Unleashing the Power of Alpha for HER2-Expressing Tumors
Targeted Thorium Conjugates (TTCs) are an emerging class of radionuclide therapy that delivers alpha radiation directly to tumors inside the body. By targeting HER2, our investigational HER2-TTC may offer a novel, powerful tool for treating a wide range of aggressive tumor types.
Certain cancers tend to grow faster and are more likely to spread and recur after initial treatment. Some particularly aggressive types of cancer have been linked to the expression of HER2, the Human Epidermal growth factor Receptor 2. There are over 20 tumor types that express HER2, including breast, stomach (gastric), ovary, endometrium, bladder and lung cancers. Current treatments targeting HER2, however, are only approved for breast and gastric cancers that express high levels of HER2.
In focus: Difficult to treat cancers
“Patients with aggressive cancers often do not have a lot of time. Current treatments are effective for some patients, but there remain significant challenges in treating HER2-expressing cancers,” says Dr Vicki Jardine, Clinical Development Lead for Bayer’s HER2-TTC program.
At Bayer, scientists are hoping to change this outlook with promising advances in the new field of targeted alpha therapies. “Our investigational HER2-TTC may offer a powerful tool for treating a wide range of HER2 expressing tumors and help to address treatment challenges,” says Dr Jardine.
HER2-TTC is the latest of Bayer’s proprietary Targeted Thorium Conjugate (TTC) technology platform to enter clinical trials. It is a combination of the alpha radionuclide thorium-227; an antibody targeting HER2, and a chelator molecule that strongly attaches the thorium to the antibody.
HER2-targeting antibodies have also been successfully used as carrier moiety to develop antibody-drug conjugates (ADCs) that deliver potent toxic ‘payloads’ to the cancer cells. Sometimes, however, cancers can develop resistance to these treatment regimens by creating mechanisms within the cells to evade and prevent the biological changes they instigate. “In these cases, people can stop responding to treatment and their cancers are able to regrow. Often by this stage, there are few or no further treatment options to try and there is a real unmet medical need for new therapies,“ explains Dr Jardine.
HER2-TTC: Delivering deadly alpha radiation to tumors
"With HER2-TTC, we are harnessing the antibody’s ability to target HER2 by using it to transport thorium-227 to the tumor. The thorium decay produces alpha particle radiation that causes highly lethal double strand DNA damage in tumor cells, which kills them. As alpha particles travel just two to ten cell diameters, there is the potential to limit impact to surrounding healthy tissue.”
This mechanism, bringing alpha radiation directly to the tumor cells, may also have other advantages. HER2 expression levels vary significantly and many tumors express HER2 only at very low levels. In these tumors, currently approved HER2-targeted therapies have not been effective treatments. Dr Jardine explains: “As alpha radiation emitted by thorium is very potent, we are very hopeful that we could also see a positive treatment effect in tumors with low HER2 expression.”
As well as having a role in the treatment of patients in a wider range of HER2-expressing tumors, and in cancers that have developed resistance to current standard-of-care regimens, HER2-TTC may also offer the potential to expand treatment options for people with cancers that actually express low levels of HER2.
Meeting patient needs across many cancer indications
Recruitment for the HER2-TTC clinical trial is ongoing. In this first-in-human study, Bayer will initially focus on breast and gastric cancers across the spectrum of HER2 expression but, in the expansion part of the study, will include patients with a range of tumor indications with HER2 expression.
For Bayer, including these additional tumor types early in development is important. Dr Jardine concludes: “We recognised this potential for HER2-TTC early in the development program. Since then it has been our goal to ensure that the right research is in place to support its development across multiple indications so that many patients may be able to benefit from this potential new treatment option.”