Idiotypic-anti-idiotypic complexes and their in vivo metabolism

Abstract

BACKGROUND Different strategies can be used to improve the tumor:non‐tumor ratio of radiolabeled antibodies in immunotargeting. One approach is to use secondary antibodies to clear out redundant, circulating primary antibodies. In the current study, the in vitro complex formation and in vivo clearing capabilities and metabolism of the monoclonal antibody TS1 and its monoclonal anti‐idiotype, αTS1, were studied. METHODS Complex formation studies were performed using polyacrylamide gel electrophoresis (PAGE), gel permeation chromatography, and electron microscopy. The clearance and metabolism of the complexes were studied in nude mice. RESULTS PAGE and gel permeation chromatography showed that more than 70% of the antibodies formed complexes. The electron microscopy studies revealed that the complexes formed between TS1 and αTS1 are mainly ring‐shaped (66.6–73.4%), comprising 4 to > 8 antibodies. These rings consist of equal numbers of idiotype and anti‐idiotype. The most commonly observed complexes were tetrameric rings (26.8–40.5%), hexameric rings (10.7–11.9%), and rings containing more than eight monoclonal antibodies (6.6–14‐4%). The in vivo study illustrated that within 24 hours 80% of the total nuclide content had been degraded and excreted via the urine, compared with 25% for similarly treated mice that did not receive any anti‐idiotype. CONCLUSIONS Interestingly, the electron microscopy study demonstrated that dimers were rare (0.4–1.2%), probably reflecting a location of epitopes incompatible with tight, sterically constrained dimeric interactions; insufficient flexibility of the immunoglobulin G1 subtype hinge regions; or both. The anti‐idiotypic clearing mechanisms proved efficient in nude mice. In vivo metabolic studies indicate that the accumulation and degradation of TS1/αTS1 immune complexes, to a large extent, take place in the liver, where a substantial amount was detected as soon as 1 hour after anti‐idiotype injection. Cancer 2002;94:1306–13. © 2002 American Cancer Society. DOI 10.1002/cncr.10301

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

“…As formation of these complexes in vivo could be impacted by the antibody dose and affinity (more stable complexes can form with higher affinity antibodies), it is possible that increases in antibody-antigen binding in circulation may translate into lower serum and tissue exposure when a more rapid clearance of the complex is anticipated. This hypothesis is supported by previous experimental data demonstrating formation of large immune complexes in mice following simultaneous administration of a therapeutic antibody with its anti-idiotypic counterpart (43). As suggested by theoretical simulations shown in Fig.…”

A White Paper—Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements

“…There are two possible scenarios in which ADA can alter the PK of biotherapeutic drugs: 1. ADA reducing the drug exposure (11)(12)(13)(14), and 2. ADA can increase the drug exposure (15,16).…”

“…However, evidence of both mechanisms exists. For example, ADA-mediated assay interferences have been identified through the use of orthogonal PK assay formats that are applied to identical ADA-positive study samples (20,21 125 -labelled anti-idiotypic antibody increased as the molar stoichiometry of the anti-idiotypic antibody and target antibody increased, presumably due to the enhanced uptake and destruction by macrophages when antibodies are cross-linked in higher-order complexes (14).…”

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

“…Second, the ADA could alter the PK of the compound. It has been shown that the formation of immune complexes between ADA and the administered mAb can change the biodistribution of mAb and lead to faster clearance (41,42). Lastly, circulating ADA could effectively compete with the binding of mAbs and interfere with analytical assays.…”