YTTRIUM-90 INDIUM-111-DOTA-PEPTIDE-CHIMERIC L6 - PHARMACOKINETICS, DOSIMETRY AND INITIAL RESULTS IN PATIENTS WITH INCURABLE BREAST-CANCER/

Background: Radioimmunotherapy (RIT) using I-131-Chimeric L6 (ChL6) an tibody has shown therapeutic promise for patients with breast cancer. To enhance this potential a novel immunoconjugate was developed that t argets adenocarcinomas like breast cancer and tightly binds yttrium-90 (Y-90) for therapy and indium-111 (In-111) for imaging. The radioimmu noconjugate consists of a macrocyclic chelator (DOTA) linked to ChL6 b y a catabolizable peptide. Y-90-DOTA-peptide-ChL6 was designed to mini mize the radiation dose to critical normal tissues, thereby improving the therapeutic index. Materials and Methods: Three patients with incu r able metastatic breast cancer received Y-90/In-111-DOTA-peptide-ChL6 for 5 pharmacokinetics/dosimetry studies and one of these patients al so received 2 therapy doses. Quantitative imaging of in vitro assay of Y-90 and In-111 in blood, urine and bone marrow samples were obtained . Results: Y-90/In-111-DOTA-peptide-ChL6 was prepared at high purity a nd was stable in vivo. Assays of bone marrow revealed no evidence for escape of Y-90 or In-111 from the chelate. In imaging of tumors was ex cellent, providing a therapeutic index for tumor to marrow radiation a s high as 229 to 1. Y-90 and In-111 provided comparable pharmacokineti cs, as did tracer and therapeutic doses of radioimmuno-conjugates. One patient that received 2 therapeutic doses of Y-90-DOTA-peptide-ChL6 s howed regression of tumors and tumor markers. Toxicities were relative ly minor and no anti-globulin response developed despite 5 immunoconju gate infusions. Conclusions: This first study in patients of radioimmu noconjugates with a catabolizable linker between the metal chelator an d the antibody confirmed that these novel Y-90/In-111-DOTA-peptide-ChL 6 radioimmunoconjugates have significant potential. Tracer doses of In -111-DOTA-peptide-ChL6 for imaging predicted the behavior of therapeut ic doses of Y-90-DOTA-peptide-ChLd The latter radioimmunoconjugate ind uced regression of tumors and tumor markers without significant toxici ty. When compared to earlier I-131-ChL6 dosimetry, Y-90-DOTA-peptide-C hL6 provided a therapeutic index several times better.