Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.
HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer.
Department of Nuclear Medicine & PET, PGIMER, Chandigarh, India.|Centre for Nuclear Medicine, Punjab University, Chandigarh, India.
Priya
P
Bhusari
Department of Nuclear Medicine & PET, PGIMER, Chandigarh, India.|Centre for Nuclear Medicine, Punjab University, Chandigarh, India.
Rakhee
R
Vatsa
Department of General Surgery, PGIMER, Chandigarh, India.
Gurpreet
G
Singh
Department of Nuclear Medicine & PET, PGIMER, Chandigarh, India.
Madan
M
Parmar
Department of Histopathology, PGIMER, Chandigarh, India.
Amanjit
A
Bal
Centre for Nuclear Medicine, Punjab University, Chandigarh, India.
Devinder K
DK
Dhawan
Department of Nuclear Medicine & PET, PGIMER, Chandigarh, India.
Bhagwant R
BR
Mittal
Department of Nuclear Medicine & PET, PGIMER, Chandigarh, India.
Jaya
J
Shukla
D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D005240:Feasibility Studies; D005260:Female; D018734:Genes, erbB-2; D006573:Heterocyclic Compounds, 1-Ring / Q000032:analysis; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008187:Lutetium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008408:Mastectomy; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010865:Pilot Projects; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013629:Tamoxifen / Q000627:therapeutic use; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D008187:Lutetium; D009363:Neoplasm Proteins; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D000068878:Trastuzumab; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C508053:ERBB2 protein, human
DOTA; HER2; Lu-177; conjugation; radioimmunotherapy; trastuzumab