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Radioimmunotherapy of PANC-1 human pancreatic cancer xenografts in NOD/SCID or NRG mice with Panitumumab labeled with Auger electron emitting, ¹¹¹In or ?-particle emitting, ¹⁷⁷Lu.

ABSTRACT:

Background

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). 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.

Results

Panitumumab 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.

Conclusion

RIT 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.

SUBMITTER: Aghevlian S

PROVIDER: S-EPMC7652961 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Radioimmunotherapy of PANC-1 human pancreatic cancer xenografts in NOD/SCID or NRG mice with Panitumumab labeled with Auger electron emitting, <sup>111</sup>In or β-particle emitting, <sup>177</sup>Lu.

Aghevlian Sadaf S Cai Zhongli Z Hedley David D Winnik Mitchell A MA Reilly Raymond M RM

EJNMMI radiopharmacy and chemistry 20201109 1

<h4>Background</h4>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). 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, <sup>111</sup>In or β-particle emitting, <sup>177</sup>Lu at amounts that were non-toxic to ...[more]

PMID: 33169241

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