Abstract
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 β-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 γ-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 μg; ~ 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 μg; ~ 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 μg; ~ 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 μg; ~ 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 μg; ~ 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 β-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.
Highlights
Epidermal 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)
The cytotoxicity per Gy in the nucleus was highest for panitumumab-metal-chelating polymer (MCP)-[111In]In, followed by panitumumab-1 7 10-tetraazacyclododecane tetraacetic acid (DOTA)-[177Lu]Lu, panitumumab-DOTA-[111In]In, but there were limited data points to fit the curves for 111In-labeled RICs
In this study, we evaluated the cytotoxicity in vitro of panitumumab labeled with AEemitting, 111In or β-particle-emitting, 177Lu on PANC-1 human PnCa cells and correlated the surviving fraction (SF) of these cells in clonogenic assays with unrepaired Deoxyribonucleic acid (DNA) double-strand breaks (DSB) in the nucleus assessed by immunofluorescence for Gamma histone-2AX (γ-H2AX) as well as the absorbed dose in the nucleus
Summary
Epidermal 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). Clinical trials of anti-EGFR monoclonal antibodies, cetuximab (Erbitux; Eli Lilly) (Crane et al, 2011) or panitumumab (Vectibix; Amgen) (Halfdanarson et al, 2019) combined with chemotherapy have not been as encouraging as hoped, possibly due to downstream KRAS mutation in PnCa which obviates the effects of blocking EGFR (Eser et al, 2014). This does not preclude EGFR-targeted radioimmunotherapy (RIT) of PnCa, since EGFR overexpression is used only to selectively deliver radiation to tumours. We previously proposed that panitumumab-MCP dual-labeled with 177Lu and 111In could represent a novel theranostic agent that combines SPECT and AE and β-particle mediated RIT (Aghevlian et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
