Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

Clinical Sciences

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Abstract

Tumor associated monoclonal antibodies (mAb's) are potential therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents being employed are various radionuclides. Their relative efficacy when conjugated to monoclonal antibodies (mAb's) is assayed and compared to that of the mAb alone. The radionuclides chosen for study span the range of radionuclidic properties available thereby assaying the effects of energy of emission, half-life, and physical characteristics of emission. Research continues to focus on expanding clinical use of Y-90 and on performing pre-clinical studies with the alpha-particle emitting radionuclides Bi-212, Bi-213, Ac-225, and At-211. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering Y-90 and future trials being planned will use the CHX-A'' DTPA. Recent results in chelate design technology have yielded the most stable bifunctional chelating agent for Ac-225 to date, a p-isothiocyanatobenzyl analog of HEHA. Efforts at evaluating the in vivo stability of this ligand and the potential efficacy of Ac-225 as the radionuclide component in a radioimmunoconjugate has been evaluated in two murine models. The results for therapy experiments in a lung tumor model cured all of the animals, yet also proved to be 100% radiotoxic with a dose of 0.5 microcuries. However, treatment of a solid, colon cancer xenograft tumor, at a similar dose, resulted in virtually complete inhibition of tumor growth indicative of need for this isotope to be extensively investigated in multiple tumor model systems. Pre-clinical results with Bi-213 using the humanized, CH2 domain deleted engineered version of mAb CC49 generated remarkable results with ~ 60% of the mice treated with a 750 microcurie dose either achieving a partial response wherein the tumor growth was arrested or a complete response with the tumor was essentially eradicated. Studies with Bi-213 have also been expanded to include investigation into use of pre-targeting protocols. Preliminary results with monoclonal antibodies humanized anti-Tac and B3 have both shown promising results. These studies will continue to optimize dose and schedule pending availability of the parent radionuclide. Plans are to expand this technology to re-examine the utility of Pb-212 and evaluate the in vivo generator system of Pb-212/Bi-212 in the same murine systems.