Generation of Anti-Idiotype Antibodies for Application in Clinical Immunotherapy Laboratory Analyses
- 1 August 2003
- journal article
- research article
- Published by Mary Ann Liebert Inc in Hybridoma and Hybridomics
- Vol. 22 (4), 219-228
- https://doi.org/10.1089/153685903322328947
Abstract
The chimeric monoclonal antibody ch806 specifically targets the tumor-associated mutant epidermal growth factor receptor (de 2-7EGFR or EGFRVIII) and is currently under investigation for its potential use in cancer therapy. The humanised monoclonal antibody hu3S193 specifically targets the Lewis Y epithelial antigen and is currently in Phase I clinical trials in patients with advanced breast, colon, and ovarian carcinomas. To assist the clinical evaluation of ch806 and hu3S193, laboratory assays are required to monitor their serum pharmacokinetics and quantitate any immune responses to the antibodies. Mice immunized with ch806 or hu3S193 were used to generate hybridomas producing antibodies with specific binding to ch806 or hu3S193 and competitive for antigen binding. These anti-idiotype antibodies (designated Ludwig Melbourne Hybridomas, LMH) were investigated as reagents suitable for use as positive controls for HAHA or HACA analyses and for measuring hu3S193 or ch806 in human serum. Anti-idiotypes with the ability to concurrently bind two target antibody molecules were identified, which enabled the development of highly reproducible, sensitive, specific ELISA assays for determining serum concentrations of hu3S193 and ch806 with a 3 ng/mL limit of quantitation using LMH-3 and LMH-12, respectively. BIAcore analyses determined high apparent binding affinity for both idiotypes: LMH-3 binding immobilized hu3S193, Ka = 4.76 × 108 M-1; LMH-12 binding immobilised ch806, Ka = 1.74 × 109 M-1. Establishment of HAHA or HACA analysis of sera samples using BIAcore was possible using LMH-3 and LMH-12 as positive controls for quantitation of immune responses to hu3S193 or ch806 in patient sera. These anti-idiotypes could also be used to study the penetrance and binding of ch806 or hu3S193 to tumor cells through immunohistochemical analysis of tumor biopsies. The generation of anti-idiotype antibodies capable of concurrently binding a target antibody on each variable domain provides reagents with high sensitivity for the assessment of safety and pharmacokinetic profiles of target antibodies administered clinically.Keywords
This publication has 15 references indexed in Scilit:
- Specific Targeting, Biodistribution, and Lack of Immunogenicity of Chimeric Anti-GD3 Monoclonal Antibody KM871 in Patients With Metastatic Melanoma: Results of a Phase I TrialJournal of Clinical Oncology, 2001
- The epidermal growth factor receptor as a target for cancer therapy.Endocrine-Related Cancer, 2001
- Clinical trials of antibody therapyImmunology Today, 2000
- Antibody humanization: a case of the ‘Emperor’s new clothes’?Immunology Today, 2000
- ZD1839 (???Iressa???)*,??? as an Anticancer AgentDrugs, 2000
- Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosidesInternational Journal of Cancer, 1997
- Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250.Journal of Clinical Oncology, 1997
- Specificity analysis of blood group Lewis-y (Le(y)) antibodies generatedagainst synthetic and natural Le(y) determinants.Proceedings of the National Academy of Sciences, 1994
- Internal image anti-idiotype antibodies related to renal-cell carcinoma-associated antigen G250International Journal of Cancer, 1994
- Growth Factors and CancerScience, 1991