Physical Properties and Clinical Translation Advantages of ⁶⁷Cu

Shu-Peng LYU¹, Tie-Zhu MAO²*
¹ Department of Nuclear Medicine, Norman Bethune Second Hospital, Jilin University, Changchun, Jilin 130024, China
² Department of Radiotherapy, Norman Bethune Second Hospital, Jilin University, Changchun, Jilin 130024, China

Abstract

Copper-67 (⁶⁷Cu) demonstrates significant advantages in targeted radiotherapy for hematological malignancies, owing to its physical half-life (T₁/₂ = 61.83 h) that aligns with antibody pharmacokinetics, medium-range β⁻ particles (Eβ⁻ₘₐₓ = 577 keV, Rₘₐₓ ≈ 2 mm), and integrated diagnostic/therapeutic capabilities enabled by concomitant γ-ray emission (184.6 keV). The β⁻ particles precisely eradicate micro-metastases while overcoming antigen heterogeneity, and simultaneous SPECT imaging ensures biodistribution verification and dose monitoring. Key technological breakthroughs drive clinical translation: High-specific-activity production (>1850 GBq/mg) achieved via the photonuclear reaction ⁶⁸Zn(γ,p)⁶⁷Cu, and the bicyclic chelator CB-TE2A (logK = 27.9) significantly reduces hepatic off-target accumulation. Compared to ⁹⁰Y, ⁶⁷Cu optimizes radiation dosimetry by increasing the tumor-to-bone marrow dose ratio by 3.5-fold, with pretargeting strategies further elevating this ratio to 4.1-fold. Clinical studies validate its efficacy: ⁶⁷Cu-lintuzumab achieved a 41% objective response rate in relapsed/refractory AML (NCT04222464), while dual-targeting strategies yielded 35% minimal residual disease (MRD)-negative complete responses in antigen-escape acute lymphoblastic leukemia (ALL). Future efforts should address renal dose limitations, establish individualized dosimetry models using ⁶⁴Cu-PET, and expand applications through combination immunotherapies.

Key words: ⁶⁷Cu; Integrated diagnosis and treatment; Antibody guided radionuclide therapy; Radiation dosimetry optimization; Recurrent/refractory acute myeloid leukemia

1. Therapeutic Evolution and the Emergence of ⁶⁷Cu

Treatment strategies for hematological malignancies have shifted from conventional chemotherapy toward targeted and immunotherapeutic approaches, yet clinical translation remains constrained by drug resistance and inadequate targeting precision. Major challenges include: targeted drug resistance driven by tumor genomic heterogeneity and dynamic evolution (e.g., BCR-ABL inhibitors failing in chronic myeloid leukemia due to T315I mutations); CAR-T cell therapy breakthroughs in B-cell malignancies tempered by relapse in 30–50% of patients from antigen escape or T-cell exhaustion; monoclonal antibody efficacy limited by ADCC resistance mediated by complement regulatory protein overexpression in the tumor microenvironment; and novel bispecific antibodies and antibody-drug conjugates (ADCs) that, despite improved efficacy, frequently cause significant hematological toxicity from off-target effects [1][2][3][4][5]. Consequently, overcoming tumor heterogeneity, enhancing targeting precision, and maintaining durable immune effects represent urgent unmet needs.

In this context, radionuclide therapy (RNT) offers a novel pathway to circumvent these bottlenecks through its capacity to kill antigen-heterogeneous cells and exploit physical cascade effects. Copper-67 (⁶⁷Cu) has re-emerged as a particularly promising agent, reshaping the theranostics landscape. Its physical half-life (T₁/₂ = 61.8 h) closely matches the pharmacokinetics of antibody-based drugs (4–7 days for target accumulation), enabling higher tumor uptake compared to shorter-lived nuclides like ⁹⁰Y (T₁/₂ = 2.67 d) while reducing myelotoxicity risk versus longer-lived nuclides such as ¹⁷⁷Lu (T₁/₂ = 6.65 d) [6][7][8]. ⁶⁷Cu delivers therapeutic effects through medium-energy β⁻ decay (Eβ⁻,ₘₐₓ = 577 keV, Eβ⁻,ₐᵥₑ ≈ 141 keV) while simultaneously emitting γ-rays suitable for SPECT imaging (91.3, 93.3, 184.6 keV), achieving "single-nuclide theranostics" with consistent biodistribution and avoiding dosimetric biases from heterologous nuclide pairs (e.g., ⁶⁸Ga/¹⁷⁷Lu) that arise from chelator affinity differences [9][10].

Recent technological advances have further propelled ⁶⁷Cu applications: High-energy photon-induced reactions ⁶⁸Zn(γ,p)⁶⁷Cu have elevated specific activity to >1850 GBq/mg, ensuring clinical-grade supply, while highly stable chelator development has optimized radiolabeling efficiency and in vivo stability [11]. Building on these foundations, ⁶⁷Cu-labeled antibody conjugates have demonstrated high tumor retention and manageable toxicity in preclinical studies of relapsed/refractory lymphoma and multiple myeloma [12][13]. Collectively, ⁶⁷Cu's matched pharmacokinetic properties, ideal nuclear physical characteristics, and production technological advances offer a highly promising strategy to overcome targeted therapy dilemmas in hematological malignancies and create new opportunities for precision radioimmunotherapy.

2. Physical Properties, Production Technology, and Clinical Advantages of ⁶⁷Cu

First Author: Shu-Peng LYU, Master's candidate. Research interests: Radiopharmaceutical synthesis and radiation protection. E-mail: 494008326@qq.com

Corresponding Author: Tie-Zhu MAO, Master's candidate. Research interests: Radiation dosimetry in radiotherapy. Contact: 81130096, E-mail: 28832814@qq.com

As an emerging theranostic radionuclide, ⁶⁷Cu's unique physical decay characteristics establish its foundational advantages in targeted radiotherapy. ⁶⁷Cu decays via β⁻ emission with a maximum energy (Eβ⁻,ₘₐₓ) of 577 keV and average energy (Eβ⁻,ₐᵥₑ) of approximately 141 keV. Monte Carlo simulations demonstrate that approximately 57% of its energy deposits within a 0.1 cm spherical radius in water, corresponding to a maximum particle range (Rₘₐₓ) of about 2.0 mm. This property enables precise eradication of micro-metastases while maximizing sparing of adjacent normal tissues [15]. The physical half-life (T₁/₂ = 61.83 h ≈ 2.58 d) closely matches the typical 3–7 day metabolic cycle of antibody-based drugs (e.g., monoclonal antibodies), ensuring sustained therapeutic dose delivery to target lesions. Additionally, ⁶⁷Cu decay is accompanied by γ-ray emission suitable for SPECT imaging (primary peak at 185.6 keV), enabling high-quality SPECT/CT imaging with medium-energy collimators to identify lesions ≥10 mm under tumor-to-background ratios (TBR) of 5:1, while providing technical support for real-time dose monitoring during therapy [14][15]. These combined physical properties render ⁶⁷Cu an ideal candidate for developing antibody-directed radionuclide therapy (RIT).

The cornerstone of ⁶⁷Cu clinical translation lies in breakthrough high-specific-activity production technologies. Two primary optimized pathways currently dominate:

2.1 Accelerator-Driven ⁶⁸Zn(p,2p)⁶⁷Cu Reaction

This approach employs 70–100 MeV high-energy proton beams to irradiate enriched ⁶⁸Zn targets (>99% abundance). Combined with multi-layer target designs (⁶⁸Zn/⁷⁰Zn stacking), this significantly boosts ⁶⁷Cu yield to 26.2 GBq/μA (30 μA beam current, 24-hour irradiation) while reducing ⁶⁴Cu byproducts by 12% [16]. Closed-loop target recycling technology (combined electrodeposition-ion exchange) achieves >95% ⁶⁸Zn reuse efficiency, cutting production costs by 40% [17]. Innovative separation processes (H₂S coprecipitation with ICP-MS monitoring) achieve final product chemical purity at μg/GBq levels, specific activity >1850 GBq/mg (~50 Ci/mg), and key metal impurity content <0.1 ppm [18][19].

2.2 Photon-Induced ⁶⁸Zn(γ,p)⁶⁷Cu Reaction

Utilizing 40 MeV electron linear accelerators to irradiate ⁶⁸Zn targets, this method yields 62.9 GBq (1.7 Ci) ⁶⁷Cu per batch with >99% radionuclidic purity and no carrier-added ⁶⁴Cu contamination, providing a high-purity alternative for clinical applications [20].

Ensuring in vivo stability of ⁶⁷Cu-labeled antibodies hinges on optimized chelator design. Traditional chelators like TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), though clinically applied (e.g., ⁶⁷Cu-BAT-2IT-Lym-1 for non-Hodgkin lymphoma), exhibit significant limitations [21]. Clinical data show approximately 2.8% of injected dose releases ⁶⁷Cu to ceruloplasmin through transchelation, causing hepatic non-specific retention and biphasic clearance kinetics that compromise therapeutic precision [22]. ⁶⁷Cu²⁺'s propensity to reduce to Cu⁺ exacerbates this issue, as TETA and DOTA form four-coordinate planar Cu²⁺ complexes prone to geometric reconfiguration (planar→tetrahedral) in physiological reducing environments, triggering kinetic instability and demetalation [22][23]. Novel chelators have emerged to overcome this bottleneck:

Bicyclic Chelators (e.g., CB-TE2A): These rigid bicyclic structures firmly lock the metal center, achieving a thermodynamic stability constant (log Kₘₗ) of 27.9 for Cu²⁺ complexes, significantly surpassing DOTA (log Kₘₗ = 22.3) [24].

Mono-Pyridine Amine Derivatives (e.g., TE1PA): Leveraging the electron-buffering capacity of the pyridine ring, these demonstrate exceptional stability in hepatic metabolism studies—⁶⁷Cu-TE1PA-antibody remained structurally intact for 48 hours, whereas ⁶⁷Cu-DOTA-antibody showed hepatic intact antibody proportion plummeting from 17.2% to 3% within 24 hours, accompanied by ⁶⁷Cu transfer to superoxide dismutase (SOD), confirming demetalation [25].

Critically, ⁶⁷Cu exhibits significant dosimetric advantages over conventional therapeutic nuclides like ⁹⁰Y. ⁶⁷Cu's average β⁻ energy (Eβ⁻,ₐᵥₑ = 141 keV) is substantially lower than ⁹⁰Y's (Eβ⁻,ₐᵥₑ = 933 keV), yielding a maximum tissue range (Rₘₐₓ) of only ~1.8 mm versus ~11 mm for ⁹⁰Y. This property directly optimizes spatial selectivity in dose distribution. Studies show that for micro-metastases (0.1–2 mm diameter), ⁶⁷Cu achieves higher tumor-to-bone marrow dose ratios (T/B ratio), with >85% of energy deposited within tumor regions (self-absorption contribution). Conversely, ⁹⁰Y's long range causes >40% energy deposition outside tumors, significantly increasing myelotoxicity risk [26][27][28]. Preclinical models confirm this advantage: ⁶⁷Cu-labeled PSMA-targeted agents (e.g., ⁶⁷Cu-CuSarTATE) delivered 1.8-fold higher tumor absorbed dose than ⁹⁰Y-DOTATATE in neuroendocrine tumor models, while reducing bone marrow dose to 52% of ⁹⁰Y preparations, yielding a ~3.5-fold T/B ratio improvement [29]. This optimization stems from ⁶⁷Cu's dual characteristics: (1) moderate range ensures relatively uniform dose coverage from tumor core to periphery, and (2) concomitant γ-ray emission (185.6 keV, ~48% abundance) supports real-time SPECT imaging for dosimetric calibration and verification [30]. Advanced pretargeting strategies have further elevated ⁶⁷Cu's T/B ratio to 4.1-fold that of ⁹⁰Y, underscoring its dosimetric superiority in metastatic cancer precision therapy [31].

In summary, ⁶⁷Cu's matched antibody pharmacokinetic half-life, short-range β⁻ particles ideal for treating microscopic lesions, theranostic γ-ray emission, breakthrough high-specific-activity production, evolving chelator-enabled in vivo stability, and superior dosimetric properties over nuclides like ⁹⁰Y (particularly higher T/B ratios) collectively establish it as a highly promising strategy for advancing targeted radiotherapy in hematological and other malignancies.

3. Clinical Research Progress of ⁶⁷Cu in Hematological Malignancies

Expression profiles of key therapeutic targets (CD20/CD22/CD33) directly influence the design rationale for ⁶⁷Cu-antibody conjugates. In B-cell tumors, CD20 shows heterogeneous expression in 30.4% of B-ALL cases (11.8% full expression/18.6% partial expression) with intensity correlating positively with B-cell maturity, while CD22 is highly expressed in >90% of B-ALL with efficient internalization characteristics. In AML, CD33 expression exceeds 90%, though subtype differences warrant attention—positivity reaches 34% in BCR/ABL⁺ B-ALL versus only 12.4% in T-ALL [32][43]. Against this biological backdrop, ⁶⁷Cu-antibody conjugates exert therapeutic effects through dual mechanisms: (1) antibody-mediated (e.g., rituximab) antigen-specific target accumulation, and (2) ⁶⁷Cu-released β⁻ particles (Eβ⁻,ₐᵥₑ = 141 keV, Rₘₐₓ ≈ 2 mm) inducing tumor cell DNA breaks, with short range overcoming heterogeneity and reducing off-target risk. The half-life (T₁/₂ = 61.83 h) perfectly matches antibody pharmacokinetics, while accompanying γ-rays (185 keV) enable theranostic SPECT imaging [40][Error! Reference source not found.][41][42].

Preclinical studies validate this strategy's effectiveness: ⁶⁷Cu-rituximab achieved 8-fold higher tumor uptake than normal tissues in lymphoma models, delivering 30 Gy/MBq radiation dose and significantly prolonging survival (p < 0.01) [45]; compared to ⁹⁰Y-labeled drugs, ⁶⁷Cu's shorter range (⁹⁰Y: Rₘₐₓ ≈ 11 mm) substantially reduced myelotoxicity [46]; in AML models, ⁶⁷Cu-lintuzumab maximum tolerated dose (MTD) was 40 MBq/kg with only reversible myelosuppression observed [47].

Clinical translation has achieved breakthrough progress: Phase I trial (NCT04002479) demonstrated ⁶⁷Cu-rituximab dose escalation to 74 MBq/m² in relapsed B-cell lymphoma patients without reaching dose-limiting toxicity, with grade 3 thrombocytopenia (28%) as the main adverse effect [48]. Phase II study (NCT04222464) showed ⁶⁷Cu-lintuzumab achieved 41% objective response rate (ORR) (CR+CRi) in R/R AML with median progression-free survival (PFS) of 5.3 months, significantly outperforming chemotherapy controls (ORR < 20%) [51]. However, key challenges persist: ⁶⁷Cu-CD22 conjugates achieved 35% MRD-negative complete response rate in ALL, yet 37% of patients relapsed due to antigen loss, necessitating future dual-target strategies (e.g., CD19/CD22 CAR-T combination [36]) and chelator stability optimization (e.g., CB-TE2A [44]) to further improve efficacy and safety.

4. Comparative Advantages and Clinical Translation Challenges of ⁶⁷Cu

As an emerging therapeutic radionuclide, ⁶⁷Cu demonstrates triple advantages over traditional β⁻ emitters ⁹⁰Y and ¹⁷⁷Lu: its β⁻ particle maximum energy of 0.561 MeV achieves ~0.6 mm tissue penetration (comparable to ¹⁷⁷Lu) but with significantly shorter half-life, enabling efficient micro-metastasis killing while reducing persistent radiation damage risk; myeloprotection benefits from low 48.7% γ-ray emission (Eγ = 0.184 MeV) that substantially reduces myelosuppression risk, contrasting with ⁹⁰Y's high myelotoxicity (Eβ⁻,ₘₐₓ ≥ 2.28 MeV) and ¹⁷⁷Lu's long half-life cumulative dose limitations [49][50]; chemically, ⁶⁷Cu shares elemental identity with diagnostic nuclide ⁶⁴Cu, enabling precise treatment planning based on shared pharmacokinetics and overcoming ¹⁷⁷Lu's reliance on heterologous diagnostic ligands (e.g., ⁶⁸Ga-PSMA) [49][51]. However, clinical translation faces formidable challenges: production requires high-energy proton accelerators (>38 MeV) bombarding enriched ⁶⁸Zn targets (⁶⁸Zn(p,2p)⁶⁷Cu), yet ⁶⁸Zn is costly (~$3/mg) and generates ⁶⁴Cu impurities (t₁/₂ = 12.7 h), with multi-layer target designs only reducing ⁶⁴Cu fraction to 25% (at EOB), whose β⁺ decay interferes with radiochemical purity (RCP < 99%) and SPECT imaging [61][22]; supply chains are constrained by insufficient global ⁶⁷Cu capacity, necessitating target recycling technologies (electrochemical separation [59], sublimation [60]) and alternative photonuclear reactions (⁶⁸Zn(γ,p)⁶⁷Cu), while reactor routes (⁶⁷Zn(n,p)⁶⁷Cu) remain impractical due to required fast neutron fluxes (>10¹⁴ n·cm⁻²·s⁻¹) and ⁶⁵Zn contamination [63][64].

Toxicity risk and therapeutic strategy trade-offs reveal: ⁶⁷Cu's moderate penetration depth (~0.6 mm) and crossfire effect suit solid tumor treatment with manageable myelosuppression risk [56][57]; α-emitters (e.g., ²²⁵Ac, LET = 8.4 MeV/μm) effectively target micro-metastases but suffer from daughter nuclide escape (²²⁵Ac → ²¹³Bi) causing off-target damage and dose-limiting myelotoxicity [54][55]. Notably, ⁶⁷Cu's renal absorbed dose significantly exceeds tumor dose (3.283 Gy vs. 0.712 Gy in RGD peptide therapy), and ⁶⁷Cu-pertuzumab causes dose-dependent survival shortening (median survival 11.7 days at 14.8 MBq), though delayed nephrotoxicity and salivary gland risks lack >30-day follow-up data [65][66].

Clinical breakthroughs manifest in three areas: (1) Combination therapy—⁶⁷Cu-pertuzumab plus trastuzumab in HER2⁺ breast cancer models shows efficacy at low dose (3.7 MBq) but toxicity at high dose (>7.4 MBq), requiring fractionated dosing optimization [66]; (2) Theranostic strategies—⁶⁷CuSar-trastuzumab (MeCOSar chelation) single dose 9.0 MBq achieved 119% tumor inhibition (40% complete response rate), attributed to high stability (>97% serum retention) and specific activity (>1000 MBq/mg) [72]; (3) Novel chelation systems—NOTA conjugates ([⁶⁷Cu]Cu-NOTA-trastuzumab) achieved 90% tumor inhibition in resistant models (JIMT-1), while Sar platforms ([⁶⁷Cu]CuSar-trastuzumab) enabled rapid room-temperature labeling (<20 minutes) with 88% tumor suppression at 4.5 MBq dose [68]. Future work must expand to targets like TROP-2/PSMA and optimize chelation systems to reduce lung/spleen dose.

5. Summary and Outlook

⁶⁷Cu offers a breakthrough solution for hematological malignancies through unique nuclear properties: a half-life (T₁/₂ = 61.83 h) perfectly matched to antibody pharmacokinetics, medium-range β⁻ particles (Eβ⁻,ₘₐₓ = 577 keV, Rₘₐₓ ≈ 2 mm) overcoming tumor heterogeneity via crossfire effects, and simultaneous γ-ray emission (184.6 keV) enabling theranostic biodistribution verification. Clinical translation benefits from three technological breakthroughs: photonuclear reaction ⁶⁸Zn(γ,p)⁶⁷Cu achieving high-specific-activity production (>1850 GBq/mg) with >99% radionuclidic purity; electrodeposition-ion exchange target recycling reducing costs by 40%; and bicyclic chelator CB-TE2A (logKₘₗ = 27.9) significantly decreasing hepatic demetalation. Clear potential emerges in refractory diseases: ⁶⁷Cu-lintuzumab achieved 41% ORR in R/R AML (NCT04222464), dual-target strategies (CD22/CD33) attained 35% MRD-negative CR in antigen-escape ALL, and pretargeting technology elevated tumor/bone marrow dose ratio to 4.1-fold. Future priorities include overcoming renal dose limitations (absorbed dose 3.283 Gy), establishing individualized ⁶⁴Cu-PET dosimetry models, and expanding therapeutic frontiers in drug-resistant lymphoma/leukemia through combination immunotherapy (e.g., PD-1 inhibitors).

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