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Purpose <p>Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers, insensitive to standard treatments as a result of its dense stroma, hypoxia, and lack of vascularization. Targeted alpha therapy (TAT) has the potential to circumvent these obstacles by releasing short-range, highly lethal α-particles selectively at the level of the cancer cells. Nevertheless, translation of Actinium-225 (<sup>225</sup>Ac) to the clinic has been hindered by insufficient stable chelators and effective antibody conjugation strategies.</p> Methods <p>We designed [<sup>225</sup>Ac]Ac-PEG<sub>6</sub>-Macropa-PAM4, a new MUC5AC-targeted radioimmunoconjugate with the antigen specificity of PAM4 and the stability of Macropa for ²²⁵Ac chelation and a PEG₆ spacer for site-specific attachment and favorable pharmacokinetics. The conjugate was prepared, radiolabeled, and characterized in vitro and in vivo.</p> Results <p>MALDI-TOF and SEC verified successful conjugation (3.7 ± 0.2 chelators/antibody) with maintained monomeric structure. Radiolabeling at pH 5.5 for 30&#xa0;min produced &gt; 97% radiochemical purity and &gt; 98% monomeric fraction. [<sup>225</sup>Ac]Ac-PEG<sub>6</sub>-Macropa-PAM4 demonstrated excellent serum stability (&gt; 95% intact radiolabel over 7 days at 37&#xa0;°C). The radioconjugate bound MUC5AC-positive BxPC-3 cells with high affinity (Kd ≈ 0.2 nM; Bmax = 1,160 ± 150 fmol/mg protein) and low nonspecific binding. In vitro assays proved highly antigen-specific α-particle cytotoxicity (IC₅₀ = 0.21–0.34 nM), which was blocked by excess PAM4. In vivo, biodistribution in NOD/SCID mice demonstrated intense tumor uptake (15.2 ± 3.0%ID/g at 24&#xa0;h), excellent tumor-to-blood ratios (&gt; 5 at 72&#xa0;h), and minimal off-target activity. Blocking decreased tumor uptake by ~ 79%, affirming specificity. Therapeutic evaluation demonstrated dose-dependent tumor regression, with complete tumor remission achieved in &gt; 80% of animals (7/8 mice) at the highest administered activity level (45&#xa0;kBq, ~ 1.2 µCi).</p> Conclusion <p>[<sup>225</sup>Ac]Ac-PEG<sub>6</sub>-Macropa-PAM4 exhibits excellent stability, antigen binding, and high therapeutic potency, validating its potential for targeted alpha therapy of MUC5AC-expressing PDAC.</p>

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Synthesis and Preclinical Evaluation of a Novel [225Ac]Ac–PEG6–Macropa–PAM4 for Targeted Alpha Therapy of Pancreatic Cancer

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Madeeha Shabnam,
  • Syed Qaiser Shah,
  • DeryaIlem-Ozdemir

摘要

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers, insensitive to standard treatments as a result of its dense stroma, hypoxia, and lack of vascularization. Targeted alpha therapy (TAT) has the potential to circumvent these obstacles by releasing short-range, highly lethal α-particles selectively at the level of the cancer cells. Nevertheless, translation of Actinium-225 (225Ac) to the clinic has been hindered by insufficient stable chelators and effective antibody conjugation strategies.

Methods

We designed [225Ac]Ac-PEG6-Macropa-PAM4, a new MUC5AC-targeted radioimmunoconjugate with the antigen specificity of PAM4 and the stability of Macropa for ²²⁵Ac chelation and a PEG₆ spacer for site-specific attachment and favorable pharmacokinetics. The conjugate was prepared, radiolabeled, and characterized in vitro and in vivo.

Results

MALDI-TOF and SEC verified successful conjugation (3.7 ± 0.2 chelators/antibody) with maintained monomeric structure. Radiolabeling at pH 5.5 for 30 min produced > 97% radiochemical purity and > 98% monomeric fraction. [225Ac]Ac-PEG6-Macropa-PAM4 demonstrated excellent serum stability (> 95% intact radiolabel over 7 days at 37 °C). The radioconjugate bound MUC5AC-positive BxPC-3 cells with high affinity (Kd ≈ 0.2 nM; Bmax = 1,160 ± 150 fmol/mg protein) and low nonspecific binding. In vitro assays proved highly antigen-specific α-particle cytotoxicity (IC₅₀ = 0.21–0.34 nM), which was blocked by excess PAM4. In vivo, biodistribution in NOD/SCID mice demonstrated intense tumor uptake (15.2 ± 3.0%ID/g at 24 h), excellent tumor-to-blood ratios (> 5 at 72 h), and minimal off-target activity. Blocking decreased tumor uptake by ~ 79%, affirming specificity. Therapeutic evaluation demonstrated dose-dependent tumor regression, with complete tumor remission achieved in > 80% of animals (7/8 mice) at the highest administered activity level (45 kBq, ~ 1.2 µCi).

Conclusion

[225Ac]Ac-PEG6-Macropa-PAM4 exhibits excellent stability, antigen binding, and high therapeutic potency, validating its potential for targeted alpha therapy of MUC5AC-expressing PDAC.