Copper-67 radioimmunotheranostics for simultaneous immunotherapy and immuno-SPECT

Abstract

Copper-67 (t1/2 = 2.58 days) decays by β− ($$\text{E}_{{\upbeta^{-}\text{max}}}$$ E β - max : 562 keV) and γ-rays (93 keV and 185 keV) rendering it with potential for both radionuclide therapy and single-photon emission computed tomography (SPECT) imaging. Prompted by the recent breakthrough of 67Cu production with high specific activity, high radionuclidic purity, and sufficient quantities, the interest in the theranostic potential of 67Cu has been rekindled. This work addresses the practicability of developing 67Cu-labeled antibodies with substantially improved quality for cancer radioimmunotheranostics. Proof of concept is demonstrated with pertuzumab, a US-FDA-approved monoclonal antibody for combination therapies of HER2-positive breast cancer. With an average number of 1.9 chelators coupled to each antibody, we achieved a two-order of magnitude increase in radiolabeling efficiency compared to literature reports. In a preclinical therapeutic study, mice (n = 4–7/group) bearing HER2+ xenografts exhibited a 67Cu-dose dependent tumor-growth inhibition from 67Cu-labeled-Pertuzumab co-administered with trastuzumab. Furthermore, greater tumor size reduction was observed with 67Cu-labeled-pertuzumab formulations of higher specific activity. The potential of SPECT imaging with 67Cu radiopharmaceuticals was tested after 67Cu-labeled-Pertuzumab administration. Impressively, all tumors were clearly visualized by SPECT imaging with 67Cu-labeled-Pertuzumab even at day 5 post injection. This work demonstrates it is practical to use 67Cu radioimmunoconjugates for cancer radioimmunotheranostics.

PSMA-Targeting Imaging and Theranostic Agents—Current Status and Future Perspective

“…For instance, an anti-PSMA mAb, E6, was reported with binding to the extracellular domains of both mouse and human PSMA and its toxicity was assessed in preclinical studies [18]. Impressively, a humanized anti-PSMA mAb, J591, demonstrated its potential to overcome the drawbacks of ProstaScint [19] when functionalized with chelators for radiolabeling with a variety of radionuclides, including 90 Y and 177 Lu for β-therapy [19,20], 213 Bi and 225 Ac for α-therapy [21,22], 111 In and 99m Tc for SPECT [23,24], and 64 Cu and 89 Zr for PET [25,26]. However, the mAb conjugates cannot be physically cleared from the blood through the glomerular filtration because of their large size, which results in a prolonged blood retention that reduces the tumor-to-background contrast.…”

“…Despite the success of the radiotheranostic pair in clinical trials, they differ in radionuclides and compound structures, which inevitably leads to different in vivo kinetics of the agents that result in discrepancies between the imaging-guided RNT expectation and the actual therapy outcome. Development of other small molecule PSMA targeting agents such as MIP-1095 [87], PSMA I&T [88], and PSMA-617 [29] introduced the same chelating moiety, which permits the coordination chemistry with either a diagnostic radionuclide (e.g., 68 Ga) for imaging or a therapeutic radionuclide (e.g., 177 Lu, 90 Y, 225 Ac) for RNT. These agents possess more compatible in vivo pharmacokinetics for theranostic applications.…”

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

“…Copper-67 has recently emerged as an especially interesting therapeutic radionuclide due to its favourable half-life, β --emission energies, range and applicability in simultane-ous therapy or SPECT, reducing the complexity in the diagnostic therapy timeline [115]. Moreover, the existence of 64 Cu, a positron emitter, permits its application as an 'authentic theranostic' pair.…”

Novel Bifunctional [16]aneS4-Derived Chelators for Soft Radiometals

“…While oxygen-based crown ethers strongly bind alkali and alkaline earth metal ions, their thioether analogues show distinct preference for the much softer late transition metals [ 24 ]. The complexation of [16]aneS4 (and derivatives thereof) with various transition metals has been studied intensively ( Table 1 ) [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Its application in radiopharmaceutical chemistry remains limited, however, and to date only a few examples have demonstrated complexation between a soft radiometal and [16]aneS 4 .…”