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Aug 1, 2013 (Vol. 33, No. 14)

Molecular Imaging Driving Development

  • Determining PK/PD

    Different imaging modalities are being used to monitor disease progression and to analyze therapeutic efficacy in preclinical stages of drug development.

    According to Werner Scheuer, Ph.D., group leader, preclinical optical imaging, pharmacology TR-PD, and pharmaceutical research at Roche Diagnostics, fluorescence and bioluminescence technologies are best because of their sheer simplicity, fast scanning times, nonhazardous radiation, and nonradioactive isotopes.

    In pharmaceutical drug development, long acquisition times can hinder efforts to determine pharmacodynamics and pharmacokinetics in preclinical models. Speaking with GEN, Dr. Scheuer explained that optical imaging has very short acquisition times, ranging from one second to two minutes.

    Using fluorescence-labeled antibodies targeting a tumor-associated surface antigen, accumulation in tumor tissue can be accomplished within six to 24 hours post-injection. As such, it is possible to monitor the biodistribution of the therapeutic antibodies in preclinical cancer xenografts. By using fluorophores that differ in their emission spectra, it is possible to examine a combination of antibodies. Such multiplexing studies cannot be performed using radioactive isotopes.

    Further, in combination with luciferase-transfected tumor cells, it is possible to monitor binding kinetics and antitumoral efficacy noninvasively and simultaneously. Fluorescence-labeled antibodies are stable ranging from six to 12 months at -20°C, making them superior to radioactive isotopes. Furthermore, noninvasive fluorescence imaging in mice allows monitoring of blood peak levels, half-life, organ distribution and saturation kinetics. It improves the quality of data for pharmacokinetic and pharmacodynamic simulation. It also reduces the number of animals needed, reducing time and costs.

    Combination of fluorescence with bioluminescence and subsequent examination of explanted organs by 3D multispectral fluorescence histology enables the monitoring of primary tumor growth, metastasis, and angiogenesis. Dr. Scheuer and his colleagues have demonstrated the advantages of optical imaging in the combined measurement of pharmacodynamics and pharmacokinetics in cancer xenografts.

  • Predicting Therapeutic Response

    Click Image To Enlarge +
    Targeted small molecules linked to chemotherapy drugs are used in conjunction with a companion imaging agent. Vintafolide consists of a small molecule targeting the folate receptor that is linked to a potent chemotherapy drug. The companion imaging agent, etarfolatide, consists of the same small molecule that targets the folate receptor, but is instead conjugated to a 99mTc-based imaging group. [Endocyte]

    Christopher P. Leamon, Ph.D., vp, research at Endocyte, presented a novel and personalized approach to identify patients who were most likely to benefit from folate receptor (FR)-targeted therapy.

    Dr. Leamon has invented small molecule drug conjugates to target receptors that are overexpressed in cancer or arthritis. Vintafolide is a small molecule targeting the folate receptor that is linked to a potent chemotherapy drug. Dr. Leamon also developed the companion imaging agent, etarfolatide, which consists of the same small molecule that targets the folate receptor, but is instead conjugated to a 99mTc-based imaging group.

    Patients who are identified using etarfolatide as overexpressing the folate receptor are then treated with vintafolide. The companion imaging agent is used to identify patients that overexpress the specific receptor, so that only patients who are likely to respond to treatment will actually be given the drug.

    Vintafolide (MK-8109/EC145) and etarfolatide (EC20) are currently being studied in a Phase III trial involving patients with platinum-resistant ovarian cancer, and a Phase IIb study on patients with non-small-cell lung cancer (NSCLC).

    Dr. Leamon reported that analysis of Phase II data shows that etarfolatide can identify ovarian cancer and NSCLC patients who could benefit from vintafolide. Patients identified with 100% FR+ target tumor lesions showed substantial progression-free survival compared to patients with 10% to 90% FR+ target lesions, when treated with single-agent vintafolide.

    “Due to the numerous benefits of companion imaging agents, including the ability to conduct a noninvasive, whole-body scan of a patient and the ability to decrease clinical risk through use early on in drug development, interest in developing companion imaging technologies will only continue to grow,” he said.

  • Translational R&D, Clinical Trials

    The increasing use of PET imaging has led to a dramatic increase in the number of novel F-18 tracers in preclinical studies, advancing into clinical development. The utility of PET imaging can be enhanced by creating new F-18 PET tracers that can pair with the ever expanding armamentarium of target drugs, said Scott Edwards, Ph.D., vp and GM, R&D, SciFluor Life Sciences.

    Researchers at SciFluor are developing new methodologies for synthesizing F-18 tracers including innovative chemistry to incorporate F-18 into a wider array of small molecule drugs.

    “SciFluor has developed SF0034 as an improved potassium channel opener for use in the treatment of partial-onset seizures,” he explained. “To aid in the preclinical and potentially clinical development of SF0034, we have also developed an F-18 radiolabeled analog of SF0034 for noninvasive PET imaging.”

    According to Dr. Edwards, “This approach allows registered medicines, compounds in clinical development that have established clinical proof of concept, to be further optimized to generate new pre-clinical candidates without an extensive drug discovery effort.”

    The mechanistic and clinical development knowledge of the parent compounds is driving preclinical and clinical development of these new chemical entities.


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