2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic-acid and Breast-Neoplasms

BrE-3 is a murine IgG1 monoclonal antibody that binds to 97% of human ductal breast cancer specimens. A previous study documented the ability of 111In-labeled 1,4-methyl-benzyl isothiocyanate diethylenetriamine pentaacetic acid (111In-MX-DTPA) BrE-3 to specifically target breast cancer tissue in patients, and the dosimetry derived from the pharmacokinetics suggested that a useful therapeutic index could be obtained with 90Y-MX-DTPA BrE-3. A Phase I maximum tolerated dose study was, therefore, initiated.. Six patients received 111In/90Y-MX-DTPA BrE-3, three of them receiving 6.25 and the other three receiving 9.25 mCi/m2 of 90Y. Pharmacokinetics, dosimetry, human anti-mouse antibody (HAMA), toxicity and clinical responses were evaluated.. Three of six patients demonstrated a minor and transient, but objective tumor response, and none of the patients had significant toxicity. Tumor dosimetry ranged from 39 to 167 rad/mCi of 90Y (442-1887 rad/ dose). HAMA response occurred in five of six patients.. Minimal toxicity, dosimetric calculations and clinical assessment indicate that a useful therapeutic index can be achieved with this therapy. Indium-111/yttrium-90-MX-DTPA BrE-3 can be safely administered to patients with metastatic breast cancer, and therapy doses yielded pharmacokinetics similar to those of tracer doses. Clinical responses, albeit transient, were achieved with single-dose therapy. Rapid onset of the HAMA response will hinder multicycle therapy, unless it is prevented with immunosuppressive drugs or the use of a "humanized" antibody. Further studies are needed to determine the optimal use of BrE-3 for radioimmunotherapy.

Topics: Breast Neoplasms; Chelating Agents; Female; Humans; Indium Radioisotopes; Middle Aged; Pentetic Acid; Radioimmunotherapy; Radiotherapy Dosage; Yttrium Radioisotopes

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibody Specificity; Biomarkers, Tumor; Breast Neoplasms; Carcinoembryonic Antigen; Female; Humans; Immunoconjugates; Indium Radioisotopes; Membrane Glycoproteins; Mice; Middle Aged; Mucin-1; Mucins; Pentetic Acid; Radioimmunodetection; Yttrium Radioisotopes

Pharmacokinetics of radiolabeled BrE3 monoclonal antibody (Mab), reactive against a breast mucin epitope, were assessed in 15 patients with advanced breast cancer. Patients received 5 mCi (185 MBq) of 111In-methyl benzyl isothiocyanate DTPA (MX-DTPA) conjugated BrE-3 Mab intravenously with total antibody doses of 10, 50 or 100 mg. Serial quantitative imaging, blood and urine clearance were obtained to measure pharmacokinetics, assess tumor localization and estimate radiation dose. Organ function was followed to determine toxicity. Mild allergic reactions occurred in four patients. Eighty-six percent of 70 known lesions and 5 unsuspected lesions were detected by antibody imaging. Biexponential modeling of radiolabeled antibody in serum showed a T1/2 alpha = 9.5 +/- 2.7 hr and T1/2 beta = 56 +/- 25.4 hr. Total urinary excretion averaged 35.5% +/- 19.3% injected dose (ID) by Day 8. Quantitative imaging showed that 0.02-2.56% ID localized in tumors. Extrapolating dosimetry from 111In-MX-DTPA-BrE-3 to 90Y-MX-DTPA-BrE-3, we estimate therapeutic radiation doses could be delivered to some tumors with tolerable toxicity.

Topics: Breast Neoplasms; Chelating Agents; Female; Humans; Indium Radioisotopes; Middle Aged; Neoplasm Metastasis; Pentetic Acid; Radioimmunodetection; Tissue Distribution

To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer.

Topics: Adult; Antibodies, Monoclonal; Breast Neoplasms; Female; Humans; Indium Radioisotopes; Middle Aged; Pentetic Acid; Radioimmunotherapy; Radiotherapy Dosage; Tomography, Emission-Computed, Single-Photon; Yttrium Radioisotopes