Drug conjugates combine precise targeting with potent cell-killing abilities, making them a highly promising form of treatment that has garnered significant attention recently. Radionuclide drug conjugates (RDCs) are an emerging cancer therapy that integrates these two advantages. They use specific ligands to deliver a radioactive payload directly to cancer cells, focusing the radiation on the tumor while minimizing damage to surrounding healthy tissue.

Structure and Mechanism of RDCs

RDCs comprise four key components: a targeting ligand (such as antibodies, peptides, or small molecules), a linker, a chelator, and a radionuclide (see Figure 1). The targeting ligand directs the radionuclide to the tumor site by binding to antigens that are highly expressed in tumor cells. Once there, the radionuclide emits α, β particles, or Auger electrons, which cause DNA damage, effectively killing the target cells. The emitted radiation from the radionuclide not only destroys tumor cells on the surface or in shallow layers but also penetrates deeply into tumor tissues. Additionally, β radiation with longer paths (^90Y, ^177Lu) can induce a bystander effect, killing neighboring tumor cells that lack the target antigen.

Figure 1. Structure of RDCs

The targeting ligand acts as an anchor, holding the therapeutic radioisotope in or near the tumor. These ligands can include peptides (e.g. octreotide acetate targeting somatostatin receptor type 2), small molecules (e.g. fibroblast activation protein inhibitors), and antibodies (e.g.  CD20, CD37, or CA 19-9 antibodies). Currently, the most popular RDC targets are prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAP), and human epidermal growth factor receptor 2 (HER2) (see Figure 3). Other targets include somatostatin receptors (SSTR), CXC chemokine receptor 4 (CXCR4), and neurotensin receptors (NTR).

A radionuclide refers to an atomic nucleus or atom with a specific nuclear charge and mass number that exists in a particular energy state. Unlike stable nuclides, radionuclides have unstable nuclei that spontaneously decay, emitting α and β radiation. This emitted radiation can be detected and harnessed for therapeutic purposes.

The linker and chelator serve as bridges, connecting the targeting ligand to the radionuclide. The choice of chelator plays a crucial role in selecting the appropriate radioisotope. Ideally, the selected bifunctional chelator (BFC) should form highly stable complexes with the radioisotope. Low stability can lead to cross-linking or transmetalation, resulting in radiotoxicity. Commonly used BFCs in RDCs include DOTA, DTPA, NOTA, and DFO, which are continually being improved and optimized.

Advantages of RDC Drugs

Compared to conventional targeted cancer therapies, RDCs offer several unique advantages due to their distinct structure and physicochemical properties.

• ▶ Integrating diagnostics and therapy: During diagnostic imaging, some radionuclides emit positrons or photons to measure the location of tumors. After the imaging is completed, RDCs equipped with α-, β- or Auger particle-emitting nuclides can be used for treatment.
• ▶ Reduced Drug Resistance: Traditional therapies often rely on the body's biochemical processes and cellular signaling pathways, which can lead to drug resistance over time. In contrast, RDCs exert their therapeutic effects primarily through physical radiation, making them less likely to encounter resistance.

RDC Drugs – Approved & In Clinical Trials

The development of RDCs has progressed rapidly, with Novartis leading the field with several RDC drugs in its portfolio. Since 2016, the FDA has approved nine RDC drugs, involving six new molecular entities. Among these, seven are used for cancer diagnosis, and two are for cancer treatment. The primary targets of these drugs are PSMA and SSTR. The two most prominent RDC therapies on the global market are Lutathera and Pluvicto, which achieved sales of $471 million and $271 million, respectively, in 2022.

Table. Approved RDC Drugs

Lutathera: The World's First RDC Drug

Lutathera is the first peptide receptor radionuclide therapy (PRRT) approved by the FDA. It was approved in Europe in October 2017 and in the United States in January 2018. Lutathera is a somatostatin analog peptide labeled with the radioactive isotope ^177Lu. The octreotide within Lutathera binds to somatostatin receptors on the surface of tumor cells, delivering the radioactive ^177Lu into the cells. The emitted β radiation damages the tumor cells, making Lutathera effective in treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that express somatostatin receptors (SSTR).

Clinical data show that Lutathera improves overall survival (OS) compared to long-acting octreotide alone. Lutathera was approved based on the NETTER-1 study, which included 229 patients with advanced SSTR-positive GEP-NETs. In 2021, ASCO reported Phase III trial results showing that patients treated with Lutathera plus long-acting octreotide (30 mg) had a median progression-free survival (PFS) of 29 months compared to 8.5 months for those treated with long-acting octreotide (60 mg) alone. This combination reduced the risk of disease progression by 79% and the risk of death by 60%. The objective response rate (ORR), which measures the probability of tumor shrinkage by more than 30%, was 13% for the Lutathera group compared to 4% for the octreotide-only group—a threefold increase. Moreover, Lutathera extended overall survival (OS) by 17.1 months compared to long-acting octreotide alone.

Pluvicto: Rapid Growth in Its First Year

Pluvicto, approved by the FDA in March 2022, quickly gained traction for treating metastatic castration-resistant prostate cancer (mCRPC). Its efficacy surpasses that of Olaparib, a leading PARP inhibitor. In treating mCRPC, Pluvicto demonstrates superior median progression-free survival (mPFS) and overall survival (OS) compared to Olaparib, with similar safety profiles and a slightly lower incidence of adverse reactions.

Prospects and Challenges of RDC Drugs

The increasing application of radionuclide drug conjugates (RDCs) in cancer imaging and treatment is driving rapid market growth and future demand, opening new avenues for the development of conjugated drugs. Despite significant technical barriers and numerous challenges—including difficulties in production, distribution, and storage; limitations in skilled personnel and equipment; the need for expert training; regulatory improvements; the alignment of clinical trials with real-world scenarios; high costs; and balancing efficacy with toxicity—there is optimism that these issues will gradually be resolved. With the involvement and strategic planning of many domestic and international pharmaceutical companies, RDC drugs hold the potential to offer patients more treatment options.

References:
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