EGFR and HER2-targeted radioimmunoconjugates for theranostic molecular imaging and Auger electron radioimmunotherapy of breast cancer
Bibliographic record
Abstract
Overexpression of the human epidermal growth receptor 1 (HER1, EGFR) and 2 (HER2) are common in breast cancer (BC) and confer a poor prognosis. HER2-targeted pertuzumab Fab fragments were modified with hexahistidine peptides for radiolabelling with 99mTc and EGFR-targeted panitumumab with DOTA chelators for radiolabelling with 111In for SPECT imaging and Auger electron (AE) radioimmunotherapy (RIT). [99mTc]His6-pertuzumab Fab exhibited saturable specific binding to BC cells in vitro (Kd = 51.3 ± 5.2 x 10-9 M). SPECT/CT at 24 h p.i. discriminated between HER2-positive (MDA-MB-361) and negative (MDA-MB-231) human BC xenografts in NOD scid mice, with a 7-fold significant difference in tumour uptake (5.6 ± 1.4 vs. 0.8 ± 0.1 %ID/g, P<0.05). [111In]In-DOTA-panitumumab exhibited EGFR-dependent binding and nuclear localisation in MCF7 (1.5 x 104 EGFR/cell), MDA-MB-231/Luc (1.7 x 105 EGFR/cell) and MDA-MB-468 (1.3 x 106 EGFR/cell) cells, with estimated nuclear absorbed doses of 1.20 ± 0.02, 2.2 ± 0.1, and 25 ± 2 Gy, respectively for treatment with 4.4 MBq [111In]In-DOTA-panitumumab (20 nM). AE RIT with [111In]In-DOTA-panitumumab induced DNA double strand breaks, G2/M cell cycle arrest, apoptosis and reduced the clonogenic survival of EGFR-overexpressing BC cells. [111In]In-DOTA-panitumumab exhibited high uptake in MDA-MB-231/Luc tumours in NOD scid mice (18 ± 2 %ID/g) enabling clear visualization by SPECT/CT at 4 d post-injection. A single administration of [111In]In-DOTA-panitumumab (22 MBq, 15 μg) significantly delayed the growth of orthotopic MDA-MB-231/Luc mammary fat pad (MFP) tumours in NRG mice. In a model of BC recurrence after excision of 231/LM2-4 Luc+ tumours in the MFP of NRG mice, SPECT revealed high uptake of [111In]In-DOTA-panitumumab in spontaneous lung, liver and lymph node metastases. Radiation absorbed doses in metastatic lymph nodes, lungs and liver of 9.1 ± 5.7, 6.4 ± 2.0 and 10.9 ± 2.6 Gy, respectively, were estimated at the No Observable Adverse Effect Level (NOAEL; 24 MBq, 15 μg). In combination with tumour excision and fractionated X-ray radiation (5 d x 6 Gy/day) of the tumour bed, adjuvant RIT with 26 MBq (15 μg) of [111In]In-DOTA-panitumumab significantly prolonged survival from 23 to 35 d post-resection (P<0.0001). These results suggest that theranostic radiopharmaceuticals targeting EGFR and HER2 for SPECT imaging and AE RIT are promising for detection and treatment of BC.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".