In today's pharmaceutical industry, an innovative therapeutic known as "Radionuclide Drug Conjugates" (RDC) is gradually making its mark. In the 2023 FDA's approval, there is one drug called flotufolastat F-18 (Posluma). It is an intravenous binder to PSMA expressed on cells for PET imaging of prostate cancer marketed by Blue Earth Diagnostics. The active ingredient is flotufolastat F 18 gallium, which is composed of a DOTAGA complex with nonradioactive gallium, and a radioactive fluorine-18 covalently bound to silicon. Upon binding to PSMA expressed on cells, F-18 can be detected using a PET scan as it is a β+ emitting radionuclide. Leveraging the power of the human immune system and advanced radioactive technologies, RDCs offer new avenues for diagnosing and battling diseases such as cancer. So, what are RDCs? This article provides a detailed explanation of RDC components, the industry landscape, and their application in the field of medicine.

The chemical structure of the Posluma API. src: Posluma package

Basic Concept of RDC

Radionuclide Drug Conjugates (RDC) represent an innovative class of theranostics (therapeutic and/or diagnostic) that combine the targeting abilities of antibodies or small molecules (including peptides) with the potent therapeutic capabilities of radioisotopes. The diagnostic application comes from the high penetrating radiative energy that can be detected by SPECT and PET, while the therapeutic application comes from the non-penetrating particles. Specifically for the latter, these RDC drugs achieve their therapeutic effect by precisely targeting tumor cells and using the energy released by radioisotopes to destroy them.

Composition of RDC

RDC drugs are primarily composed of four parts: the targeting antibody or small molecule (Ligand), the Linker, the Chelator, and the cytotoxic/imaging agent (radioisotope).

Four components of a typical RDC. src: Kostelnik, T. I. & Orvig, C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 119, 902–956 (2019).

• Targeting antibody or small molecule (Ligand/Bioconjugate): This critical component of RDC drugs accurately identifies and binds to tumor cell surfaces, guiding the drug to the targeted location.

  
  

• Linker: The linker connects the antibody or small molecule to the radionuclide, ensuring drug stability and targeting while also releasing the radioisotope when appropriate.

  
  

• Chelator: Chelators firmly bind to radioisotopes, preventing their free spread within the body, thus ensuring the drug's safety and efficacy.

  
  

  Structurally speaking, chelators can be divided into marcocyclic chelators and acyclic chelators. The former require minimal physical manipulation as a result of the inherently constrained geometries and partially pre-organized metal ion binding sites. Examples include DOTA and DOTA derivatives such as p-SCN-Bn-DOTA (currently the primary workhorse chelators for radiochemistry and is considered one of the gold standard for a number of isotopes) and NOTA and its derivatives (one of the oldest and most successful chelators for use with Ga-67/68 and Cu-64). On the contrary, acyclic chelators have to undergo a change in physical orientation and geometry in solution for coordination to happen. But acylic chelators excel in coordination kinetics and radiolabeling efficiency. In other words, acyclic chelators could coordinate with radionuclides faster than macrocyclic chelators do without the need for heating.

Structure of DOTA-NHS ester

Structure of a DOTA derivative, CAS No. 127985-74-4, p-SCN-Bn-DOTA

Structure of NOTA

• Cytotoxic/imaging agent (radioisotope/radiometal): This core component of RDC drugs damages tumor cells by releasing energy or assists in medical imaging, helping doctors more accurately determine a tumor's location and size.

Industry Supply Chain

• Upstream raw material suppliers: RDC drugs' upstream primarily includes suppliers of antibodies, small molecules, linkers, chelators, and radioisotopes. Typically, radioisotopes can be obtained through nuclear reactors, particle accelerators, or radioactive waste processing. The quality and supply stability of these materials significantly impact the research, development, and production of RDC drugs. What further makes RDC 'special' is that the core material - radioisotopes can be of restricted accessibility, which makes the RDCs of high entry barrier. For instance in China, other than NMPA, the National Energy Administration, the Ministry of National Defense, and the Ministry of Ecology and Environment, etc. oversee the manufacturing, logistics, and storage of RDCs.

  
  

• Drug research and manufacturing companies: After obtaining upstream materials, these companies need to precisely synthesize and process them to ensure RDC drugs' quality and therapeutic effect. Additionally, extensive clinical trials are required to verify the drug's safety and efficacy.

  
  

• Pharmaceutical distribution and sales channels: Once RDC drugs succeed in development and approval, they enter hospitals, pharmacies, and other terminal markets through distribution and sales channels for patient use. Logistics, warehousing, and distribution play key roles in the drug supply chain and accessibility. Because some isotopes have relatively short half-lives, the RDC manufacturing sites and the distribution sites sometimes are located within a certain geographic radius of qualified hospitals to ensure the accessibility of high-efficacious RDCs.

  
  

• Medical institutions and patients: Medical institutions are the primary sites for RDC drug use, where doctors select appropriate drugs for treatment based on the patient's condition and needs. Patients are the ultimate beneficiaries of RDC drugs, as the treatment can improve their health and quality of life.

Application Prospects of RDC

With the ongoing development of medical science and technology, RDC drugs have an increasingly broad application prospect in cancer treatment. Compared to traditional chemotherapy and radiotherapy, RDC drugs offer higher targeting precision and lower side effects, allowing for more accurate tumor cell eradication while minimizing damage to normal cells. Moreover, RDC drugs can be combined with medical imaging technologies to assist doctors in more accurately determining the size and location of tumors, providing a more precise basis for treatment.

In summary, as an innovative form of therapy, RDC drugs are bringing new changes to the field of medicine. They offer new possibilities for cancer treatment by precisely targeting and destroying tumor cells. As technology continues to advance and clinical applications deepen, RDC drugs are expected to become a significant role in precision medicine.

References

Peltek, O. O., Muslimov, A. R., Zyuzin, M. V. & Timin, A. S. Current outlook on radionuclide delivery systems: from design consideration to translation into clinics. J Nanobiotechnol 17, 90 (2019).

Department of Biocatalysis and Isotope Chemistry, Almac, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, UK & Kitson, S. L. Application of Radionuclides and Antibody-Drug Conjugates to Target Cancer. Cancer Stud Mol Med Open J 1, 8–15 (2014).

Amoroso, A. J., Fallis, I. A. & Pope, S. J. A. Chelating agents for radiolanthanides: Applications to imaging and therapy. Coordination Chemistry Reviews 340, 198–219 (2017).

Price, E. W. & Orvig, C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 43, 260–290 (2014).