A pretherapy biodistribution and dosimetry study of indium-111-radiolabeled trastuzumab in patients with human epidermal growth factor receptor 2-overexpressing breast cancer.
OBJECTIVE
The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of (111)Indium ((111)In)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether (90)Y-MxDTPA-trastuzumab should be evaluated in subsequent clinical therapy trials.


METHODS
Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4-8 mg/kg IV), followed 4 hours later by 5 mCi (111)In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days.


RESULTS
Eight (8) patients received (111)In-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with (90)Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi.


CONCLUSIONS
In summary, results from this study indicate that (90)Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to (111)In-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other (90)Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity.
Wong
Jeffrey Y C
JY
Department of Radiation Oncology and Radiation Research, Beckman Research Institute, Duarte, California 91010, USA. jwong@coh.org
Raubitschek
Andrew
A
Yamauchi
Dave
D
Williams
Lawrence E
LE
Wu
Anna M
AM
Yazaki
Paul
P
Shively
John E
JE
Colcher
David
D
Somlo
George
G
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007205:Indium Radioisotopes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D011379:Prognosis; D011874:Radiometry / Q000379:methods; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014018:Tissue Distribution; D000068878:Trastuzumab; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D015021:Yttrium Radioisotopes