Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Siantar, C. L. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Siantar, C. L. H.
Clinical Cancer Research Vol. 9, 3938S-3944S, September 1, 2003
© 2003 American Association for Cancer Research

Session IV: CLINICAL STUDIES: SOLID TUMORS

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 RIT1

Sally J. DeNardo2, Gerald L. DeNardo, A. Yuan, Carol M. Richman, Robert T. O’Donnell, Primo N. Lara, David L. Kukis, Arutselvan Natarajan, Kathleen R. Lamborn, Frederik Jacobs and Christine L. Hartmann Siantar

University of California–Davis School of Medicine, Sacramento, California 95816 [S. J. D., G. L. D., A. Y., C. M. R., R. T. O., P. N. L., A. N.]; University of California–San Francisco School of Medicine, San Francisco, California 94143 [K. R. L.]; Biomira, Inc., Edmonton, Alberta, Canada T6N 1H1; Lawrence Livermore National Laboratory, Livermore, California 94550 [C. L. H. S.]; and Equine Analytical Chemistry Laboratory, University of California–Davis, Davis, California 95617 [D. L. K.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
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: 111In-DOTA-2IT-m170 and 111In-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.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
RIT3 in lymphoma has proven to be clinically useful using several different RICs (1, 2, 3) . RIT at myeloablative levels with 131I MAb and bone marrow support has demonstrated higher tumor response, marked increase in complete response, and nonmarrow normal organ toxicities that correlated with the calculated dose to the organs estimated from imaging (1 , 4 , 5) . These studies provided an approach for high-dose RIT with marrow support whereby tolerable administered doses could be selected from imaging-based calculations. Because marrow support can now be provided by APBSCs, high-dose myelotoxic and myeloablative RIT combined with APBSCs could become useful therapy for a broader range of patients and cancers (6) . In this general approach, other organs become dose limiting.

MAbs conjugated with RMCs have been increasingly selected to deliver radioisotope therapy because of greater tumor uptake and retention of the radionuclide compared with 131I (7, 8, 9) . 90Y provides more homogeneous tumor irradiation because of its energetic ß emissions, minimal need for shielding of medical personnel and family members, and predictive dosimetry calculations projected from 111In analogues of the 90Y RICs (1 , 10, 11, 12, 13, 14) . RIT dosimetry calculations from most RMCs demonstrate the liver to be the next dose-limiting organ after marrow (6 , 15 , 16) . Because a large fraction of RICs are bound to hepatocyte receptors, internalized, and retained, their decay can result in significant absorbed dose to the liver. In contrast, hepatocyte processing removes 131I from 131I MAb in a manner that allows rapid hepatic and body clearance. To take advantage of enhanced tumor uptake and retention of RMCs, we sought to promote hepatocyte cleavage of the RMC from its MAb carrier, in a manner that might result in rapid elimination of the RMC from the liver and body, but not tumor, by placing a peptide having a specific cathepsin B cleavage site between the RMC and MAb (17, 18, 19, 20) .

Many investigators over the past 25 years have studied possible hepatocyte biodegradable MAb RMC linkages to reduce liver retention and radiation dose (21, 22, 23, 24, 25) . A variety of radiolabeled MAbs with such linkages have been developed and evaluated in vitro and in vivo. A few have demonstrated modestly enhanced TI in animal models (24, 25, 26) . Considering a different approach, a peptide originally developed for lysosomotropic prodrug delivery (27) , Ala-leu-ala-leu, was evaluated as a MAb-radiochelate linker that might be digested in liver cells, accelerating the clearance of radiolabeled chelate (28) . Although in vitro this RIC linkage was rapidly cleaved by the liver protease cathepsin B, in vivo studies in mice demonstrated no decrease in liver retention of the radiometal (22) . The possible effect of charge on retention of cleaved RIC, led to the design of a cathepsin degradable linkage in which the cleaved RIC had a net charge of zero (19 , 29) . This peptide chelate linkage, DOTA-GGGF-ITC, was initially studied in breast cancer patients as the RIC 111In/90Y-DOTA-peptide-ChL6 (30) . Decreased liver activity and excellent tumor targeting provided a remarkable tumor:liver TI as high as 35:1 (30) . Lack of available ChL6 MAb for additional clinical studies prohibited comparison of the same MAb with different RIC linkers.

Here, we report the comparative study of two RICs of the pancarcinoma MAb m170 (31, 32, 33) , differing only in the RIC linkage (Fig. 1)Citation . Each patient received 111In-DOTA MAb m170 either with (DOTA-peptide) or without the GGGF tetra-peptide linkage (2IT-BAD). Pharmacokinetics were obtained from quantitative imaging and blood clearance, and the 90Y dosimetry was calculated. Radiation dose (rads/mCi) was evaluated for blood, body, tumor, and normal organs for each patient in the two patient groups, and the groups were compared with the intent to determine whether a clinically relevant decrease in radiation dose to liver was achieved with the GGGF-linked RIC without a significant reduction in the mean tumor dose, or an increased dose to other normal organs.



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Schematic illustrating the two linkages of DOTA Mab: 2IT-BAD-m170 (top) and DOTA-GGGF-m170 (DOTA-peptide; bottom) linkage designed for cleavage by cathepsin B (->). MAb m170 was used in both ICs.

 

   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patient Characteristics.
Twenty-five patients who had androgen-independent progressive prostate cancer were entered on one of two RIT protocols, each requiring a RIC quantitative imaging pharmacokinetic/dosimetry study 1 week before RIT. Both protocols required a Karnofsky score of 70% and adequate liver function studies (normal bilirubin and aspartate aminotransferase <1.5 x the upper limit of normal), normal renal function, adequate blood counts (neutrophils, >1599 µl; platelets, >100,000/µl; hemoglobin, >10.0), and less than 25% bone marrow involvement. All patients had computed tomography and bone scan evaluations before protocol entry. The initial quantitative imaging pharmacokinetic/dosimetry study from each patient was used in this comparative analysis.

Radiopharmaceuticals.
MAb m170 is a murine IgG developed using a synthetic asialo GM1 terminal disaccharide immunogen related to the Thompson-Friedenreich disaccharide (31, 32, 33) . m170 binds to a variety of human adenocarcinomas with high affinity (4 x 108 M-1; Ref. 34 ), and scintigraphic studies previously demonstrated targeting of breast, prostate, lung, and ovarian cancers with no normal tissue targeting (6 , 31) . m170 (cyclic GMP grade) was obtained in human use form, manufactured under appropriate good manufacturing practice regulations by Biomira, Inc. (Edmonton, Canada), was greater than 95% monomeric IgG by PAGE, and met United States Food and Drug Administration guidelines.

Preparation of ICs.
DOTA was conjugated to m170 as 2IT-BAD-m170 (IC), as described previously (35 , 36) . Briefly, 2IT-BAD-m170 was prepared as follows. BAD, 2IT, and m170 were combined in 0.1 M tetramethylammonium phosphate (pH 7.8) at final concentrations of 2 mM, 1 mM, and 0.1 mM, respectively. The solution was incubated at 37°C for 30 min. The IC was purified and transferred for radiolabeling to 0.1 M ammonium acetate buffer by molecular sieving filtration (Sephadex G50–80; Pharmacia, Upsala, Sweden; Refs. 37 and 38 ).

DOTA-peptide-m170 was prepared as follows. DOTA-peptide-ITC was prepared by the methods described previously (39) . DOTA-peptide-ITC and m170 were combined in 0.1 M tetramethylammonium phosphate (pH 9) at final concentrations of 1.75 mM and 0.46 mM, respectively. The solution was incubated for 60 min at 37°C. The IC was purified and transferred for radiolabeling to 0.1 M ammonium acetate by molecular sieving filtration. Both ICs were evaluated to assure sterile, pyrogen-free status and one to three metal-binding sites per MAb by published methods (40) .

Radiolabeling and Quality Control.
To prepare 111In-2IT-BAD-m170 and 111In-DOTA-peptide-m170, the IC and 111In (Amersham, Arlington Heights, IL; or Nordion, Kanata, Ontario, Canada) were combined in 0.1 M ammonium acetate (pH 5.0) and incubated 30 min at 37°C. To scavenge nonspecifically bound 111In, EDTA was added to a final concentration of 10 mM for 15 min at room temperature. The RICs were purified by molecular sieving chromatography.

RICs were examined by molecular sieving high-performance liquid chromotography (Beckman Coulter System Gold 127; Beckman, San Ramon, CA; SEC-3000 molecular sieving column), cellulose acetate electrophoresis (Gelman Sciences, Inc., Ann Arbor, MI), and RIA (40 , 41) . Immunoreactivity was assayed retrospectively by allowing the RICs to decay to background, then performing a competitive assay against lightly iodinated 125I-m170. In this competitive assay, the decayed RIC competed with 125I-labeled m170 for binding with rabbit anti-m170 idiotype in the solid state. Unmodified m170 was assayed as a control. High-performance liquid chromotography indicated that 95% or more of radiometal was associated with RICs. Cellulose acetate electrophoresis indicated that 98% or more of all RICs were in monomeric form. Immunoreactivity for all pharmaceutical preparations far exceeded the defined Food and Drug Administration Investigative New Drug guidelines requiring the competitive binding of the decayed pharmaceutical against 125I-m170 to be greater than 50% of unmodified m170.

Pharmacokinetics and Radiation Dosimetry.
111In RIC (5 mCi of 111In with 6–8 mg of m170) was injected i.v., followed by quantitative imaging over the next 7 days, serial blood samples, and quantitated urine samples from each 24-h collection. Blood and urine radioactivity was counted in a gamma well counter and compared with a standard prepared from the radiopharmaceutical that was injected into the patient. The %ID in the blood was calculated using the body weight to estimate blood volume, and daily %ID in urine output was calculated using the collected daily total urine volume; a biexponential function was used to determine cumulated activity in blood.

Pharmacokinetic data from imaging was obtained as described previously (10 , 42) . Briefly, planar whole body and regional images of conjugate views were acquired immediately, at 4 h, and at least three times during the remaining 7-day period after administration of 111In-2IT-BAD-m170 or 111In-DOTA-peptide-m170 (Ref. 10 ; Fig. 2Citation ). The geometric-mean method was used to quantify activity in the organs and tumors clearly delineated on conjugate views (e.g., liver and spleen), and photon attenuation was corrected using the transmission scan (43) . The effective-point source method was used to quantify activity in most tumors and kidneys. For these small organs and tumors, photon attenuation was corrected using measured values that matched the small-source geometry. Lung activity was derived as described previously, using a posterior view area of interest over a central nontumored area of each lung field, normalized to total pixels for the given lung (42) .



View larger version (63K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Planar scintigraphic images of the posterior pelvis of two prostate cancer patients 3 days after receiving 111In-DOTA-peptide-m170 (A) and 111In-2IT-BAD-m170 (B). Tumor uptake is easily visualized.

 
Cumulated activity in tissues other than liver was obtained by fitting pharmacokinetic data to a monoexponential function. In the liver, pharmacokinetic data, as decay-corrected activity, was fit with a cubic spline, assuming constant decay-corrected activity beyond the final time point measured. Cumulative activity of tumors was also determined by area under cublic spline if a monexponential fit was not possible. Cumulated activity was converted to radiation dose for 90Y using the Medical Internal Radiation Dose formula, Medical Internal Radiation Dose S values, and reference-man masses (44) . The radiation dose from blood to marrow was calculated as described previously: Dtotal = 0.25 Ãblood {Delta}np, where Ãblood is the cumulated activity in 1 ml of blood and {Delta}np is the mean energy emitted per nuclear transition for nonpenetrating 90Y emissions. The constant 0.25 was used to account for the difference between the specific activities of marrow and that of circulating blood (45) . Radiation dose determined for marrow to marrow dose was extrapolated as described previously from uptake in three lumbar vertebra in patients without evidence of tumor involvement in this area (36 , 43) .

For accurate tumor dosimetry, only tumors with a measured volume of 10 ml or greater were used for dosimetric calculations. Tumor dimensions were determined using radiographic measurements; volume was determined as described previously (36) . Thirty-two sites of metastatic prostate cancer with 111In-2IT-BAD-m170 and 23 with 111In-DOTA-peptide-m170 met the criteria for dosimetric analysis.

For the initial calculations (Table 1)Citation , no dose losses attributable to ß particles exiting the tumor volumes were assumed. Absorbed dose values were then calculated based on individual tumor volumes (Ref. 46 ; Table 2Citation ).


View this table:
[in this window]
[in a new window]

  		Table 1 Radiation dose (rads/mCi) to organs in each patient

 

View this table:
[in this window]
[in a new window]

  		Table 2 Mean radiation dose (rads/mCi) for each RIC

 
Statistical Methods.
The cumulative activity for organs, tumor, and blood and body per patient was determined as described previously. To test for differences between the linkers, a Wilcoxon rank sum test was used. All reported Ps were two tailed.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Pharmacokinetic and imaging studies were performed in the 25 prostate cancer patients, 17 with 111In-2IT-BAD-m170 and 8 with 111In-DOTA-peptide-m170. Quality of the radiopharmaceuticals was equivalent with >98% of the RIC pharmaceuticals in monomeric form at the time of injection, and retrospective analysis demonstrated excellent immunoreactivity. The blood clearances (mean ± 1 SD) for both RICs are shown in Fig. 3ACitation and were not statistically different.



View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. A, blood clearance (mean ± SD) 111In-2IT-BAD-m170 ({blacksquare}) and 111In-DOTA-peptide-m170 (•) from the two groups of prostate cancer patients. B, liver uptake (%ID; mean ± SD) at 1, 4, 24, 72, and 144 h after injection of 111In-2IT-BAD-m170 ({blacksquare}) and 111In-DOTA-peptide-m170 (•). The difference in uptake of the two RICs in liver not only occurred early but increased over time.

 
Data for quantitative analysis of tumor and normal organs in both patient groups are provided in Table 1Citation . The mean cumulative activity and, therefore, the mean liver radiation dose (rads/mCi) for DOTA-peptide-m170 was 30% less than the mean 2IT-BAD-m170 liver dose (Table 2)Citation . Mean liver uptake (%ID) of each group over the 7-day study is shown in Fig. 3BCitation .

The mean urinary excretion of radioactivity from both RICs comprised 16–17% of the injected radioactivity by 6 days after injection and 1–4% by 24 h. Although not statistically different, there was an apparent difference in the mean urinary excretion between the two RIC groups, with the DOTA-peptide-m170 patients excreting >2% more of the injected dose during the first 24 h. This difference was maintained over several days. If 2% of ID radioactivity is converted to µCi/h and calculated as additional uCi/h in the liver of the DOTA-peptide-m170 patients, the 31% difference of mean radiation dose to liver between the two RIC groups (rads/mCi) becomes less than a 15% difference.

The rads/mCi to other normal organs with DOTA-peptide-m170 was either lower (lung) or not statistically different. Imaging studies demonstrated excellent tumor uptake for both RICs (Fig. 2)Citation , and calculated tumor dose (rads/mCi) for the two RICs was not statistically different (Table 2)Citation . Radiation dose (rads/mCi; marrow to marrow) from lumbar vertebra imaging was indistinguishable between groups (2IT-BAD, 4.1–9.0; DOTA-peptide, 3.6–9.7).


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Patients with androgen-independent metastatic prostate cancer have limited therapeutic options. Once metastases have occurred, androgen ablation is the only treatment that prolongs life, resulting in 50% survival at 2.5 years (47, 48, 49) . Standard therapies merely provide temporary or incomplete palliation of symptoms. Because this disease has shown little substantial response to cytotoxic chemotherapy, but is relatively responsive to radiation, a therapy that delivers tumoricidal radiation to widespread metastatic deposits has the potential to provide useful impact. Conceptually, tumor-targeted high-dose RIT with marrow support or RIT as part of combined multimodality therapy can offer effective therapy for this lethal disease.

Using CC49, 131I RIT studies in prostate cancer patients have demonstrated only modest tumor targeting, with no patients having objective criteria for response (50 , 51) . In a recently reported Phase I maximum tolerated dose study of 111In/90Y-2IT-BAD-m170 in patients with metastatic prostate cancer, excellent targeting of both bony and soft tissue metastasis, as well as temporary palliation of pain and effect on prostate-specific antigen levels were demonstrated (52) . Other RMC/RIT pharmaceuticals under development have been reported to have therapeutic response in animal models (53) and excellent tumor targeting in clinical studies (54) . Such RMCs for RIT have generally resulted in greater tumor radiation dose per administered radionuclide dose than was demonstrated in 131I RIT studies, but this has been accompanied by a substantial increase in the radiation dose to liver (7 , 8 , 54) . Published studies provide 90Y dosimetry (rads/mCi) calculated from 111In kinetics with liver dose ranging from 17 rads/mCi of 90Y anti-CD20 (Zevalin) in 27 patients specifically evaluated for dosimetry (15) to 29 rads/mCi of 90Y-DTPA-C84.66 in patients with metastatic carcinoembryonic antigen-producing malignancies (16) . Similar results have been reported by others (55, 56, 57) . Because the hepatic toxicity dose limit approximates 3000 rads from external beam irradiation (58) , such a limitation, if applicable, would allow 100–150 mCi of 90Y MAb for APBSC-supported RIT therapy with these respective RICs.

To provide tumor-targeted therapy to metastatic prostate cancer at a level that can be tumoricidal, enhancing the TI between the radiation dose to tumor and that delivered to the most sensitive and, therefore, dose-limiting tissue becomes the key to success. Because bone marrow support by APBSC is now available to ameliorate hematological toxicity, the radiation dose to liver becomes the limiting factor. As described previously, a peptide having a specific cathepsin B cleavage site was placed between the RMC DOTA and the MAb m-170 to increase elimination of radioactivity from the liver and, thus, minimize the hepatic dose. Here, we have reported the comparison of yttrium dosimetry from indium pharmacokinetics for this RIC, In-DOTA-peptide-m170, and In-2IT-BAD-m170 in two similar groups of prostate cancer patients. The m170 MAb has been studied previously as an imaging agent as both 111In DTPA MAb and 99mTc-MAb (32) , and RIT studies with 111In/90Y-2IT-BAD-m170 have been reported in breast cancer patients (6 , 59) . The therapeutic potential of 90Y-2IT-BAD-m170 in metastatic breast cancer was minimized by a mean liver dose of 18 rads/mCi, although excellent tumor targeting was achieved.

In this study, the prostate cancer patients receiving 111In/90Y-2IT-BAD-m170 had excellent targeting of tumor in both bone and soft tissue, with a mean tumor radiation dose of 36.4 rads/mCi but a mean liver dose of 14.7. The patients receiving 111In-DOTA-peptide-m170 had 31% less cumulative radioactivity in the liver (10.2 rads/mCi), whereas the tumor dose between the two groups was not statistically different (Table 2)Citation . Because both RIC pharmaceuticals were documented to meet the same rigorous standards at the time of administration, including the molecular size profile, and the resulting blood clearances (Fig. 3A)Citation were remarkably equivalent, the difference in liver cumulative activity and radiation dose likely results from differences in RIC kinetics in liver cells. The liver uptake (%ID) demonstrated a difference in the mean uptake of each group, and the difference during the first 48 h is approximately 4%ID (Fig. 3B)Citation . The mean %ID excreted in the urine by the two groups is not statistically different, but because only a difference in 4–5%ID dose in the liver results in 31% difference in liver radiation dose between the RICs, it should be noted that the mean of the measured excreted radioactivity of DOTA-peptide-RIC was >2% greater than that from 2IT-BAD-RIC. It is possible that small differences in excretion of the ID radioactivity in the urine, which are difficult to document, may account for the RIC difference in net liver %ID and, thus, in calculated radiation dose. Thus, the 31% reduction of the mean liver dose/mCi between the two RICs could be because of small differences in net hepatic uptake, processing, and excretion of the radioactive portion of DOTA-peptide-m170. The divergence of the mean %ID in liver between the two RIC groups over time (Fig. 3B)Citation , as the blood radioactivity is decreasing toward 10%ID, may suggest an ongoing hepatic output function for the DOTA-peptide-RIC not occurring with 2IT-BAD. Of note, only minimal bowel radioactivity (<2%) was detected in stool collections of patients in either group (data not shown).

Here, we describe the pharmacokinetics and 90Y dosimetry for two RICs for prostate cancer RIT. The new radiopharmaceutical differs only in the RIC peptide linkage, a cathepsin B cleavable linkage, resulting in a small noncharged RMC peptide product in the published in vitro studies (20) . The RICs pharmacokinetics and calculated tumor- and normal organ-absorbed radiation doses were similar, except for a significant decrease in the dose to the liver and lungs with the DOTA-peptide IC. No reasons could be found for the decrease in lung dose. Because mean tumor dose was not statistically different, the increase in calculated TI provides radiation dose estimates that suggest a substantial impact could be achieved using APBSC to ameliorate hematological toxicity. This should allow dosimetry-driven escalation of the administered dose of this RIC in metastatic prostate cancer patients to achieve clinically relevant therapeutic levels.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. This study was supported by grants from the National Cancer Institute (PO1-CA47829), the Department of Energy (DE-FG01-00NE22944), and the Department of Defense (DAMD 17-01-1-0177). Back

2 To whom requests for reprints should be addressed, at Radiodiagnosis and Therapy, Molecular Cancer Institute, University of California–Davis, 1508 Alhambra Boulevard, Room 3100, Sacramento, California 95816. Phone: (916) 734-3787; Fax: (916) 451-2857; E-mail: sjdenardo{at}ucdavis.edu Back

3 The abbreviations used are: RIT, radioimmunotherapy; 131I, iodine-131; ChL6, chimeric mouse-human IgG1 L6 monoclonal antibody; 111In, indium-111; 90Y, yttrium-90; DOTA, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; 2IT, 2-iminothiolane; BAD, 2-[p(bromoacetamido)benzyl]-1,4,7,10-tetraazocyclododecane-N,N',N'',N'''-tetraacetic acid; RIC, radioimmunoconjugate; IC, immunoconjugate; DTPA, diethylenetriaminepentaacetic acid; %ID, percentage of injected dose; MAb, monoclonal antibody; TI, therapeutic index; DOTA-GGGF-ITC, DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide; DOTA-peptide-m170, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-glycylglycylglycyl-L-(p-isothiocyanate)-phenylalanine amide; m170, MAb 170H.82; APBSC, autologous peripheral blood stem cell; RMC, radiometal chelate. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. DeNardo S. J., Williams L. E., Leigh B. R., Wahl R. Radioimmunotherapy: choosing an optimal dose for clinical response. Cancer (Phila.), 94(Suppl.4): 1275-1286, 2002.
  2. Wiseman G. A., White C. A., Witzig T. E., Gordon L. I., Emmanouilides C., Raubitschek A., Janakiraman N., Gutheil J., Schilder R. J., Spies S., Silverman D. H., Grillo-Lopez A. Radioimmunotherapy of relapsed non-Hodgkin’s lymphoma with Zevalin, a 90Y-labeled anti-CD20 monoclonal antibody. Clin. Cancer Res., 5: 3281s-3286s, 1999.
  3. Kaminiski M. S., Zelenetz A. D., Press O. W., Saleh M., Leonard J., Fehrenbacher L., Lister T. A., Stagg R. J., Tidmarsh G. F., Kroll S., Wahl R. L., Knox S. J., Vose J. M. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J. Clin. Oncol., 19: 3918-3928, 2001.[Abstract/Free Full Text]
  4. Johnson T. A., Press O. W. Therapy of B-cell lymphomas with monoclonal antibodies and radioimmunoconjugates: the Seattle experience. Ann. Hematol., 79: 175-182, 2000.[CrossRef][Medline]
  5. Press O. W. Radiolabeled antibody therapy of B-cell lymphomas. Semin. Oncol., 26: 58-65, 1999.[Medline]
  6. Richman C. M., DeNardo S. J., O’Donnell R. T., Goldstein D. S., Shen S., Kukis D. L., Kroger L. A., Yuan A., Boniface G. R., Griffith I. J., DeNardo G. L. Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibodies 170H. 82 with autologous stem cell support and cyclosporin A. Clin. Cancer Res., 5: 3243s-3248s, 1999.
  7. Halpern S. E., Hagan P. L., Garver P. R., Koziol J. A., Chen A. W., Frincke J. M., Bartholomew R. M., David G. S., Adams T. H. Stability, characterization, and kinetics of 111In-labeled monoclonal antitumor antibodies in normal animals and nude-mouse human tumor models. Cancer Res., 43: 5347-5355, 1983.[Abstract/Free Full Text]
  8. Pimm M. V., Perkins A. C., Baldwin R. W. Differences in tumor and normal tissue concentrations of iodine and indium labeled monoclonal antibody. II. Biodistribution studies in mice with human tumor xenografts. Eur. J. Nucl. Med., 11: 300-304, 1985.[CrossRef][Medline]
  9. Hnatowich D. J. Antibody radiolabeling, problems and promises. Nucl. Med. Biol., 17: 49-55, 1990.
  10. Erwin W. D., Groch M. W., Macey D. J., DeNardo G. L., DeNardo S. J., Shen S. A radioimmunoimaging and MIRD dosimetry treatment planning program for radioimmunotherapy. Nucl. Med. Biol., 23: 525-532, 1996.[CrossRef][Medline]
  11. Shen S., DeNardo G. L., Sgouros G., O’Donnell R. T., DeNardo S. J. Practical determination of patient-specific marrow dose using radioactivity concentration in blood and body. J. Nucl. Med., 40: 2102-2106, 1999.[Abstract/Free Full Text]
  12. Juweid M. E., Stadtmauer E., Hajjar G., Sharkey R. M., Suleiman S., Luger S., Swayne L. C., Alavi A., Goldenberg D. M. Pharmacokinetics, dosimetry and initial therapeutic results with 131I- and 111In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody (MAb) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). Clin. Cancer Res., 5: 3292s-3303s, 1999.
  13. DeNardo G. L., Juweid M. E., White C. A., Wiseman G. A., DeNardo S. J. Role of radiation dosimetry in radioimmunotherapy planning and treatment dosing. Crit. Rev. Oncol. Hematol., 39: 203-218, 2001.[Medline]
  14. Williams L. E. Estimation of absorbed doses in radioimmunotherapy. Med. Phys., 22: 958 1995.
  15. Wiseman G. A., Leigh B., Erwin W. D., Lamonica D., Kornmehl E., Spies S. M., Silverman D. H. S., Witzig T. E., Sparks R. B., White C. A. Radiation dosimetry results for Zevalin radioimmunotherapy of rituximab-refractory non-Hodgkin lymphoma. Cancer (Phila.), 94: 1349-1357, 2002.
  16. Wong J. Y. C., Chu D. Z., Yamauchi D. M., Williams L. E., Liu A., Wilczynski S., Wu A. M., Shively J. E., Doroshow J. H., Raubitschek A. A. A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies. Clin. Cancer Res., 6: 3855-3863, 2000.[Abstract/Free Full Text]
  17. Studer M., Kroger L. A., DeNardo S. J., Kukis D. L., Meares C. F. Influence of a peptide linker on biodistribution and metabolism of antibody-conjugated benzyl-EDTA. Comparison of enzymatic digestion in vitro and in vivo. Bioconjug. Chem., 3: 424-429, 1992.[CrossRef][Medline]
  18. Kukis D. L., Novak-Hofer I., DeNardo S. J. Cleavable linkers to enhance selectivity of antibody-targeted therapy of cancer. Cancer Biother. Radiopharm., 16: 457-467, 2001.[CrossRef][Medline]
  19. DeNardo G. L., Kroger L. A., Meares C. F., Richman C. M., Salako Q. A., Shen S., Lamborn K. R., Peterson J. J., Miers L. A., Zhong G. R., DeNardo S. J. Comparison of 1,4,7,10-tetraazacyclododecaine-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts. Clin. Cancer Res., 4: 2483-2490, 1998.[Abstract/Free Full Text]
  20. DeNardo G. L., DeNardo S. J., Peterson J. K., Miers L. A., Lam K. S., Hartmann-Siantar C., Lamborn K. R. Preclinical evaluation of cathepsin-degradable peptide linkers for radioimmunoconjugates. Clin. Cancer Res., 9 (Suppl.): 3865s-3872s, 2003.
  21. Haseman M. K., Goodwin D. A., Meares C. F. Metabolizable 111In-chelate conjugated anti-idiotype monoclonal antibody for radioimmunodetection of lymphoma in mice. Eur. J. Nucl. Med., 12: 455-460, 1986.[Medline]
  22. Deshpande S. V., DeNardo S. J., Meares C. F., McCall M. J., Adams G. P., DeNardo G. L. Effect of different linkages between chelates and monoclonal antibodies on levels of radioactivity in the liver. Nucl. Med. Biol., 16: 587-597, 1989.
  23. Arano Y., Mukai T., Uezono T., Wakisaka K., Motonari H., Akizawa H., Taoka Y., Yokoyama A. A biological method to evaluate bifunctional chelating agents to label antibodies with metallic radionuclides. J. Nucl. Med., 35: 890-898, 1994.[Abstract/Free Full Text]
  24. Quadri S. M., Vriesendorp H. M., Leichner P. K., Williams J. R. Evaluation of In-111- and yttrium-90-labeled linker immunoconjugates in nude mice and dogs. J. Nucl. Med., 34: 938-945, 1993.[Abstract/Free Full Text]
  25. Paik C. H., Yokoyama K., Reynolds J. C., Quadri S. M., Min C. Y., Shin S. Y., Maloney P. J., Larson S. M., Reba R. C. Reduction of background activities by introduction of a diester linkage between antibody and a chelate in radioimmunodetection of tumor. J. Nucl. Med., 30: 1693-1701, 1989.[Abstract/Free Full Text]
  26. Lewis M. R., Shively J. E. Maleimidocysteineamido-DOTA derivatives: new reagents for radiometal chelate conjugation to antibody sulfhydryl groups undergo pH-dependent cleavage reactions. Bioconjug. Chem., 9: 72-86, 1998.[CrossRef][Medline]
  27. Trouet A., Masquelier M., Baurain R., Deprez-De Campeneere D. A covalent linkage between daunorubicin and proteins that is stable in serum and reversible by lysosomal hydrolases, as required for a lysosomotropic drug-carrier conjugate: in vitro and in vivo studies. Proc. Natl. Acad. Sci. USA, 79: 626-629, 1982.[Abstract/Free Full Text]
  28. Studer M., Meares C. F. A convenient and flexible approach for introducing linkers on bifunctional chelating agents. Bioconjug. Chem., 3: 420-423, 1992.[CrossRef][Medline]
  29. Li M., Meares C. F. Synthesis, metal chelate stability studies, and enzyme digestion of a peptide-linked DOTA derivative and its corresponding radiolabeled immunoconjugates. Bioconjug. Chem., 4: 275-283, 1993.[CrossRef][Medline]
  30. DeNardo S. J., Richman C. M., Goldstein D. S., Shen S., Salako Q. A., Kukis D. L., Meares C. F., Yuan A., Welborn J. L., DeNardo G. L. Yttrium-90/indium-111-DOTA-peptide-chimeric L6: pharmacokinetics, dosimetry and initial results in patients with incurable breast cancer. Anticancer Res., 17: 1735-1744, 1997.[Medline]
  31. McEwan A. J. B., MacLean G. D., Hooper H., Sykes T., McQuarrie S. A., Goldberg L., Bodnar D. M., Lloyd S. L., Noujaim A. A. MAb 170H. 82: an evaluation of a novel panadenocarinoma monoclonal antibody labeled with 99Tcm and with 111In. Nucl. Med. Commun., 13: 11-19, 1992.[Medline]
  32. MacLean G. D., McEwan A., Noujaim A., Hooper H., Sykes T. R., Bodnnar D., Lloyd S., Golberg L. Two novel monoclonal antibodies have potential for gynecologic cancer imaging. Antibody Immunoconj. Radiopharm., 4: 297-308, 1991.
  33. DeNardo S. J. Radioimmunotherapy for breast cancer: systemic tumor-targeted irradiation. Adv. Oncol., 15: 23-29, 1999.
  34. Alexander C., Villena-Heinsen C. E., Trampert L., Lung-Kurt S., Oberhausen E., Kirsch C. M., Schmidt W. Radioimmunoscintigraphy of ovarian tumors with technetium-99m labelled monoclonal antibody-170: first clinical experiences. Eur. J. Nucl. Med., 22: 645-651, 1995.[CrossRef][Medline]
  35. McCall M. J., Diril H., Meares C. F. Simplified method for conjugating macrocyclic bifunctional chelating agents to antibodies via 2-iminothiolane. Bioconjug. Chem., 1: 222-226, 1990.[CrossRef][Medline]
  36. DeNardo G. L., O’Donnell R. T., Shen S., Kroger L. A., Yuan A., Meares C. F., Kukis D. L., DeNardo S. J. Radiation dosimetry for 90Y-2IT-BAD-Lym-1 extrapolated from pharmacokinetics using 111In-2IT-BAD-Lym-1 in patients with non-Hodgkin’s lymphoma. J. Nucl. Med., 41: 952-958, 2000.[Abstract/Free Full Text]
  37. Penefsky H. S. A centrifuged-column procedure for the measurement of ligand binding by beef heart F1. Methods Enzymol., 56G: 527-530, 1979.[Medline]
  38. Meares C. F., McCall M. J., Reardan D. T., Goodwin D. A., Diamanti C. I., McTigue M. Conjugation of antibodies with bifunctional chelating agents: isothiocyanate and bromoacetamide reagents, methods of analysis, and subsequent addition of metal ions. Anal. Biochem., 142: 68-78, 1984.[CrossRef][Medline]
  39. DeNardo S. J., Burke P. A., Leigh B. R., O’Donnell R. T., Miers L. A., Kroger L. A., Goodman S. L., Matzku S., Jonczyk A., Lamborn K. R., DeNardo G. L. Neovascular targeting with cyclic RGD peptide (cRGDf-ACHA) to enhance delivery of radioimmunotherapy. Cancer Biother. Radiopharm., 15: 71-79, 2000.[Medline]
  40. Kukis D. L., DeNardo G. L., DeNardo S. J., Mirick G. R., Miers L. A., Greiner D. P., Meares C. F. Effect of the extent of chelate substitution on the immunoreactivity and biodistribution of 2IT-BAT-Lym-1 immunoconjugates. Cancer Res., 55: 878-884, 1995.[Abstract/Free Full Text]
  41. Moi M. K., Meares C. F., DeNardo S. J. The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-Nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,-N',N'',N'''-tetraacetic acid and study of its yttrium (III) complex. J. Am. Chem. Soc., 110: 6266-6267, 1988.[CrossRef]
  42. DeNardo S. J., O’Grady L. F., Macey D. J., Kroger L. A., DeNardo G. L., Lamborn K. R., Levy N. B., Mills S. L., Hellstrom I., Hellstrom K. E. Quantitative imaging of mouse L-6 monoclonal antibody in breast cancer patients to develop a therapeutic strategy. Int. J. Radiat. Appl. Instrum. [B], 18: 621-631, 1991.
  43. Shen S., DeNardo G. L., DeNardo S. J., Yuan A., DeNardo D. A., Lamborn K. R. Reproducibility of operator processing for radiation dosimetry. Nucl. Med. Biol., 24: 77-83, 1997.[CrossRef][Medline]
  44. Snyder W. S., Ford M. R., Warner G. G., Watson S. B. . "S" Absorbed Dose Per Unit Cumulated Activity for Selected Radionuclides and Organs. MIRD Pamphlet No. 11, 82-83, Society of Nuclear Medicine New York 1975.
  45. Dillman L. T. . Radionuclide Decay Schemes and Nuclear Parameters for Use in Radiation-Dose Estimation, Part 2. MIRD Pamphlet No. 6, 5-32, Society of Nuclear Medicine New York 1970.
  46. Siegel J. A., Stabin M. G. Absorbed fractions for electrons and beta particles in spheres of various sizes. J. Nucl. Med., 35: 152-156, 1994.[Abstract/Free Full Text]
  47. Denis L. J., Carnelro de Moura J. L., Bono A., Sylvester R., Whelan P., Newling D., Depauw M. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology, 42: 119-130, 1993.[CrossRef][Medline]
  48. Goktas S., Crawford E. D. Optimal hormonal therapy for advanced prostatic carcinoma. Semin. Oncol., 26: 162-173, 1999.[Medline]
  49. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists’ Collaborative Group. Lancet, 355: 1491-1498, 2000.[CrossRef][Medline]
  50. Slovin S., Scher H., Divgi C., Reuter V., Sgouros G., Moore M. A., Weingard K., Pettengall R., Imbriaco M., El-Shirbiny A. M., Finn R., Bronstein J., Brett C., Milenic D. E., Dnistrian A., Shapiro L., Schlom J., Larson S. M. Interferon-{gamma} and monoclonal antibody 131I-labeled CC49; outcomes in patients with androgen-independent prostate cancer. Clin. Cancer Res., 4: 643-651, 1998.[Abstract]
  51. Meredith R. F., Bueschen A. J., Khazaeli M. B., Plott W. E., Grizzle W. E., Wheeler R. H., Schlom J., Russell C. D., Liu T., LoBuglio A. F. Treatment of metastatic prostate carcinoma with radiolabeled antibody CC49. J. Nucl. Med., 35: 1017-1022, 1994.[Abstract/Free Full Text]
  52. O’Donnell R. T., DeNardo S. J., Yuan A., Shen S., Richman C. M., Lara P. N., Griffith I. J., Goldstein D. S., Kukis D. L., Martinez G. S., Mirick G. R., DeNardo G. L., Meyers F. J. Radioimmunotherapy with 111In/90Y-2IT-BAD-m170 for metastatic prostate cancer. Clin. Cancer Res., 7: 1561-1568, 2001.[Abstract/Free Full Text]
  53. McDevitt M. R., Barendswaard E., Ma D., Lai L., Curcio M. J., Sgouros G., Ballangrud A. M., Yang W., Finn R. D., Pellegrini V., Geerlings M. W., Lee M., Brechbiel M. W., Bander N. H., Cordon-Cardo C., Scheinberg D. A. An {alpha}-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer. Cancer Res., 60: 6095-6100, 2000.[Abstract/Free Full Text]
  54. Vallabhajosula S., Kuji I., Kostakoglu L., Smith-Jones P. M., Zoe H., Bander N. H., Goldsmith S. J. Radiolabeled humanized monoclonal antibodies to PSMA: phase I dose escalation studies with 111In-DOTA-HU-J591. J. Nucl. Med., 42: 122P-123P, 2001.
  55. Juweid M., Sharkey R. M., Swayne L. C., Griffiths G. L., Dunn R., Siegel J., Goldenberg D. M. Rhenium-188-labeled antibodies in cancer radioimmunotherapy: pharmacokinetics, dosimetry, and toxicity of the 188Re-anti-CEA monoclonal antibody, MN-14, in patients with gastrointestinal cancers. J. Nucl. Med., 39: 34-42, 1998.[Abstract/Free Full Text]
  56. Breitz H. B., Fisher D. R., Weiden P. L., Durham J. S., Ratliff B. A., Bjorn M. J., Beaumier P. L., Abrams P. G. Dosimetry of rhenium-186-labeled monoclonal antibodies: methods, prediction from technetium-99m-labeled antibodies and results of phase I trials. J. Nucl. Med., 34: 908-917, 1993.[Abstract/Free Full Text]
  57. Griffiths G. L., Goldenberg D. M., Diril H., Hansen H. J. Technetium-99m, rhenium-186, and rhenium-188 direct-labeled antibodies. Cancer (Phila.), 73: 761-768, 1994.
  58. Emami B., Lyman J., Brown A., Coia L., Goitein M., Munzenrider J. E., Shank B., Solin L. J., Wesson M. Tolerance of normal tissue to therapeutic radiation. Int. J. Radiat. Oncol. Biol. Phys., 21: 109-122, 1991.[Medline]
  59. Richman C. M., DeNardo S. J. Systemic radiotherapy in metastatic breast cancer using 90Y-linked monoclonal MUC-1 antibodies. Crit. Rev. Oncol. Hematol., 38: 26-35, 2001.



This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
T. A. Sulchek, R. W. Friddle, K. Langry, E. Y. Lau, H. Albrecht, T. V. Ratto, S. J. DeNardo, M. E. Colvin, and A. Noy
Dynamic force spectroscopy of parallel individual Mucin1-antibody bonds
PNAS, November 15, 2005; 102(46): 16638 - 16643.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Siantar, C. L. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Siantar, C. L. H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online