A radioligand has three modules. The ligand binds an antigen on the surface of the tumor cell. A chelator (a ring of donor atoms which holds a metal ion) carries the radiometal, and a linker joins the two and sets the charge and clearance of the whole molecule. Since the chelator binds both gallium and lutetium, the same molecule is used for imaging when it is labeled with ⁶⁸Ga and for therapy when it is labeled with ¹⁷⁷Lu.
Antigens over-expressed on solid tumors with few treatment options and expressed at low levels in healthy adult tissue. Because the same ligand is used for imaging, the presence of the target is confirmed in each patient by a PET scan (positron emission tomography) before any therapy is given.
Peptides of fewer than 40 amino acids. Molecules of this size penetrate tumor tissue and are cleared from the blood within hours, so the dose to healthy organs is small in comparison to that from an antibody, which circulates for days. Each candidate is designed against a defined patch on the target and ranked on what is measured rather than on what is predicted.
Gallium-68 (⁶⁸Ga) for PET imaging and lutetium-177 (¹⁷⁷Lu) for therapy, on the same ligand. Since ¹⁷⁷Lu also emits gamma rays, the dose delivered to the tumor and to each organ is measured by SPECT after each treatment rather than assumed. An alpha-emitting payload is in development for the tumors that need more energy deposited over a shorter range.
A radioligand needs a binder with a long residence time on the target, a short residence time everywhere else, and a site at which a chelator can be attached without disturbing either. No single discovery technology delivers all three on every target, so we run several in parallel and let the measured data decide which candidates go forward. Peptides are the first modality, since a peptide of fewer than 40 residues clears within hours and carries a chelator without difficulty; small molecules are pursued where the target has a pocket a peptide cannot reach.
Whichever technology finds the binder, the same measurements decide whether it is a candidate: off-rate on the target, clearance from healthy organs, and a labeling site that survives conjugation.
A hit becomes a candidate by surviving three stages in order: lead optimization, candidate nomination, and radiolabeling method development. Each stage has its own measurements and its own reasons for stopping a compound, and the radiochemistry is in the room from the first of them, since a binder which cannot be labeled is not a drug.
Affinity is the entry ticket; residence time, selectivity, and clearance are what are optimized. Analogs are made by solid-phase synthesis, measured label-free for the off-rate, and profiled for stability in serum, for organ clearance, and for the net charge and lipophilicity that govern where the dose goes. The chelator and its attachment site are fixed early, because moving them later changes everything measured before.
The ⁶⁸Ga and ¹⁷⁷Lu versions of the two or three best compounds are compared head to head in tumor-bearing animals for tumor uptake, retention, and organ clearance. A candidate is nominated on that data, with a written target product profile and the first specification of what the clinical product will have to be.
The labeling reaction is developed into a method a manufacturing site can run: precursor amount, buffer, temperature and time, radiolytic protection, and the quality-control methods which prove radiochemical purity and identity. The method is written so that the same procedure serves the imaging agent and the therapy, and so that it transfers without rework.
Two radionuclides carry every program into the clinic, one for imaging and one for therapy, and an alpha-emitting payload is in development on the same ligands. Each ligand carries a chelator that binds ⁶⁸Ga for PET and ¹⁷⁷Lu for therapy, and the imaging agent enters the clinic first, to show that the target is present in patients and that the ligand reaches it at a useful concentration.
Gallium-68
PET
Lutetium-177
β⁻, γ for SPECT
Alpha emitter
in development
| Radionuclide | Emission | Half-life | Range in tissue | Role | Supply |
|---|---|---|---|---|---|
| Gallium-68 | β⁺ (positron), for PET | 68 min | Not used for therapy | Imaging and patient selection | ⁶⁸Ge/⁶⁸Ga generator at the imaging site |
| Lutetium-177 | β⁻, with γ lines at 113 and 208 keV for SPECT | 6.65 d | 0.67 mm mean, 2 mm maximum | Therapy, with post-treatment imaging and dosimetry | Reactor-produced, no-carrier-added |
| Alpha emitter | α, one or more per decay | Hours to days | 50–100 µm | Alpha therapy, in development | Undisclosed |
Half-lives and emissions are evaluated values (ENSDF, IAEA). Ranges are approximate values in soft tissue.
Beta and alpha particles differ in energy, in range, and in the kind of damage they do to DNA, and each suits a different kind of tumor. Beta emitters such as ¹⁷⁷Lu are suited to larger and heterogeneous tumors, since a beta particle travels far enough to irradiate neighboring cells that carry less of the target (the cross-fire effect). Alpha emitters are suited to small metastases and to resistant, hypoxic cells, since a few alpha traversals kill a cell regardless of its oxygen supply. Our ligands are designed to carry either, which is why the chelator and the conjugation site are fixed before a panel is synthesized.
A radiopharmaceutical is made for a named patient and used within hours of manufacture, so there is no opportunity to test a batch at length before it is given. Quality has to be designed into the process from the first clinical batch, the process has to transfer to a site that can run it on the day it is needed, and the whole supply chain has to work to the clock set by the half-life. CMC is a core competence of the company, not a service bought in.
Analytical methods for identity, radiochemical and radionuclidic purity, specific activity, and sterility are developed and validated to ICH and pharmacopoeial standards, with acceptance criteria set by the product's own data rather than borrowed from another.
Processes and methods are transferred to contract manufacturers with complete documentation, on-site training, and comparability data, and the sites are managed under quality agreements that state who decides what. We have done this on both sides of the agreement.
Every dose is scheduled backwards from the time of administration: radionuclide delivery, labeling, release testing, and transport are planned per patient with the decay accounted for at each step, so that the activity that arrives is the activity that was prescribed.
Release testing that fits inside the half-life, a stability program that sets the shelf life, and a quality system that keeps the whole process in agreement with the approved filing.
Every dose is manufactured, released, and administered on a schedule set by the half-life of the radionuclide, which for ⁶⁸Ga is 68 minutes. The process has to work the first time, since there is rarely time to repeat it.