Radionuclide drug conjugates (RDCs) can be classified in terms of the form of targeting molecules as antibody targeted radionuclide antibody conjugates (RACs), and small molecule based (including peptides) radionuclide drug conjugates. RDC, as an innovative drug conjugate form, has many similarities from both antibody drug conjugates (ADC) and small molecule drug conjugates (SMDC). In terms of drug structure, RDC consists mainly of an antibody or small molecule served as ligand that mediates the targeting action, a linker, a chelator, and a bifunctional effector molecule, radioisotope, used as cytotoxic and imaging factor, which is the similarity between RDC with ADC and SMDC. The main difference between RDC and ADC and SMDC is the drug load, as RDC is no longer a small molecule but a radionuclide, different medical radionuclides can be used for different functions of imaging or therapy, and some radionuclides have both capabilities.
The small size of radioisotopes that is only one atom leads to low stability and uncontrollability of radioisotopes. Therefore, it is expected that radioisotope should be stapled into larger functional molecule, such as antibodies, to achieve better control. Radiolabeled antibodies, that is antibody-radioisotope probes, are able to recognize and interact with specific antigens to provide targeted imaging or specific damage to human tumor cells. In addition, for solid tumors, radioisotope probes coupled with small size antibodies such as single structural domain antibodies or scFv offer the advantages of higher clarity to visualize tumors and monitor progression due to their small size and good tissue penetration. As a result, monoclonal antibodies can be developed as the radionuclide delivery tools for imaging and treatment of various cancers.
In both RDCs and ADCs, the targeting ligands are both used to guide the cytotoxic or radionuclide to the target, while differences in composition between RDC and ADC, requiring the addition of a specific functional group structure for chelating toxins. Antibody and radionuclide of RDC are connected by two parts, linker and chelator that is used to chelate radionuclide. In the case of chelates linked to antibodies via Linker, the conventional covalent binding of reactive functional groups can be used. For example, N-hydroxysuccinimide ester (NHS), thiocyanate (SCN) and anhydride are the most commonly used reactive electrophile groups, which can react with the ε-amine group of lysine on the antibody under alkaline conditions. Under such conditions, chelators containing NHS- or SCN can be linked to antibodies through strong covalent bonds, and the radiolabeling is performed by the complexation process of chelators. However, if NHS or SCN is used for the chemical coupling reaction, it may result in a lack of site specificity. In general, chelation of radioisotopes to antibodies requires the use of chelators. Such as 131I, 123I and other non-metallic radioisotopes can be bound to tyrosine residues of monoclonal antibodies or small molecules, while metallic radioisotopes need to be coupled by macrocyclic and acidic molecular chelators, including DOTA, DTPA, TETA, NOTA, HEBD, etc.
Radioisotopes also called radionuclides are atoms with excess energy. The nucleus can spontaneously emit particles or rays, releasing a certain amount of energy, while the number of protons or neutrons changes and transforms into the nucleus of another element. This property of an element is called radioactivity, and such a process is called radioactive decay, mainly including α-decay, β-decay, electron capture and isometric transition. Decay is a random process occurring at the level of individual atoms and cannot be predicted for a particular atom. Considering the physical properties and availability of radionuclides, most clinical development programs for radioimmunotherapy involve the use of β-decay radionuclides.
Therapeutic RDCs are the use of antibodies or small molecules including peptides to achieve the purpose of precise radiotherapy, killing tumors while reducing radiation to normal tissues. Diagnostic RDCs carry radionuclides and can perform functions for tumor scanning, imaging and diagnosis, meeting the clinical demand for integrated radionuclides therapy and treatment.