Radiation therapy has been explored as a treatment for cancer right back to the turn of the 20th century, only a few years after the discovery of X-rays. [1] A lot of research has gone into making radiation therapy safer and more effective, including the development of radioconjugates – targeted molecules designed to carry radionuclides directly to cancerous cells, lowering systemic exposure and increasing the precision of treatment.
Targeted conjugates: an introduction
Targeted drug conjugates were a step forward in cancer treatment by improving efficacy and safety compared with conventional chemotherapeutics. These combine a tumour-targeting ligand (an antibody, peptide or small molecule) with a cytotoxic molecule, connected by a chemical linker. By taking the chemotherapeutic to the cell, the conjugates reduce off target effects, lower the risk of resistance and allow the precision use of higher toxicity drugs. [2] The concept of targeted drug conjugates has been extended to create radioconjugates (also known as radionuclide-drug conjugates or RDCs) that carry radioisotopes directly to cancer cells, for diagnostic imaging, and to deliver radiotherapy. Radioconjugates have a similar make-up to the targeted drug conjugates: a tumour-targeting ligand, a linker/chelator and a radioisotope payload.
The role of the targeting ligand is to guide the radioconjugate to its desired location, where it can bind to the target on the cell. The ligand can be an antibody (creating a radionuclide antibody conjugate or RAC) or a peptide or small molecule chosen for its high affinity to the antigens on the surface of the target cell. [3-5]
Examples of targeting ligands for radioconjugates: [5]
· Antibodies
o CD20, CD37, CA 19-9
· Peptides
o Octreotide acetate targeting somatostatin receptor type 2
· Small molecules
o Fibroblast activation protein inhibitors
The linker and chelator connect the targeting ligand and the payload. Non-metallic isotopes, such as I-131 and I-123, can be connected directly to a ligand using a linker alone, whereas metallic isotopes need a chelator (such as DOTA and DTPA) as well as a linker. The linker and chelator must be designed to not affect the binding ability or the targeting ligand or the activity of the isotope. The linkers are generally non-cleavable to reduce cross-linking, improve the stability and increase the safety of the conjugate. [3-6]
The choice of radioisotope payload will depend on whether the conjugate is designed to be a therapeutic or an imaging agent. Diagnostic isotopes are β+- or γ-emitting and can be detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The chosen radionuclide should have a short half-life and the conjugate should be eliminated from the body rapidly to limit radiation exposure to the patient. Examples include Tc-99m, I-123, I-124, F-18, Cu-64, Zr-89, Ga-67 and Ga-68.
Therapeutic isotopes generally emit short-range particles such as α or β particles that kill target cells, and examples include Ac-225, I-131, Lu-177, Y-90, and Ra-223. Alpha emitters can be more effective for faster growing cancers, and the longer paths of β radiation emitted by Y-90 and Lu-177 can also trigger a bystander effect, which can kill nearby cells that don’t carry the target antigen. The isotope half-life should be long enough for therapeutic efficacy. [3, 5, 6]
The challenges and benefits of radioconjugates
Radioconjugates need to be manufactured and shipped to patients within hours or days, especially when they are being used as a last line of treatment in seriously ill patients. However, the logistics can be challenging as the radionuclides have a specific half-life, their availability may be limited and there are regulations around their handling and shipping. The manufacturing process for the radioconjugates is also complex. [4, 6]
By targeting a radionuclide directly to the cancer site, therapeutic radioconjugates reduce overall system exposure to radiation, while allowing a higher local dose of a radionuclide, reducing damage to healthy tissues....
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