Radimmune is developing antibody-targeted radiation therapeutics, also known as radioimmunotherapy and liquid radiation. An alpha-emitting and/or beta-emitting radioisotope is guided to a universal target antigen. Radimmune has developed proprietary antibodies targeting extracellular accumulations of, normally, intracellular substances. As illustrated in Panel A of Figure 1 below, necrotic cancer cells found in rapidly growing tumors can lose membrane integrity and become leaky. In contrast, normal cells remain intact and do not release their intracellular contents. Because of the cell membrane changes in cancer cells, intracellular proteins and pigments become more readily accessible and are released into the space outside of and between cancer cells. Radimmune antibody-targeted radiation therapeutics can bind to the now accessible intracellular substances and kill nearby cancer cells (see Panel B of Figure 1). As the antibody-targeted radiation therapeutics kill more cancer cells, more and more of the target intracellular substance is released and the anti-tumor effect of repeated doses is amplified and perpetuated (see Panel C of Figure 1).
Radimmune’s greatest assets are its proprietary antibodies, as described below:
- ANTI-MELANIN ANTIBODY:
Approximately 75% of advanced cutaneous melanoma patients that are treated with checkpoint inhibitors targeting CTLA-4 or PD(L)-1 do not respond to treatment or develop refractory and progressive disease. Other melanoma populations, such as uveal melanoma patients, do not respond to checkpoint inhibitors and remain without specific, approved drugs. The difference in responsiveness to therapy is not surprising, considering the difference in molecular drivers of different types of melanoma. However, there is one universal feature of the melanomas: melanin. Melanin was selected as a target, because it is ubiquitous in all melanomas, including cutaneous, mucosal, acral, and uveal subtypes. Uveal melanoma, alone, accounts for up to 3-5% of all invasive melanomas and results in fatal, metastatic disease in approximately 50% of cases. By targeting melanin, Radimmune aims to benefit all patients with advanced melanoma, without regard to genotype, biochemical pathway activation, or individual immune responsiveness. In addition, antibody-targeted radiation therapeutics directed at extracellular tumor deposits of intracellular melanin has the potential to convert immunologically “cold” tumors, unresponsive to approved checkpoint inhibitors (i.e., PD-1 inhibitors and CTLA-4 inhibitors), into immunologically “hot” and responsive disease.
- ANTI-CENTRIN-1 ANTIBODY:
Approximately 64% of pancreatic ductal adenocarcinoma (PDAC) patients have advanced-stage disease at the time of diagnosis. The vast majority of these patients are resistant to checkpoint inhibitor therapy. Such patients have a dismal 3% survival rate at 5 years. In 2013, investigators at The Johns Hopkins University, School of Medicine reported that centrin-1 was a novel cancer testis antigen with markedly increased expression, relative to normal tissue, in both PDAC (25-fold increase) and prostate cancers (6-fold increase). Centrin-1 and the other centrins are EF-hand superfamily Ca++-binding proteins involved in centrosome separation during cell division. Because of greater than 80% homology with ubiquitous centrin-2, efforts to characterize and generate antibodies against centrin-1 has been challenging. Centrin-1 binding antibodies were ultimately created by one of Radimmune’s co-founders, Dr. Ekaterina Dadachova.
As illustrated in Figure 2, below, Radimmune’s antibodies function much like the radar and guidance system of a missile, while the attached radioisotope functions much like a warhead. Radimmune is evaluating alpha-emitting radioisotopes alone, beta-emitting radioisotopes alone, and the sequential delivery of both kinds of radioisotopes.
Alpha-emitters and beta-emitters have individual strengths and limitations. Radimmune is focused on identifying the best radioisotopes and best combinations of radioisotopes. Select characteristics of alpha-emitters (e.g., bismuth-213 and actinium-225) and beta-emitters (e.g., lutetium-177 and rhenium-188) are highlighted below.
- High linear energy transfer
- Induce lethal double-stranded DNA breaks
- Limited and non-uniform tissue penetration of 2-3 cell diameters
- Active on hypoxic tissues
- Greater than 5 cell diameter tissue penetration
- Readily available and currently used in approved products
- Requires greater radiation shielding precautions
- Familiar to hospital nuclear medicine practitioners
Radimmune is currently conducting preclinical studies to determine the optimal radioimmunotherapy approach to melanoma.