Preclinical Evaluation of an Anti-Tumor Monclonal Antibody/ Streptavidin Conjugate for Pretargeted 90y Radioimmunotherapy in a Mouse Xenograft Model

Axworthy, Donald B.; Fritzberg, Alan R.; Hylarides, Mark D.; Mallett, Robert; Theodore, Louis; Gustavson, L. M.; Su, F-M.; Beaumier, Paul L.; Reno, John M.

doi:10.1097/00002371-199408000-00049

Cited by 43 publications

(50 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several of the early studies with bispecific mAb pretargeting reported uptake in the range 3% to 5% ID/g (56), but Axworthy et al (57), using a ''two-step'' streptavidinpretargeting method, showed that, when properly adjusted, the uptake of radiolabeled biotin was similar to that of the directly radiolabeled IgG and that this procedure could result in improved therapeutic responses compared with a directly radiolabeled IgG (58). Since then, there have been several other reports where the therapeutic efficacy of pretargeting is superior to direct targeting (59 -63).…”

Section: Pretargeting For Improved Therapymentioning

confidence: 99%

Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods

Sharkey

Karacay

Cardillo

et al. 2005

Clinical Cancer Research

113

102

View full text Add to dashboard Cite

The article reviews the background and current status of pretargeting for cancer imaging and therapy with radionuclides. Pretargeting procedures were introduced f20 years ago as an alternative to directly radiolabeled antibodies. Because they were multistep processes, they were met with resistance but have since progressed to simple and improved procedures that could become the next generation of imaging and therapy with radionuclides. The separation of the radiolabeled compound from the antibody-targeting agent affords pretargeting procedures considerable flexibility in the radiolabeling process, providing opportunities for molecular imaging using g-or positron-emitting radionuclides and a variety of h-and a-emitting radionuclides of therapeutic applications. Pretargeting methods improve tumor/ nontumor ratios, exceeding that achieved with directly radiolabeled FabV fragments, particularly within just a few hours of the radionuclide injection. In addition, tumor uptake exceeds that of a FabV fragment by as much as 10-fold, giving pretargeting a greatly enhanced sensitivity for imaging. Advances in molecular biology have led to the development of novel binding proteins that have further improved radionuclide delivery in these systems. Studies in a variety of hematologic and solid tumor models have shown advantages of pretargeting compared with directly radiolabeled IgG for therapy, and there are several clinical studies under way that are also showing promising results. Thus, the next generation of targeting agents will likely employ pretargeting approaches to optimize radionuclide delivery for a wide range of applications.Radiation continues to play an integral role in the management of cancer, from the use of X-rays and computed tomography for detection to the use of external beam and interstitial radiotherapy (brachytherapy and rapid interstitial therapy) for treatment. Nuclear medicine, which involves the use of internally administered radionuclides, traditionally has played a minor role in the management of cancer, initially relying primarily on the use of [ 67 Ga]citrate for lymphoma imaging and 131 INa for thyroid cancer treatment. However, with the advent of positron emission tomography and [ 18 F]deoxyglucose, and thanks to the development of new antibody-guided therapeutics for non-Hodgkin's lymphoma and emerging peptide-targeted therapeutics, the role of nuclear medicine in the management of cancer is increasing (1, 2).Except for 131 INa and radionuclides used for palliation of bone pain that are selectively taken up by their respective tissues, the specificity for cancer of internally administered radionuclides depends on its coupling to a targeting compound. For example, [18 F]deoxyglucose is concentrated in cancers because they are more metabolically active than most other cells in the body and therefore will accrue more deoxyglucose than surrounding cells. Antibodies have been one of the most commonly used targeting agents, with an extensive history spanning over 50 years (3). During this...

show abstract

Section: Pretargeting For Improved Therapymentioning

confidence: 99%

Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods

Sharkey

Karacay

Cardillo

et al. 2005

Clinical Cancer Research

113

102

View full text Add to dashboard Cite

show abstract

“…This pretargeting approach has been demonstrated to improve the ratios of radiation delivered to tumors compared with the doses delivered to normal organs in preclinical and clinical models. [12][13][14][15][16][17][18][19][20][21][22][23][24] Recent work using human carcinoma xenografts demonstrated that a single treatment of pretargeted 90 Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin resulted in rapid effective blood clearance of non-tumorbound antibody, improved tumor-to-normal organ ratios of absorbed radioactivity, and superior objective and durable remissions with minimal toxicity. 25 Synthetic clearing agents have been introduced as an additional refinement to pretargeting protocols to more efficiently deplete immunoconjugates lingering in the bloodstream before administration of the radioactive moiety.…”

Section: Introductionmentioning

confidence: 99%

Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas

Pagel

Hedin

Subbiah

et al. 2003

Blood

109

View full text Add to dashboard Cite

Radiolabeled anti-CD20 antibodies produce responses in 60% to 95% of patients with relapsed non-Hodgkin lymphoma (NHL); however, absorbed radiation ratios between tumors and normal organs are relatively low, and many patients have relapses. In this study we compared the abilities of anti-CD45 (BC8) and anti-CD20 (1F5) antibodies to target human Ramos lymphoma xenografts in athymic mice. When direct radioiodination was performed with conventional methods, BC8 delivered 2-to 4-fold more radioiodine to tumors than 1F5, with tumor-to-normal organ ratios as high as 20:1 using radiolabeled BC8 compared with a maximal ratio of 9.8:1 using radioiodinated 1F5. To optimize the biodistribution of radioactivity, we performed studies following a pretargeting method using streptavidin (SA)-conjugated BC8 and 1F5. Injection of a synthetic clearing agent decreased the circulating level of conjugates by 80% to 90% within 1 hour. Pretargeting with BC8-SA resulted in a 2-to 4-fold greater tumor uptake of radiolabeled biotin than with 1F5-SA, with maximal tumor-to-normal organ ratios of more than 80:1 and approximately 16:1, respectively. Therapy experiments demonstrated that 400 Ci (14.8 MBq) or more of yttrium-90-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin cured 100% of mice treated with BC8-SA and more than 90% of mice pretargeted with 1F5-SA, with complete remission occurring 8 to 10 days sooner in mice receiving BC8-SA. After treatment with 200 Ci (7.4 MBq) 90 Y-DOTA-biotin, 70% of the mice treated with BC8-SA were cured, but no mice were cured using 1F5-SA. Doses up to 800 Ci (29.6 MBq) 90 Y-DOTA-biotin were delivered with minor toxicity using either antibody conjugate. These lymphoma xenograft data suggest that pretargeted radioimmunotherapy using either anti-CD20 or anti-CD45 conjugates is highly effective and minimally toxic. (Blood.

show abstract

“…This result is partly due to the fact that maximal tumor uptake of intact mAb 1A3 did not occur until 24 h after injection, when the 64Cu had decayed through about two half-lives. Increased tumor delivery of 64Cu may be achieved with the use of agents, such as mAb fragments, that have more rapid tumor uptake (4,30) or with pretargeting approaches (31). Table 2 compares our results with those in other RIT studies that similarly used intact mAb in colon cancer models.…”

Section: Discussionmentioning

confidence: 80%

Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu.

Connett

Anderson

Guo

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

124

View full text Add to dashboard Cite

ABSTRACT67Cu (tl2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 6"Cu (t1l2 = 12.8 h)has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu-and 67Cu-bromoacetamidobenzyl-1,4,8,1 1-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu-or 67Cu-BAT-21T-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were 210 g. Of the hamsters with small tumors (mean weight 0.43 ± 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-21T-1A3 or 0.4 mCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu-and 67Cu-BAT-21T-lA3 were 586 and 1269 rad (1 rad = 0.01 Gy), respectively. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-21T-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 months because of tumor regrowth. When hamsters with larger tumors (mean weight 0.66 + 0.11 g) were treated with 64Cu-or 67Cu-BAT-21T-lA3, survival was extended compared with controls, but only one animal remained tumor-free to 6 months. These results demonstrate that 64Cu-and 67Cu-BAT-21T-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but additional strategies to deliver higher tumor doses will be needed for larger tumors.

show abstract

Preclinical Evaluation of an Anti-Tumor Monclonal Antibody/ Streptavidin Conjugate for Pretargeted 90y Radioimmunotherapy in a Mouse Xenograft Model

Cited by 43 publications

References 0 publications

Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods

Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods

Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas

Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu.

Contact Info

Product

Resources

About