Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer.
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.
Division of Nuclear Medicine, New York University Kaplan Cancer Center, New York University Medical Center, New York 10016, USA.
E L
EL
Kramer
L
L
Liebes
C
C
Wasserheit
M E
ME
Noz
E W
EW
Blank
A
A
Zabalegui
J
J
Melamed
P
P
Furmanski
J A
JA
Peterson
R L
RL
Ceriani
D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D015899:Tomography, Emission-Computed, Single-Photon; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; D004369:Pentetic Acid