Actinium's Antibody Radio-Conjugate Platform
Actinium's Warhead Enabling (AWE) platform can be used to produce AWE conjugates, a highly potent and selective form of targeted therapy. Application of the AWE technology precisely targets the proven therapeutic power of radiation to tumors. AWE conjugates exploit the use of highly selective targeted biological agents such as monoclonal antibodies that can seek out and bind cancer antigens found on the tumor cell surface. Once there, the AWE conjugate delivers a potent tumor-destroying dose of the radiation from the actinium warhead. The power of this technology lies in its alpha emitting payload actinium-225. It emits a powerful dose of high energy but only over a very short distance - about the distance of a few cells or less than the thickness of a piece of paper. This focuses the radiation on the cancer cells and limits exposure to normal tissues. The energy delivered is so strong that one or two targeted actinium warheads may be sufficient to kill a tumor cell. The figure below depicts therapeutic Antibody (or Alpha) Radio-Conjugates (ARCs) using different types of targeting agents.
Alpha particles are an ideal payload for targeted cancer radiotherapy. Actinium’s AWE technology has been evaluated in multiple preclinical models of both blood cancers, such as acute myeloid leukemia, and solid tumors like breast cancer, prostate cancer and colon cancer demonstrating broad potency across a number of different tumor types. This encouraging preclinical data led to the initiation of several clinical trials in humans, particularly in patients with acute myeloid leukemia (AML).
AWE conjugates generated by the AWE Technology Platform forms the basis for three of The Company’s drug candidates; Actimab-A that is being studied in a Phase 2 trial for patients with acute myeloid leukemia (AML), Actimab-M that is in a Phase 1 trial for patients with multiple myeloma and Actimab-MDS that is expected to begin a Phase 2 trial as a bridge to transplant for patients with myelodysplastic syndrome (MDS) that have a p53 genetic mutation. Each of these programs targets the CD33 protein found on most types of AML cells and on certain forms of multiple myeloma cells.
The AWE conjugate is made up of three main component parts, (1) the targeting vehicle, which may be a monoclonal antibody, an antibody fragment, or a small molecule like a peptide; (2) the potent actinium-225 radioactive warhead; and (3) a linker-chelator that connects the targeting vehicle to the actinium warhead. The targeting vehicle carries the actinium-225 warhead to the site of the tumor, where it can deliver its highly potent tumor cell killing energy. The chelator keeps the actinium-225 warhead stably attached to the targeting vehicle, so that its powerful radiation is efficiently delivered to the tumor site. This limits the radiation to the tumor, potentially sparing normal tissues and organs. This approach contrasts with external radiation where the radiation may pass through and damage normal tissue on its way to the tumor. Once at the tumor site, the AWE Platform generated actinium radio-conjugate or AWE conjugate binds to the surface of tumor cells and may be internalized inside the tumor cells. As the actinium-225 radionuclide warhead decays, whether on the surface or inside the cell, it can emit a total of 4 high energy bursts in the form of alpha particles, each of which can elicit a powerful anti-cancer punch on the bound and targeted tumor cell or even on adjacent untargeted tumor cells. As a result, a small number of AWE conjugates can be very potent even in cancers where the amount of the cancer antigen on the tumor cell surface differs across cancer cells. The cell-killing effect is further compounded by the “bystander effect” where nearby tumor cells may be susceptible to the actinium-225 warhead of the AWE conjugate that is bound to another tumor cell.
Enablement via the AWE technology has the potential to dramatically improve the potency of a therapeutic antibody or another targeting biologic agent. Many therapeutic antibodies rely solely on the patient’s immune system, so-called “effector function”, to help slow the growth of cancer. However, the addition of an actinium-225 warhead may significantly enhance the anti-cancer activity of the antibody, making it potentially a more effective therapy. Through AWE technology there is the potential to generate more efficacious and safer therapies for patients.