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Dose predictions for [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ in NRG mice with HNSCC patient-derived tumour xenografts based on [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ - implications for a PET theranostic strategy.

ABSTRACT:

Background

Epidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab')₂ of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, ¹⁷⁷Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂.

Results

Panitumumab F(ab')₂ were conjugated to DOTA and complexed to ⁶⁴Cu or ¹⁷⁷Lu in high radiochemical purity (95.6 ± 2.1% and 96.7 ± 3.5%, respectively) and exhibited high affinity EGFR binding (K_d = 2.9 ± 0.7 × 10^- 9 mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ (5.5-14.0 MBq; 50 μg) or [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ (6.5 MBq; 50 μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ or microSPECT/CT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ but not with irrelevant [¹⁷⁷Lu]Lu-DOTA-trastuzumab F(ab')₂. Tumour uptake at 24 h p.i. of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ [14.9 ± 1.1% injected dose/gram (%ID/g) and [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ (18.0 ± 0.4%ID/g) were significantly higher (P < 0.05) than [¹⁷⁷Lu]Lu-DOTA-trastuzumab F(ab')₂ (2.6 ± 0.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ based on the BOD of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ compared to those estimated directly from the BOD of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ except for the liver and whole body which were modestly underestimated by [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂. Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ predicted that a 2 cm diameter HNSCC tumour in a patient would receive 1.1-1.5 mSv/MBq and the whole body dose would be 0.15-0.22 mSv/MBq.

Conclusion

A PET theranostic strategy combining [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ is feasible. RIT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.

SUBMITTER: Ku A

PROVIDER: S-EPMC8360260 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common approach in advanced neuroendocrine neoplasms. Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites than in commonly used agonists. We evaluated PRRT with SSTR agonist 177Lu-DOTATOC and antagonist 177Lu-DOTA-JR11 longitudinally in an orthotopic murine pancreatic neuroendocrine neoplasm model expressing human SSTR2. Morphologic and metabolic changes during treatment were assessed using multimodal imaging, including hybrid PET/MRI and SPECT/CT. Methods: In vitro radioligand binding and internalization assays and cell-cycle analysis were performed. SSTR2-transfected BON cells (BON-SSTR2) were used for in vivo experiments. Tumor-bearing mice received 2 intravenous injections of 100 μL of saline, 30 MBq of 177Lu-DOTATOC, or 20 MBq of 177Lu-DOTA-JR11 with an interval of 3 wk. Weekly T2-weighted MRI was performed for tumor monitoring. Viability of the tumor tissue was assessed by 18F-FDG PET/MRI once after PRRT. Tumor and kidney uptake of the respective radiopharmaceuticals was measured 24 h after injection by SPECT/CT. Results: Compared with 177Lu-DOTATOC, 177Lu-DOTA-JR11 treatment resulted in an increased accumulation of cells in G2/M phase. Animals treated with the SSTR antagonist showed a significant reduction in tumor size (P < 0.001) and an increased median survival (207 d; interquartile range [IQR], 132-228) compared with 177Lu-DOTATOC (126 d; IQR, 118-129). SPECT/CT revealed a 4-fold higher median tumor uptake for the antagonist and a 3-fold higher tumor-to-kidney ratio in the first treatment cycle. During the second therapy cycle, tumor uptake of 177Lu-DOTATOC was significantly lower (P = 0.01) whereas 177Lu-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for 177Lu-DOTA-JR11 despite further tumor growth. These results were confirmed by 18F-FDG PET, revealing the least amount of viable tumor tissue in 177Lu-DOTA-JR11-treated animals, at 6.2% (IQR, 2%-23%). Conclusion: 177Lu-DOTA-JR11 showed a higher tumor-to-kidney ratio and a more pronounced cytotoxic effect than did 177Lu-DOTATOC. Additionally, tumor uptake was more stable over the course of 2 treatment cycles.

Project description:BackgroundThe [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11.Results[225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11.Conclusion[225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Project description:PurposeAfter peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues.MethodsThe annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.ResultsOf the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy.ConclusionNephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

Project description:BackgroundEpidermal growth factor receptors (EGFR) are overexpressed on >?90% of pancreatic cancers (PnCa) and represent an attractive target for the development of novel therapies, including radioimmunotherapy (RIT). Our aim was to study RIT of subcutaneous (s.c.) PANC-1 human PnCa xenografts in mice using the anti-EGFR monoclonal antibody, panitumumab labeled with Auger electron (AE)-emitting, 111In or ?-particle emitting, 177Lu at amounts that were non-toxic to normal tissues.ResultsPanitumumab was conjugated to DOTA chelators for complexing 111In or 177Lu (panitumumab-DOTA-[111In]In and panitumumab-DOTA-[177Lu]Lu) or to a metal-chelating polymer (MCP) with multiple DOTA to bind 111In (panitumumab-MCP-[111In]In). Panitumumab-DOTA-[177Lu]Lu was more effective per MBq exposure at reducing the clonogenic survival in vitro of PANC-1 cells than panitumumab-DOTA-[111In]In or panitumumab-MCP-[111In]In. Panitumumab-DOTA-[177Lu]Lu caused the greatest density of DNA double-strand breaks (DSBs) in the nucleus measured by immunofluorescence for ?-H2AX. The absorbed dose in the nucleus was 3.9-fold higher for panitumumab-DOTA-[177Lu]Lu than panitumumab-DOTA-[111In]In and 7.7-fold greater than panitumumab-MCP-[111In]In. No normal tissue toxicity was observed in NOD/SCID mice injected intravenously (i.v.) with 10.0?MBq (10??g; ~?0.07 nmoles) of panitumumab-DOTA-[111In]In or panitumumab-MCP-[111In]In or in NRG mice injected i.v. with 6.0?MBq (10??g; ~?0.07 nmoles) of panitumumab-DOTA-[177Lu]Lu. There was no decrease in complete blood cell counts (CBC) or increased serum alanine aminotransferase (ALT) or creatinine (Cr) or decreased body weight. RIT inhibited the growth of PANC-1 tumours but a 5-fold greater total amount of panitumumab-DOTA-[111In]In or panitumumab-MCP-[111In]In (30?MBq; 30??g; ~?0.21 nmoles) administered in three fractionated amounts every three weeks was required to achieve greater or equivalent tumour growth inhibition, respectively, compared to a single amount of panitumumab-DOTA-[177Lu]Lu (6?MBq; 10??g; ~?0.07 nmoles). The tumour doubling time (TDT) for NOD/SCID mice with s.c. PANC-1 tumours treated with panitumumab-DOTA-[111In]In or panitumumab-MCP-[111In]In was 51.8?days and 28.1?days, respectively. Panitumumab was ineffective yielding a TDT of 15.3?days vs. 15.6?days for normal saline treated mice. RIT of NRG mice with s.c. PANC-1 tumours with 6.0?MBq (10??g; ~?0.07 nmoles) of panitumumab-DOTA-[177Lu]Lu increased the TDT to 20.9?days vs. 11.5?days for panitumumab and 9.1?days for normal saline. The absorbed doses in PANC-1 tumours were 8.8?±?3.0?Gy and 2.6?±?0.3?Gy for panitumumab-DOTA-[111In]In and panitumumab-MCP-[111In]In, respectively, and 11.6?±?4.9?Gy for panitumumab-DOTA-[177Lu]Lu.ConclusionRIT with panitumumab labeled with Auger electron-emitting, 111In or ?-particle-emitting, 177Lu inhibited the growth of s.c. PANC-1 tumours in NOD/SCID or NRG mice, at administered amounts that caused no normal tissue toxicity. We conclude that EGFR-targeted RIT is a promising approach to treatment of PnCa.

Project description:PurposeGastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein.MethodsOverall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy.ResultsAmong 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry.ConclusionThe characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature.Study registrationClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

Dataset Information

Dose predictions for [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ in NRG mice with HNSCC patient-derived tumour xenografts based on [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ - implications for a PET theranostic strategy.

Background

Results

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OmicsDI is part of the ELIXIR infrastructure

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Dose predictions for [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ in NRG mice with HNSCC patient-derived tumour xenografts based on [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ - implications for a PET theranostic strategy.