Preclinical evaluation of an ¹¹¹In/²²⁵Ac theranostic targeting transformed MUC1 for triple negative breast cancer

Abstract

<b>Rationale</b>: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer. TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells. Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC. <b>Methods</b>: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy. hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry). Lastly, <i>in vivo</i> biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model. <b>Results</b>: hTAB004 was shown to bind and internalize into tMUC1-expressing cells. A production method of ²²⁵Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and ¹¹¹In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed. The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum. In NSG female mice bearing orthotopic HCC70 xenografts, the <i>in vivo</i> tumor concentration of ¹¹¹In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection). A single ²²⁵Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001, day 22) and increased survival compared to controls (P<0.007). The human dosimetry results were comparable to other clinically used agents. <b>Conclusion</b>: The results obtained with hTAB004 suggest that the ¹¹¹In/²²⁵Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.