Selecting an intervention time for intravascular enzymatic cleavage of peptide linkers to clear radioisotope from normal tissues.

UNLABELLED: Protease degradable linkers have been proposed to improve the therapeutic index (TI) (i.e., tumor to normal tissue) of molecular targeted radioisotope therapy by reducing unbound radiotargeting agent in the blood and other normal tissues. If the radioisotope is detached from the circulating targeting agent once the radioisotope level in the tumors has been maximized, the success of this system depends on the ability to anticipate a preferred intervention time that will lead to significantly improved TIs. This paper presents a method to predict preferred intervention times and TIs by using pharmacokinetic tracer studies carried out without intervention. METHODS: Pharmacokinetic data for the blood and tumors from tracer doses of 111In-labeled chimeric and mouse monoclonal antibodies in patients and in mice were used as surrogates for corresponding 90Y radioimmunoconjugates. Data were fit with simple pharmacokinetic functions. A set of formulas was then developed to estimate the improvement in therapeutic index and the preferred intervention time, using simple modeling assumptions. RESULTS: A modeled introduction of enzymatic cleavable linkers resulted in an increase in the tumor-to-blood TI by a factor of 3.2-1.6 for the systems analyzed. As expected, the preferred intervention times varied depending on the pharmacokinetic data, but could be predicted based on a priori knowledge of the actual or anticipated pharmacokinetics in the absence of intervention. CONCLUSIONS: These results highlight the potential value of cleavable linkers in substantially increasing the TI, and provide an approach for estimating a preferred intervention time, using actual or predicted pharmacokinetic data obtained without intervention.

Dosimetry for quantitative analysis of the effects of low-dose ionizing radiation in radiation therapy patients.

We have developed and validated a practical approach to identifying the location on the skin surface that will receive a prespecified biopsy dose (ranging down to 1 cGy) in support of in vivo biological dosimetry in humans. This represents a significant technical challenge since the sites lie on the patient's surface outside the radiation fields. The PEREGRINE Monte Carlo simulation system was used to model radiation dose delivery, and TLDs were used for validation on phantoms and for confirmation during patient treatment. In the developmental studies, the Monte Carlo simulations consistently underestimated the dose at the biopsy site by approximately 15% (of the local dose) for a realistic treatment configuration, most likely due to lack of detail in the simulation of the linear accelerator outside the main beam line. Using a single, thickness-independent correction factor for the clinical calculations, the average of 36 measurements for the predicted 1-cGy point was 0.985 cGy (standard deviation: 0.110 cGy) despite patient breathing motion and other real-world challenges. Since the 10-cGy point is situated in the region of high-dose gradient at the edge of the field, patient motion had a greater effect, and the six measured points averaged 5.90 cGy (standard deviation: 1.01 cGy), a difference that is equivalent to approximately a 6-mm shift on the patient's surface.

Radiation phantom with humanoid shape and adjustable thickness (RPHAT).

A new radiation phantom with humanoid shape and adjustable thickness (RPHAT) has been developed. Unlike the RANDO phantom which is a fixed thickness, this newly designed phantom has adjustable thickness to address the range of thicknesses of real-world patients. RPHAT allows adjustment of the body thickness by being sliced in the coronal (instead of axial) direction. Centre slices are designed so that more sections can be added or removed while maintaining the anthropomorphic shape. A prototype of the new phantom has been successfully used in a study investigating peripheral dose delivery, where the amount of scatter within the patient, and therefore the patient thickness, plays a critical role in dose deposition. This newly designed phantom is an important tool to improve the quality of radiation therapy.

Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients: comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT.

PURPOSE: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. EXPERIMENTAL DESIGN: (111)In-DOTA-2IT-m170 and (111)In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. RESULTS: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

Radiation dosimetry for radionuclide therapy in a nonmyeloablative strategy.

Radionuclide therapy extends the usefulness of radiation from localized disease of multifocal disease by combining radionuclides with disease-seeking drugs, such as antibodies or custom-designed synthetic agents. Like conventional radiotherapy, the effectiveness of targeted radionuclides is ultimately limited by the amount of undesired radiation given to a critical, dose-limiting normal tissue, most often the bone marrow. Because radionuclide therapy relies on biological delivery of radiation, its optimization and characterization are necessarily different than for conventional radiation therapy. However, the principals of radiobiology and of absorbed radiation dose remain important for predicting radiation effects. Fortunately, most radionuclides emit gamma rays that allow the measurement of isotope concentrations in both tumor and normal tissues in the body. By administering a small "test dose" of the intended therapeutic drug, the clinician can predict the radiation dose distribution in the patient. This can serve as a basis to predict therapy effectiveness, optimize drug selection, and select the appropriate drug dose, in order to provide the safest, most effective treatment for each patient. Although treatment planning for individual patients based upon tracer radiation dosimetry is an attractive concept and opportunity, practical considerations may dictate simpler solutions under some circumstances. There is agreement that radiation dosimetry (radiation absorbed dose distribution, cGy) should be utilized to establish the safety of a specific radionuclide drug during drug development, but it is less generally accepted that absorbed radiation dose should be used to determine the dose of radionuclide (radioactivity, GBq) to be administered to a specific patient (i.e., radiation dose-based therapy). However, radiation dosimetry can always be utilized as a tool for developing drugs, assessing clinical results, and establishing the safety of a specific radionuclide drug. Bone marrow dosimetry continues to be a "work in progress." Blood-derived and/or body-derived marrow dosimetry may be acceptable under specific conditions but clearly do not account for marrow and skeletal targeting of radionuclide. Marrow dosimetry can be expected to improve significantly but no method for marrow dosimetry seems likely to account for decreased bone marrow reserve.