may interact with the therapeutic antibody.

Key Words: Antiidiotypic; antiiso/allotypic; immunotherapy; "internal image"; idiotypic network; immune response.

1. Introduction

Facilitated by their better availability monoclonal antibodies (MAbs) are increasingly used for therapeutic purposes. Especially for the therapy of neoplasm MAbs are applied either conjugated with cytotoxic agents or in native form (1-7). In every case, antibody application may induce the formation of human antibodies directed against the immunogenic iso-, alio-, and idiotypic epitopes presented on the therapeutic MAb. For therapy with conjugated antibodies the formation of such human antibodies is an undesired side effect that negatively affects the pharmacokinetics and may diminish therapeutic activity (8-10). However, in the last year different immunotherapeutic treatment strategies have been developed for cancer therapy intended to induce a tumor-specific humoral response of the host organism by triggering the idiotypic network, which leads to formation of a cascade of highly specific antiidiotypic antibodies (11-14).

Antiidiotypic antibodies are directed against idiotypic epitopes (idiotopes), which are formed by the hypervariable region on the Fab portion of an antibody and, which are unique and representative for the specific antibody clone. Thus, antiidiotypic antibodies formed after antibody therapy react highly specific with the therapeutic antibody. A subset of antiidiotypic antibodies bind to the antigen-combining site (paratope) of the therapeutic antibody. These so-called "internal image" antibodies can functionally mimic a part of the three-dimensional structure of the original antigen (15) and their binding to the therapeutic antibody is inhibited by the antigen. For the immunotherapeutic treatment strategies the formation of "internal image" antibodies plays an essential role; it is supposed that vaccination with adequate antibodies may evoke specific immune responses against tumor antigens mediated via idiotype-anti-idiotype interactions of "internal image" antibodies within the immunoregulatory network (11-16).

Formation of human antibodies against isotypic and allotypic epitopes that are located on the constant regions of the Fc and the Fab portions of the antibody only occurs when therapeutic antibodies with immunogenic nonself iso/allo-types are administered. Thus, the vast majority of MAbs clinically used for targeted cancer therapy are humanized to evade antiiso/allotypic immune responses and to minimize the immunogenicity of the antibodies, but in some cases antiidiotypic immune responses have been observed also with humanized antibodies (17,18). On the other hand, for the immunotherapeutic concept an immune response with antibody formation represents the desired effect so that therapeutic antibodies with high immunogenicity are required. In every case, monitoring of the immune response to antibody application by measuring the newly formed human antibodies is a useful tool to assess the course of therapy. Especially for immunotherapy it is important to discriminate the newly formed antibodies according to their specificity. Thus, assay systems are needed that can specifically detect antiiso/allotypic antibodies, antiidiotypic antibodies, and internal image antibodies, respectively.

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