Background: Radioimmunotherapy (RIT) using 131I-Chimeric L6 (ChL6) antibody has shown therapeutic promise for patients with breast cancer. To enhance this potential a novel immunoconjugate was developed that targets adenocarcinomas like breast cancer and tightly binds yttrium-90 (90Y) for therapy and indium-111 (111In) for imaging. The radioimmunoconjugate consists of a macrocyclic chelator (DOTA) linked to ChL6 by a catabolizable peptide. 90Y-DOTA-peptide-ChL6 was designed to minimize the radiation dose to critical normal tissues, thereby improving the therapeutic index. materials and Methods: Three patients with incurable metastatic breast cancer received 90Y/111In-DOTA-peptide-ChL6 for 5 phamacokinetics/dosimetry studies and one of these patients also received 2 therapy doses. Quantitative imaging of 111In and in vitro assay of 90Y and 111In in blood urine and bone marrow samples were obtained. Results: 90Y/111In-DOTA-peptide-ChL6 was prepared at high purity and was stable in vivo. Assays of bone marrow revealed no evidence for escape of 90Y or 111In from the chelate. 111In provided comparable pharmacokinetics, as did tracer and therapeutic doses of radiommunoconjugates. One patient that received 2 therapeutic doses of 90Y-DOTA-peptide-ChL6 showed regression of tumors and tumor markers. Toxicities were relatively minor and no anti-globulin response developed despite 5 immunoconjugate infusions. Conclusions: This first study in patients of radioimmimoconjugates with a catabolizable linker between the metal chelator and the antibody confirmed that these novel 90Y/111In-DOTA-peptideChL6 radiommunoconjugates have significant potential. Tracer doses of 111In-DOTA-peptide-ChL6 for imaging predicted the behavior of therapeutic doses of 90Y-DOTA-peptideChL6. The latter radioimmunoconjugate induced regression of tumors and tumor markers without significant toxicity. When compared to earlier 131I-ChL6 dosimetry, 90Y-DOTA-peptide-ChL6 provided a therapeutic index several times better.