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. 2023 Aug 14;8(1):18.
doi: 10.1186/s41181-023-00204-4.

In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer

Ashleigh Hull  1   2 , William Hsieh  3   4 , William Tieu  5 , Dylan Bartholomeusz  4   6 , Yanrui Li  3 , Eva Bezak  3   5
Affiliations

In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer

Ashleigh Hull et al. EJNMMI Radiopharm Chem. .

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [177Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [177Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC.

Results: A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [177Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [177Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [177Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [177Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [177Lu]Lu-DOTA-C595.

Conclusion: [177Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [177Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.

Keywords: C595; Lutetium-177; MUC1; Pancreatic cancer; Radioimmunotherapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
A Cell binding of [177Lu]Lu-DOTA-C595 at 1 × 105 cells corrected for background and B linear regression of the percentage of positive MUC1-CE cells and average cell binding counts per minute
Fig. 2
Fig. 2
Background- and decay-corrected cell counts across 48 h representing A surface binding, B internalised fraction, C total binding including surface and internalised and D rate of internalisation
Fig. 3
Fig. 3
Representative flow cytometry histograms of γH2AX expression in PANC-1 and AsPC-1 cells at A and B 1 h, and C and D 24 h following [177Lu]Lu-DOTA-C595 treatment
Fig. 4
Fig. 4
Clonogenic survival of A PANC-1 and AsPC-1 at varying concentrations of [177Lu]Lu-DOTA-C595, B PANC-1 and C AsPC-1 cell survival following exposure to equivalent concentrations of [177Lu]Lu-DOTA-C595, Lu-177, DOTA-C595 and C595 and D intra-observer reliability of manual counting determined using the intra-class correlation coefficient (ICC). Data are presented as mean ± standard deviation. *p < 0.05, **p < 0.01, ***p < 0.001
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