The pace of biomarker development is accelerating as investigators report new studies on cancer, diabetes, Alzheimer disease, and other conditions in which the evaluation and isolation of workable markers is prominently featured. CHI’s “ADAPT” meeting, to be held later this month, will profile various new strategies being developed by both the academic and private sectors.
Wei Zheng, Ph.D., leader of the R&D immunoassay group at EMD Chemicals, is overseeing a program to develop biomarker immunoassays to monitor drug-induced toxicity, including kidney damage.
Although immunohistochemistry has traditionally been looked upon as the gold standard for these studies, this approach is slow and cannot be adapted to multiplexing. “One of the principle reasons for drugs failing during development is because of organ toxicity,” says Dr. Zheng. “This results in proteins being liberated into the serum and urine in abnormal amounts. These proteins can serve as biomarkers of adverse response to drugs, as well as disease states.”
Through collaborative programs with Rules-Based Medicine (RBM), the EMD group has released panels for the profiling of human renal impairment and renal toxicity. These urinary biomarker based products fit the FDA and EMEA guidelines for assessment of drug-induced kidney damage in rats.
Although the FDA has not yet approved kidney toxicity biomarker tests, the industry is clearly moving in that direction, according to Dr. Zheng. “We see this trend, not only for drug-induced organ damage but also for biomarkers for disease states affecting organ function.”
The group recently performed a screen for potential protein biomarkers in relation to kidney toxicity/damage on a set of urine and plasma samples from patients with documented renal damage. Multiplexed immunoassays were used to quantify protein analytes and standard blood and urine chemistries were also measured.
Additionally, Dr. Zheng is directing efforts to move forward with the multiplexed analysis of organ and cellular toxicity. Diseases thought to involve compromised oxidative phosphorylation include diabetes, Parkinson and Alzheimer diseases, cancer, and the aging process itself.
Good biomarkers allow Dr. Zheng to follow the mantra, “fail early, fail fast.” With robust, multiplexible biomarkers, EMD can detect bad drugs early and kill them before they move into costly large animal studies and clinical trials. “Recognizing the severe liability that toxicity presents, we can modify the structure of the candidate molecule and then rapidly reassess its performance.”
Scientists at Oncogene Science a division of Siemens Healthcare Diagnostics, are also focused on biomarkers. “We are working on a number of antibody-based tests for various cancers, including a test for the Ca-9 CAIX protein, also referred to as carbonic anhydrase,” Walter Carney, Ph.D., head of the division, states.
CAIX is a transmembrane protein that is overexpressed in a number of cancers, and, like Herceptin and the Her-2 gene, can serve as an effective and specific marker for both diagnostic and therapeutic purposes. It is liberated into the circulation in proportion to the tumor burden.
Dr. Carney and his colleagues are evaluating patients after tumor removal for the presence of the Ca-9 CAIX protein. If the levels of the protein in serum increase over time, this suggests that not all the tumor cells were removed and the tumor has metastasized.
Dr. Carney and his team have developed both an immunohistochemistry and an ELISA test that could be used as companion diagnostics in clinical trials of CAIX-targeted drugs.
The ELISA for the Ca-9 CAIX protein will be used in conjunction with Wilex’ Rencarex®, which is currently in a Phase III trial as an adjuvant therapy for non-metastatic clear cell renal cancer.
Additionally, Oncogene Science has in its portfolio an FDA-approved test for the Her-2 marker. Originally approved for Her-2/Neu-positive breast cancer, its indications have been expanded over time, and was approved for the treatment of gastric cancer last year. It is normally present on breast cancer epithelia but overexpressed in some breast cancer tumors.
“Our products are designed to be used in conjunction with targeted therapies,” says Dr. Carney. “We are working with companies that are developing technology around proteins that are overexpressed in cancerous tissues and can be both diagnostic and therapeutic targets.”
The long-term goal of these studies is to develop individualized therapies, tailored for the patient. Since the therapies are expensive, accurate diagnostics are critical to avoid wasting resources on patients who clearly will not respond (or could be harmed) by the particular drug.
“At this time the rate of response to antibody-based therapies may be very poor, as they are often employed late in the course of the disease, and patients are in such a debilitated state that they lack the capacity to react positively to the treatment,” Dr. Carney explains.