NEW YORK (GenomeWeb) – A team led by researchers at Memorial Sloan Kettering Cancer Center has developed an antibody-based approach to monitoring a key prostate cancer pathway.
The antibody, 11B6, binds human kallikrein-related peptidase 2 (hK2), a prostate-specific antigen involved in the androgen receptor (AR) pathway. In a study published last month in Science Translational Medicine, the researchers demonstrated its utility for tracking AR activity via imaging, which could allow for better selection and monitoring of prostate cancer therapy.
The antibody could also prove useful as a drug delivery system, allowing clinicians to target prostate tumor cells by coupling it to therapeutic compounds, said David Ulmert, a senior research scientist at MSKCC and senior author on the study.
Ulmert said that he has patented the use of the antibody for imaging and other purposes and these patents have been licensed to biotech firm Diaprost, which has begun production of the antibody and done toxicity testing in non-human primates. The company, in which Ulmert is a shareholder and board member, plans to begin testing of the antibody in humans next year, starting with a phase I trial looking at the kinetics of the antibody and its usefulness for targeting the AR pathway via imaging in humans, he said.
AR pathway activation is a known driver of prostate cancer, making assessment of its activity potentially useful for tracking disease progression and guiding patient treatment. The commonly used prostate cancer biomarker, prostate-specific antigen (PSA), is linked to AR pathway activity, but PSA measurements have proved of limited reliability for diagnosing and monitoring the disease.
Looking for an improved marker of AR activity, Ulmert and his colleagues targeted hK2, which in men is produced only by prostate tissue and correlates with AR activity.
The protein sits downstream of the AR and rises in expression along with AR, Ulmert said. "For example, if you take a [prostate cancer] patient and you castrate that patient, you will see that hK2 levels go down. Then, when that patient becomes castration-resistant, once AR increases, hK2 expression also increases."
This, he noted, is different from PSA, which is down-regulated in cancerous tissue compared to non-cancerous tissue and is not necessarily expressed in castration-resistant prostate cancer patients.
"HK2 is the marker that correlates best to antigen receptor activity, and you still have an expression of hK2 in castration-resistant cancers as well," Ulmert said. "It's the target that we still see expressed in very advanced cases."
This makes it a potentially useful marker for monitoring treatment targeting the AR pathway. The researchers also hope to use it to monitor metastases and, in the STM study, demonstrated the ability of a radio-labeled 11B6 antibody combined with positron emission tomography (PET) to identify bone metastases in two models of the disease.
A major challenge of targeting secreted proteins like hK2 for antibody-based imaging is the fact that, as the authors wrote, "antibody-bound complexes wash out of the disease site." This, they noted, has meant such approaches in prostate cancer have typically targeted cell-surface receptors, which are not typically tissue- or disease-specific enough to serve as highly effective imaging markers or drug targets.
Research from Brigham and Women's Hospital scientists has shown, though, that the neonatal Fc receptor (FcRn) enables uptake into the lumen of antibodies targeting secreted proteins.
BWH researcher "[Richard] Blumberg has shown that if you give an antigen to a mouse and you inject an antibody to this antigen into the blood, that antibody has the ability via FcRn to go from the blood to the gut lumen and complex with the [target] antigen," Ulmert said. Then this complex, rather than being reintroduced into blood circulation and washed out, is again processed by the FcRn and deposited in the lamina propria.
Given the high levels of FcRn expression in prostate tissue, Ulmert and his colleagues thought a similar approach could work for targeting hK2.
"We had the idea that, if you have a glandular organ with high expression of FcRn and you have an antibody to a known antigen, in this case hK2, then the antibody, via the mechanism of FcRN, will get over to the lumen, complex with the cell antigen, and then the antibody-antigen complex is retaken up by the cell," he said. "And that's what we saw in our study."
To show the potential utility of the hK2 marker, the researchers simulated a full course of surgical treatment in a mouse model of prostate cancer using PET to first measure disease burden then checked surgical margins to ensure full removal of tumor tissue, and then they performed a post-operative scan, which identified a remaining section of prostate tissue.
The initial trial Diaprost has planned for the 11B6 antibody is for imaging applications, but Ulmert said he anticipates the agent will be useful for delivering therapy as well.
"You can use it for imaging and diagnosis, and you can also use it for therapy by delivering toxic compounds using this antibody as a vehicle," he said, laying out a scenario wherein clinicians use the antibody initially to detect prostate cancer and metastases and then follow that with treatment using the antibody to guide drugs specifically to those tissues.
Ulmert and his colleagues are also exploring the possibility of targeting other secreted proteins via the FcRn-facilitated approach used in the STM study. Additionally, they are looking at the potential usefulness of hK2 as a breast cancer marker, where it could be helpful for monitoring and treating the triple-negative subtype of the disease, he said.
"Expression is lower in breast cancer cells, and we need to turn it on by giving the cells testosterone," Ulmert said. "But when you treat triple-negative breast cancer cells with testosterone they start to express hK2. So, potentially, if you give the triple-negative breast cancer patient a dose of testosterone, then you start to up-regulate hK2, and then you can [use the 11B6 antibody] to deliver both diagnostic and therapeutic compounds to the tumor."
"If we are successful with prostate cancer patients, we will likely proceed with breast cancer patients, as well," he said.