Targeted radiotherapeutics (TRT) deliver radionuclides that are chemically attached to high affinity ligands to the disease site. The TRT is administered by injection and directs delivery of the radionuclide payload to the target of the ligand, such as a tumor-associated antigen.
By selecting the appropriate target antigen and a specific radionuclide with the optimal range of radiation emissions, precision medicine can be used to deliver high doses of radioactivity to cancer cells while sparing healthy tissue.
Advantages of Targeted Radiotherapeutics over Radiation Therapy
Radiation beam therapy is currently used to treat over 55% of the world’s cancer patients. It’s a powerful treatment modality as it:
- Is effective against diverse types of cancer (breast, lung, prostate, etc.)
- Can kill heterogeneous tumors composed of diverse cell types
- Can treat tumors at a distance
However, radiation beam therapy has major limitations – it requires concomitant imaging of tumors and has the side-effect of exposing healthy tissues to radiation.
Targeted radiotherapeutics combine the precision of targeted molecules with the power of radiation treatment. We can employ nuclear isotopes with radiation energy that only penetrate small distances in tissues. This spares healthy tissue from receiving exposure to radiation, while the targeting molecule delivers high levels of radiation to the tumor. Further, the targeting molecules can seek out and treat micro-metastases that would not be detectable by imaging.
In short, targeted radiotherapeutics deliver precision medicine to enhance efficacy and reduce side effects.
The Unmet Need in Metastatic Brain Tumors
30% of all patients with advanced solid tumors develop brain metastases. In the US, this represents between 100,000 to 170,000 people annually. Chemotherapeutic and biologic molecules have had limited success in accessing and treating metastatic lesions in the brain. Additionally, patients often develop brain metastases despite their primary tumors remaining in complete remission.
The current treatment paradigm for patients with brain metastases is to undergo stereotactic radiosurgery (SRS) with or without whole brain radiation therapy (WBRT). Recent clinical studies have shown that WBRT reduces intracranial failure rates, but at the cost of neurocognitive impairment and reduced quality-of-life factors. Overall survival benefits of both approaches remain limited due to safety constraints of exposing healthy brain tissue to radiation. To successfully target and treat brain metastases it is important to improve both efficacy and safety.
Breast Cancer Brain Metastases
One-third of HER2+ breast cancer patients develop brain metastases. While chemotherapeutics such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies are currently used to treat HER2+ tumors in the periphery, most of these drugs fail to reach brain metastases at sufficient therapeutic concentrations due to drug properties and/or molecular size. Further, patients with brain metastases are often excluded from clinical trial participation for fear of negative outcomes. Cereius’ lead program is directed at this population with high unmet-need, though our technology is amenable to both peripheral solid tumors and brain tumors.
CER-101 uses a VHH Targeting Ligand
VHHs, or nanobodies, were reported in 1993 by Raymond Hamers1. They consist of single-domain, heavy-chain only molecules derived from antibodies in camels, llamas, and alpacas. While capable of the same targeting affinity as that of full-size antibodies, they are 1/10th the size, and thus are quickly cleared from circulation, thus reducing exposure to normal tissues and organs. VHHs are also able to transit the brain-tumor barrier making them ideally suited for targeted therapy to tumor cells in the brain.
1Hamers-Casterman C., Atarhouch, T., Muyldermans, S., Robinson, G., Hamers, C., Songa, E.B., Bendahman, N. and Hamers, R. (1993) Naturally occurring antibodies devoid of light chains. Nature, 363, 446–448.
α- and β-emitting Radiation
Radionuclides have different types of radioactive emissions and properties. Both α and β particles can be used with our platform and the choice of isotope depends on the specific need. α Particle emissions are charged helium nuclei that have a short penetration range (30-100mm) which favors single-cell penetration. α Particles are strong ionizers and damage individual cells by causing double-strand DNA breaks, leading to high cell killing power. By comparison, β-particle emissions are high energy electrons that travel at higher speeds and can penetrate several cell depths (2-10mm), thus making them suitable for targeting heterogeneous tumors and micro-metastases.
Examples of Radioisotopes with α– or β-emitting Energy
|Half-life||8.0 d||6.6 d||7.2 hr||10 d|
|Avg. Penetration||0.4 mm||0.28 mm||<100 µm||<100 µm|
Halogens vs Metals Radionuclides
Medical radionuclides typically belong to one of two chemical classes: halogens or metals. This classification is important as it determines several properties of the radionuclide.
First, the chemical class determines the chemistry required to radiolabel a targeting ligand. Radiometals (e.g.177Lu, 225Ac, 111In, 68Ga, 99mTc) require the use of chelating agents such as DOTA, NOTA, and others. These agents allow the isotope to form a stable complex on the targeted radiopharmaceutical. Radiohalogens (e.g.131I, 18F, 76Br, 125I, 211At), however, can be covalently conjugated to the targeting ligand through either direct or indirect labeling methods.
Second, the chemical class of a radionuclide influences its biological distribution and accumulation. Iodine and astatine, for example, demonstrate biological uptake in the thyroid tissue and the gut, but exceedingly low uptake in other tissues. For halogens, dose-limiting toxicity is typically driven by renal exposure and clearance of the TRT. Cereius’ advanced radiolabeling chemistry is designed to prevent halogens from being trafficked to normal healthy tissue, providing a greater therapeutic window to improve safety and drive efficacy.
Radiometals, likewise, are subject to concerns of renal exposure and clearance. In addition, the inherent charge of radiometals, as well as the lipophilicity of chelating complexes, together drive high uptake by hepatic cells. Thus, radiometal TRT face the additional hurdle of liver and biliary exposure.
At Cereius, we have focused our first generation of pipeline compounds on radiohalogens. We believe the stability and safety of the covalent chemistry, favorable pharmacokinetics, and low biodistribution to healthy tissues provide an attractive advantage for development of clinical radiotherapeutics.