Pharmaceutical development and clinical application of radiolabeled rituximab

Abstract

Monoclonal antibodies have proven their significant role in the treatment of malignant and benign diseases. Next to their therapeutic role, monoclonal antibodies also offer the application of radioimmunoscintigraphy and radioimmunotherapy. The basic concept is to use monoclonal antibodies as a carrier to transport a radionuclide to the target sites, exploiting the mechanism of selective binding of the antibody to an antigen. These antibody-based modalities require the development and the use of radiolabeled monoclonal antibodies. We have developed and validated an improved method for labeling and purification of radiolabeled rituximab, a chimeric anti-CD20 monoclonal antibody. The integrity and immunoreactivity of rituximab were largely preserved (70%) and thus the radiolabeled product could be used for further clinical studies. The method is applicable for low doses as well as high doses of radioactivity. The labeling process was accompanied by a low and acceptable radiation exposure to involved personnel. We have demonstrated a robust product for both therapy and imaging. In an ongoing clinical trial, 2 patients received 131I-rituximab. The first patient was scheduled for radioimmunotherapy as consolidation therapy after remission induction treatment, unexpectedly showed no targeting of 131I-rituximab in a remaining proven vital and CD20 positive lymphoma lesion. In the second patient, acceptable targeting was found after which he received a therapeutic dose. This case demonstrated the feasibility of this therapy, and the predictable pharmacokinetics of 131I-rituximab supports the safe use of this treatment strategy. However, no response to the radioimmunotherapy was found. The clinical application of the radioconjugate as radioimmunotherapeutic agent revealed unexpected new insights that emphasizes the need for further research to find the optimal target population and time point. For this, radiolabeled rituximab can be used for diagnostic imaging to assist in optimal treatment selection. Radiolabeling rituximab with 124I allows imaging with positron emission tomography, a technique that provides wholebody imaging with better sensitivity and spatial resolution than conventional scintigraphy, in a 3-dimensional and quantitative approach. Furthermore, using a combined PET and computed tomography (PET/CT) system, the biodistribution of the antibody can be correlated with anatomical structures. We have investigated the disposition of diagnostic doses of 124I-rituximab in patients with rheumatoid arthritis with or without pretreatment with unlabeled rituximab. We have shown that a diagnostic dose of 50 MBq of 124I-rituximab has favorable physical properties and pharmacokinetics for imaging over several days. However, our results also indicated that prior dosing with unlabeled rituximab is crucial, to avoid elimination of the tracer molecule due to targeting of the normal CD20 positive B-cell population in the spleen. Using this strategy, we were able to demonstrate the feasibility of CD20 antigen imaging using 124I-rituximab, for the detection of inflamed joints in rheumatoid arthritis patients. Whether 124I-rituximab can achieve good image quality and sensitivity in detection of lymphoma needs to be determined in further investigations. 124I-rituximab as radioimmunoscintigraphic agent for PET/CT imaging of the CD20 antigen is feasible and is promising for several clinical purposes. Interesting challenges lie ahead for further improvement of this application for imaging.