Experimental approaches to increase radiolabeled antibody localization in tumors

Academic Article

Abstract

  • Approaches have been developed to improve the localization of radiolabeled monoclonal antibodies (MAbs) in experimental tumors, to reduce their uptake in normal tissues, and, thus, to improve the time-dependent tumor:normal tissue (T:NT) ratios so that higher and more frequent doses of radionuclide could be used for radioimmunotherapy. These approaches involve three general strategies: (a) modifying antibodies or radiolabeling techniques; (b) increasing the clearance of radiolabeled MAbs; and (c) modifying tumor delivery, tumor antigen expression, or increasing tumor vascular permeability or blood flow. The use of animal models permits the assessment of a wide range of MAbs, radiolabeling conditions, and the efficacy of administration methods before their initial use in clinical trials. MAbs with specificity for binding to tumor-associated antigens or growth factor receptors expressed on tumor cells have been utilized in experimental studies of radiolabeled antibody targeting. Tumor-associated targets present on endothelial cells should be highly accessible to systemically administered radiolabeled MAbs. The use of indirect radioiodination techniques and labile linker-chelates may provide an improvement in tumor retention and T:NT ratios. The addition or deletion of glycosylation to MAbs by alteration of recombinant immunoglobulin genes or by biochemical modification can alter the pharmacokinetics of blood and whole body clearance of radiolabeled MAbs. Genetically engineered chimeric or humanized MAbs have shown equivalent or greater tumor localization compared to murine MAbs. By using MAbs with greater affinity and avidity, an increase in the uptake and retention of radiolabeled MAbs in tumors and an increase in their therapeutic efficacy may be achieved. Several approaches in the administration methods of MAbs have been developed in an attempt to improve tumor localization and therapeutic results and to reduce toxicity. These approaches include: (a) predosing with unlabeled antibody before administering a radiolabeled MAb; (b) using a mixture or "cocktail" of MAbs rather than a single radiolabeled antibody; and (c) administering multiple doses of radiolabeled MAbs. Various approaches have been tested for increasing the blood clearance of radiolabeled MAbs and, thus, for increasing the T:NT ratio. It has been found that compared to intact antibody, the smaller antibody fragments (F(ab′)2, Fab, or single-chain Fv) can bind to tumor cells with a more homogeneous distribution. The antibody fragments and domain deletions often have a more rapid catabolism in blood, in tumors, and in normal tissues than an intact antibody does. In general, the use of antibody fragments leads to higher T:NT ratios but a lower percentage of injected dose delivered to the tumor. In an attempt to maximize MAb deposition into tumor sites while minimizing radionuclide exposure to the bone marrow, investigators have designed several pretargeting strategies to separate these two components. These systems have produced preferential tumor targeting in animal models and in radioimaging studies in man. Regional administration of radiolabeled MAbs may lead to increased tumor localization if the antibody binds rapidly to the target antigen. Experimental studies have shown that IFN increases the localization of radiolabeled MAbs in tumors, resulting in greater tumor growth inhibition than with radiolabeled antibody alone. Several approaches that affect tumor vascularity, blood flow, and vascular permeability have resulted in increased tumor localization of radiolabeled MAbs. These include external beam irradiation, hyperthermia, and the use of vasoactive conjugates. The prospects of radiolabeled antibodies in cancer detection and therapy remain promising because of their specificity for binding to antigens on tumor cells. It appears that methods that increase the localization of radiolabeled MAbs in solid tumors while reducing the uptake in normal tissues will be required to deliver a sufficient radiation-absorbed dose for curative treatment of radioresistant tumors in clinical radioimmunotherapy.
  • Published In

  • Cancer Research  Journal
  • Author List

  • Buchsbaum DJ
  • Volume

  • 55
  • Issue

  • 23 SUPPL.