Copper-67 (67Cu)

Properties:

Copper-67 (⁶⁷Cu) is a beta-emitting radionuclide with a half-life of 61.8 h. Its main beta emissions take place at 392 keV (57%), at 483 keV (22%) and at 577 keV (20%). ⁶⁷Cu is also a gamma emitter at 185 keV (45%) and at 93 keV (16%). The mean path length is 0.7 mm. Tenth value layer (TVL) is 7.1 cm for concrete and 1.1 mm for lead. Maximum specific activity of ⁶⁷Cu is 756 Ci/mg. The commercialized ⁶⁷Cu has presently a specific activity of about 200 Ci/mg.

Manufacturing:

⁶⁷Cu is obtained by proton irradiation of targets in accelerators following the reaction process [⁶⁸Zn(p,2p)⁶⁷Cu] (medium energy around 70 MeV or high energy above 160 MeV) or [⁷⁰Zn(p,α)⁶⁷Cu] (30 MeV cyclotrons). During these processes ⁶⁴Cu is also generated and so far, this contaminant cannot be separated from ⁶⁷Cu in a proper way in this process except by playing with the difference of half-lives (half-life of ⁶⁴Cu: 12.7 hours), which indirectly leads to very low yields for ⁶⁷Cu.
At this stage, two alternatives have to be explored on the basis of this cyclotron production route:
 A 50-100 MeV accelerator/cyclotron associated with a mass separator may be an interesting solution for producing purified ⁶⁷Cu. Feasibility and real manufacturing costs needs to be evaluated as this may increase the CoGs drastically.
 The dosimetry related to the ⁶⁴Cu impurity may be of secondary importance considering the high beneficial interest of ⁶⁷Cu for the patient. Therefore, the development of mixtures of labeled molecules with ⁶⁴Cu and ⁶⁷Cu could be realistic, providing a reproducible ⁶⁴Cu/⁶⁷Cu ratio during manufacturing is feasible and health authorities accept this concept.
Several alternative production routes are now explored in parallel. Although the preferred route for production of ⁶⁷Cu is via spallation using an accelerator, low levels (mCi level) of no carrier added ⁶⁷Cu can be produced in a nuclear reactor by the (n,p) reaction via irradiation of the very expensive enriched ⁶⁷Zn targets [⁶⁷Zn(n,p)⁶⁷Cu] (high flux of fast neutrons).
A phototransmutation reaction [⁶⁸Zn(γ,p)⁶⁷Cu] can also be used to produce ⁶⁷Cu using high energy photons from Bremsstrahlungen generated by electrons accelerated at 30-60 MeV. This technology developed at Idaho University (Idaho Accelerator Center) is now producing routinely ⁶⁷Cu in small amounts (200 mCi per batch) but without contamination with 64Cu. With a larger accelerator and a different target, it can be expected that such a tool could produce up to 500-700 Ci ⁶⁷Cu a year. Rhodotron from IBA is another tool that should be able to reach the same results based on the route [⁶⁸Zn(γ,p)⁶⁷Cu]. A maximum capacity of 40 Ci/day is theoretically possible, which means a yearly capacity per accelerator above 5,000 Ci seems also realistic. This tool however, still needs to be industrialized.
Nusano (formerly Alpha Source, Inc.). is now also proposing an alternative route based on [⁶⁴Ni(α,n)⁶⁷Cu] which could lead up to thousand Ci/y nca ⁶⁷Cu with a single linear accelerator at 30 MeV and 4.0 mA, without production of the by-product ⁶⁴Cu, and even with higher yields at 50 MeV. Same capacity range as with Rhodotrons can be expected.

Derivatives:

Only a very few molecules labeled with ⁶⁷Cu have so far reached early-stage clinical trials. A larger number of molecules have been tested preclinically in tumor treatments such as ovarian cancer, colon carcinoma, or lymphoma. Very recently (May 2019) Clarity Pharmaceuticals initiated a Phase I/II study with ⁶⁷Cu-SARTATE in meningioma patients.

Clinical studies using ⁶⁷Cu-labeled antibodies in lymphoma, colon carcinoma and bladder cancer patients went through phase I/II studies but are presently on hold. ⁶⁷Cu-labeled antibodies show some advantages over ¹³¹I-labeled molecules in terms of higher uptake and better tumor/blood ratios with however, a negative impact on the radiation dose to the liver in both lymphoma and colon carcinoma patients.

Given the favorable properties of ⁶⁷Cu-labeled antibodies, it is the reliable availability of the ⁶⁷Cu nuclide which is the limiting factor for their more widespread evaluation in radioimmunotherapy trials.

COPPER-67-LABELED MOLECULES UNDER DEVELOPMENT

Target/Mechanism	D	Molecule	Company	Issues – Comments
Bombesin receptor GRPR	–	67Cu-SAR-BBN	Clarity Pharmaceuticals	Preclinical
CEA	3	67Cu-CTPA-mAb35	Generic	Colon cancer
sstr	3	67Cu-SARTATE	Clarity Pharmaceuticals	Phase I initiated in 2019 in meningioma
VPAC1	–	67Cu-NV-VPAC1	NuView Life Sciences	Breast cancer – Preclinical

Source and availability:

A series of reactors over the world have tried to produce and are selling small amounts of ⁶⁷Cu. Other solutions based on high-energy accelerators generate smaller amounts of ⁶⁷Cu. No producer is able to provide batches of bulk ⁶⁷Cu in high amounts (several curies) with a high purity. Largest batch sizes for bulk ⁶⁷Cu obtained from the cyclotron production route and therefore, containing ⁶⁴Cu (less than 3%) are in the range of 300 mCi after 8 to 10 days irradiation (30 MeV cyclotron, 100µA).

In 2011 the Idaho Accelerator together with the Idaho State University claimed to have developed a technologically advanced method for producing ⁶⁷Cu. In July 2014, ISU obtained a license to produce ⁶⁷Cu for research purpose and clean ⁶⁷Cu is now available from this site. Maximum batch size is presently 200 mCi (obtained after 10 h irradiation in an 8 kV/h accelerator).
The company Iotron is also commercializing a new production method developed at the LEAF Linac located at Argonne National Laboratory in Chicago based on electron beam

technology (phototransmutation technology with a compact electron beam linac). Since 2018 Argonne is producing about 1 Ci/batch. Upon increasing request, Iotron is willing to implement a private production unit with higher capacity.

In October 2016, NIDC announced that ⁶⁷Cu would become routinely available from the DoE (BNL and Argonne National Laboratory). BNL is producing on the basis of the proton irradiation of a ⁶⁸Zn target while Argonne will produce on the basis of the phototransmutation (γ,p) reaction. Indeed, ⁶⁷Cu became available in small amounts from January 2020 on, (monthly basis, 1 Ci batches, with an EOB specific activity of 50 Ci/mg). At the same time (March 2020), Korean researchers (KAERI) announced that they made ⁶⁷Cu available in South Korea for research purpose. The 30 MeV cyclotron capacity would be of about a dozen mCi of ⁶⁷Cu, in other words far below the large needs of a drug on the market. Distribution should begin during the second half of 2020.
Since January 2021, the company Iotron is producing ⁶⁷Cu on a bi-weekly basis in batches of 2-10 GBq (54-270 mCi).

Other non-regular production sites include PSI (Switzerland, 67 MeV cyclotron 70 A; irradiation of ^natZn; 2.45 GBq/day) and KIPT (Ukraine; electron Linac 41 MeV 200 µA; irradiation of ^natZn; 36.3 GBq/day).

Price:

Due to the long irradiation time, the difficult purification process and the very low yields, doses of ⁶⁷Cu are produced on a single animal or patient basis. A rough calculation showed that in absence of improvement of the production yields (cyclotron route), a single patient dose of ⁶⁷Cu could cost more than EUR 30,000 (US$ 39,000), a figure that kills any full-scale development project, even if the radionuclide had the most interesting profile. The new production tools could bring this price in the same range as the competitor ¹⁷⁷Lu.
The new approach from IAC allows the production of small amounts of ⁶⁷Cu with a catalogue price for the time being set at US$100/mCi. Specific activity is also high at about 450 Ci/mg.

Issues with the cyclotron route:

 ⁶⁷Cu production yields remain low, explaining the rare clinical trials that have been initiated so far.
 Highest specific activity obtained so far via the cyclotron route is around 200 Ci/mg compared to the theoretical specific activity which should be around 755 Ci/mg.
 All batches of ⁶⁷Cu contain high amounts of ⁶⁴Cu, which can be reduced, if one leaves the bulk product decay over a few days. Unfortunately, overall yields are also reduced. Present specifications require ⁶⁴Cu content to remain below 3% which remains quite high for therapeutic doses.
 Zinc contamination is possible depending upon the quality of purification process.
Zinc is of course competing with copper for labeling.
To solve all these problems, the best solution will be to implement production sites based on new technology, i.e., some high level investment (two or three times EUR 30-40 million) will be needed to guarantee sustainable access.

Comments:

⁶⁷Cu is a beta emitter with a nice therapeutic profile that, when combined with ⁶⁴Cu could even provide a nice pair of theranostics. Although, because ⁶⁷Cu is also a gamma emitter, this latter could be self-sufficient as a theranostic. There are huge investment needed to solve, to reach the worldwide capacity needs and the adequate purity. Present limitations in manufacturing larger amounts of ⁶⁷Cu are freezing most of the investment interest because projects based on ⁶⁷Cu are presently not economically viable. The radionuclide will have a future only when the manufacturing issues will be solved. It seems that the Idaho accelerator process, the Rhodotron solution and the AlphaSource option are two realistic alternatives that could start a new life for ⁶⁷Cu.
If the high production capacity of the new production projects is confirmed, then one single center and a backup center on another continent could be sufficient to answer to the worldwide needs. In this case the price of ⁶⁷Cu will drop and one can estimate that ⁶⁷Cu will not be much more expensive than ¹⁷⁷Lu (even taking in account the future drop of price of ¹⁷⁷Lu due to high competition).
In any case, one should now consider that ⁶⁷Cu will be part of the future armamentarium of the developers of radiotherapeutics. The company Clarity Pharmaceuticals has already entered this strategy.