The objective of this proposal is to test whether a genetically engineered anti-CD20/streptavidin fusion protein can be used for the initial pretargeting step in the treatment of non-Hodgkin' lymphoma using a pretargeted radioimmunotherapy (PRITTM). PRIT is a multistep delivery system that takes advantage of antibody specificity and small molecule radioligand pharmacokinetics to increase the therapeutic ratio by reducing the exposure of normal marrow and other organs to radiation. In PRIT, the role of the antibody has been modified from the carrier of the therapeutic isotope to the carrier of a receptor for the therapeutic isotope. The therapeutic radiation is delivered on a small molecule and binds to the previously administered antibody/receptor that has localized at the tumor antigen. The avidinbiotin approach to PRIT has previously been evaluated using a pancarcinoma antibody/streptavidin conjugate in patients with adenocarcinomas and an anti-CD20 antibody/streptavidin conjugate in patients with lymphoma. A genetically engineered, single chain Fv-Streptavidin (scFv/SA) fusion protein has now been constructed from an anti-CD20 antibody, B9E9, expressed, and purified in E.coli. This fusion protein will be first evaluated in patients as a carrier for avidin binding reactivity to sites of known lymphoma. It will then be studied as a substitute for intact antibody/streptavidin in the PRIT approach. The mass dose of the fusion protein and the subsequent components will be varied, as will the timing of administration of the second (clearing agent) and the third components (radiolabeled DOTA-biotin), until an optimal schema has been developed. These initial studies will use 186Re, a gamma emitting radionuclide, for biodistribution studies, and to determine dosimetry. Y-90 DOTA-biotin will be utilized as the therapeutic agent, and dose levels increased to define the maximum tolerated dose. These phase I studies will define schema and doses for a subsequent phase II study of PRIT using the fusion anti-CD20/streptavidin protein in patients with CD20+ non-Hodgkin's lymphoma.
| Weiden, P L; Breitz, H B (2001) Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL). Crit Rev Oncol Hematol 40:37-51 |
