Preparation and preclinical evaluation of131I-trastuzumab for breast cancer.
Trastuzumab that targets the human epidermal growth factor receptor type 2 (HER2) is known to benefit patients with HER2+ metastatic breast cancer. The objective was to explore the potential of131I-trastuzumab for treatment of breast cancers. Radioiodination of trastuzumab was carried out by chloramine-T method, purified by using PD-10 column, and characterized by size exclusion high-performance liquid chromatography on a gel column. In vitro studies were carried out in HER2+ cells to determine the specificity of the radioimmunoconjugate. Uptake and retention of131I-trastuzumab were determined by biodistribution studies in tumor-bearing non-obese diabetic/severe combined immunodeficiency and normal severe combined immunodeficiency mice. The radiochemical purity (RCP) of131I-trastuzumab was 98 ± 0.4% with retention time of 17 minutes by high-performance liquid chromatography. In vitro stability studies exhibited RCP of more than 90% in serum at 37°C after 120 hours of radioiodination. In vitro cell binding with131I-trastuzumab in HER2+ cells showed binding of 28% to 35% which was inhibited significantly, with unlabeled trastuzumab confirming its specificity. Kdvalue of131I-trastuzumab was 0.5 nM, while its immunoreactivity was more than 80%. Uptake of more than 12% and retention were observed in the tumors up to 120 hours p.i.131I-trastuzumab prepared in-house-exhibited RCP of more than 98%, excellent immunoreactivity, affinity to HER2+ cell lines and good tumor uptake thereby indicating its potential for further evaluation in HER2+ breast cancers.
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India.
Mythili
M
Kameswaran
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India.
Vikram
V
Gota
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India.
Rajwardhan
R
Ambade
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India.
Sudeep
S
Gupta
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India.
Ashutosh
A
Dash
D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000737:chemistry*
D000074322:Antineoplastic Agents, Immunological; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
131I-trastuzumab; HER2+ cells; SCID mice; breast cancers; targeted therapy