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  • 1
    Online Resource
    Online Resource
    Evaluation of CD20, CD22, and HLA-DR Targeting for Radioimmunotherapy of B-Cell Lymphomas
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 12 ( 2007-06-15), p. 5921-5928
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 12 ( 2007-06-15), p. 5921-5928
    Abstract: Despite the promise of radioimmunotherapy using anti-CD20 antibodies (Ab) for the treatment of relapsed patients with indolent non-Hodgkin lymphoma (NHL), most patients treated with conventional doses of 131I-tositumomab or 90Y-ibritumomab eventually relapse. We did comparative assessments using conventional radioimmunotherapy targeting CD20, CD22, and HLA-DR on human Ramos, Raji, and FL-18 lymphoma xenografts in athymic mice to assess the potential for improving the efficacy of radioimmunotherapy by targeting other NHL cell surface antigens. Results of biodistribution studies showed significant differences in tumor localization consistent with variable antigenic expression on the different lymphoma cell lines. Interestingly, the radioimmunoconjugate that yielded the best tumor-to-normal organ ratios differed in each tumor model. We also explored administering all three 111In-1,4,7,10-tetra-azacylododecane N,N′,N″,N‴-tetraacetic acid antibodies in combination, but discovered, surprisingly, that this approach did not augment the localization of radioactivity to tumors compared with the administration of the best single radiolabeled Ab alone. These data suggest that conventional radioimmunotherapy using anti-CD20, anti–HLA-DR, or anti-CD22 Abs is effective when used singly and provides targeted uptake of radiolabel into the tumor that is dependent on the levels of antigen expression. Improvements in tumor-to-normal organ ratios of radioactivity cannot be achieved using directly labeled Abs in combination but may be afforded by novel pretargeting methods. [Cancer Res 2007;67(12):5921–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-0080
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Conventional and Pretargeted Radioimmunotherapy with Bismuth-213 to Target and Treat CD20-Expressing Non-Hodgkin Lymphoma: A Preclinical Model for Consolidation Therapy to Eradicate Minimal Residual Disease.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2705-2705
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2705-2705
    Abstract: Abstract 2705 Poster Board II-681 Conventional radioimmunotherapy (RIT) with directly radiolabeled anti-B cell antibodies (Ab) induces remissions in 50 to 80% of patients with relapsed or refractory indolent non-Hodgkin lymphomas (NHL). Although administering RIT as consolidation after chemotherapy improves response rates and produces long-term durable remissions in treatment-naïve patients, the β-emitting radionuclides used in current RIT schemes may not be ideal for irradiating the microscopic tumors and the isolated tumor cells present in the setting of minimal residual disease (MRD). RIT with α-emitting radionuclides may be advantageous in the treatment of MRD because the short path length and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to the surrounding normal tissues. Our group has successfully demonstrated that pretargeted RIT (PRIT) using streptavidin (SA)-Ab and radiolabeled biotin allows rapid specific localization of radioactivity at tumor sites. PRIT using α-emitting radionuclides may be particularly attractive since the most promising α-emitting radionuclides in clinical settings, such as 213Bi (t½ = 46 min), have short half-lives and pretargeting allows the delivery of radioactivity to tumor sites before the activity decays. We therefore performed in vivo studies to evaluate the biodistribution of 213Bi with PRIT. Athymic mice with B-cell NHL (Ramos) xenografts received a tetravalent anti-CD20 (1F5) single-chain (scFv)4SA fusion protein (FP) or a CC49 (scFv)4SA FP (non-binding negative control) followed by an N-acetyl galactosamine clearing agent (CA) and subsequent 213Bi-DOTA-biotin infusion. Tumors, blood, and major organs were collected to determine the percent injected dose per gram (%ID/g) at various time points within ∼3 half-lives of 213Bi. Maximal tumor uptake for 1F5 (scFv)4SA FP was 16.5 ± 7.0 %ID/g at 90 minutes vs. 2.3 ± 0.9 %ID/g for the control FP (p = 0.0001). Biodistributions of 213Bi using a conventional RIT scheme with directly labeled Ab were also evaluated. Athymic mice with Ramos xenografts received 213Bi labeled 1F5 Ab or 213Bi labeled HB8181 Ab (a murine isotype matched nonbinding control). Maximum tumor uptake for 1F5 Ab was 3.0 ± 0.9 %ID/g at 180 minutes vs. 2.3 ± 0.7 %ID/g for the control Ab (p = 0.171). There were no significant differences in tumor uptake and normal organ distribution between the two Ab within 180 minutes of radiolabeled Ab injection presumably due to the protracted circulating half-life of radiolabeled Abs. These results were concordant with our previous experiments using other radionuclides, showing that maximal targeting of radiolabeled Ab occurs between 20 to 24 hours; well beyond the effective half-life of 213Bi. When the results of PRIT and RIT studies were directly compared, tumor-to-blood ratios were 58 to 426-fold higher with PRIT than with conventional RIT. Tumor-to-normal organ ratios of nearly 100:1 were observed with PRIT compared to 3:1 or less with conventional RIT. Using the most favorable PRIT schemes defined in the biodistribution experiments, the therapeutic efficacy of 213Bi was evaluated. Mice treated with PRIT using 1F5 (scFv)4SA FP followed by a CA and 600 μCi 213Bi-DOTA-biotin experienced significant delays in tumor growth. The 1F5 (scFv)4SA FP treated animals had a mean tumor volume of 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 for the CC49 control group at 19 days (p = 0.0006). The median survival for 1F5 group was not reached after 90 days; whereas, the median survival was 23 days for the CC49 group (p = 0.0019) and 16 days for untreated mice (p = 0.0023). The treatment was well tolerated, with no treatment-related mortalities in any group. These data demonstrate that PRIT using 213Bi has a favorable biodistribution profile and excellent therapeutic efficacy. This model may be particularly effective in MRD settings and further studies are ongoing. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2705.2705
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas
    American Society of Hematology ; 2007
    In:  Blood Vol. 109, No. 11 ( 2007-06-01), p. 4980-4987
    Details
    In: Blood, American Society of Hematology, Vol. 109, No. 11 ( 2007-06-01), p. 4980-4987
    Abstract: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SA)–conjugated antibodies (Abs), followed by clearing agent and radiolabeled biotin is a promising method that can increase the effectiveness of RIT, while decreasing the toxicities associated with directly labeled Abs. Although CD20 has been the traditional target antigen for RIT of non-Hodgkin lymphoma (NHL), studies targeting HLA DR and CD22 have yielded promising results. Targeting all 3 antigens at once may further augment the effect of PRIT. This study compares the targeting of Ramos, Raji, and FL-18 lymphoma xenografts with either anti-CD20 Ab/SA (1F5/SA), anti-HLA DR Ab/SA (Lym-1/SA), anti-CD22 Ab/SA (HD39/SA), or all 3 conjugates in combination, followed 24 hours later by a biotin-N-acetyl-galactosamine clearing agent, and 3 hours after that by 111In-DOTA-biotin. The Ab/SA conjugate yielding the best tumor uptake and tumor-to–normal organ ratios of radioactivity varied depending on the target antigen expression on the cell line used, with 1F5/SA and Lym-1/SA yielding the most promising results overall. Also, the best tumor-to–normal organ ratios of absorbed radioactivity were obtained using single conjugates optimized for target tumor antigen expression rather than the combination therapy. This study highlights the importance of screening the antigenic expression on lymphomas to select the optimal reagent for PRIT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2006-11-056895
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Anti-CD45 Ab Pretargeted Radioimmunotherapy Using An Alpha Emitting Radionuclide (213Bi) Delivers Selective Radiation to Human Myeloid Leukemias in a Mouse Xenograft Model and Results in High Rates of Complete Remission and Long Term Survival.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1035-1035
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1035-1035
    Abstract: Abstract 1035 Poster Board I-57 Little change has been seen over the past two decades in the progression-free survival of patients with Acute Myeloid Leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT). Efforts to decrease the risk of relapse after HCT have included increasing the intensity of the preparative regimen. Our group has focused on targeted radioimmunotherapy using an anti-CD45 antibody (Ab) as part of the preparative regimen prior to HCT. Despite the promise of this approach, recurrent malignancy remains a problem, particularly for patients with high-risk disease. More recently we have explored a pretargeted RIT (PRIT) strategy to augment the anti-tumor efficacy of the transplant preparative regimen while diminishing overall toxicity. These studies have employed an anti-CD45 Ab conjugated to streptavidin (SA) followed by a biotinylated, N-acetylgalactosamine-containing clearing agent (CA) to remove circulating Ab-SA conjugate from the blood and then with radiobiotin using beta-emitting radionuclides that have relatively low energy transfer characteristics and long path lengths that may result in suboptimal killing of leukemia cells and normal organ toxicity due to cross-fire from malignant cells. Alpha-emitting radionuclides exhibit very high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to beta-emitting radionuclides. Therefore, we have now employed PRIT using an anti-CD45 Ab-SA conjugate, CA, and biotin labeled with an alpha-emitting radionuclide (213Bi) in mice with human erythroid leukemia (HEL) xenografts. Results of biodistributions of radioactivity demonstrated excellent localization of 213Bi-biotin to tumors with minimal uptake into normal organs due to elimination of non-specific radiation exposure from blood-borne radiolabeled Ab. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor (% ID/g). Imaging using a novel alpha camera demonstrated uniform radionuclide distribution within tumor tissue at 10 minutes after 213Bi-biotin injection. Estimated radiation-absorbed doses delivered to HEL xenografts delivered 3.4-and 2.1-fold more radiation to tumor than to liver and lungs, respectively. These target-to-non-target ratios of absorbed radiation obtained using PRIT with 213Bi were similar to those observed using a beta-emitting (90Y) radionuclide in the same animal model. Based on these encouraging results, we conducted therapy experiments in a minimal disease xenograft model using a single dose of 213Bi-biotin given 24 hours after anti-CD45 Ab-SA conjugate. In an initial attempt to compare 90Y and 213Bi, we gave equal μCi doses of each radionuclide. Eighty percent of mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi-biotin survived leukemia-free for 〉 100 days with minimal toxicity. By comparison, only 20% of mice treated with PRIT anti-CD45 Ab-SA conjugate followed by 800 μCi 90Y-biotin exhibited long term leukemia-free survival. While we acknowledge that equal μCi doses may not necessarily result in equivalent doses delivered to normal tissue, these data suggest that anti-CD45 PRIT using an alpha-emitting radionuclide may be highly effective and minimally toxic for the treatment of myeloid leukemias. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1035.1035
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Design and Synthesis of Bis-Biotin-Containing Reagents for Applications Utilizing Monoclonal Antibody-Based Pretargeting Systems with Streptavidin Mutants
    American Chemical Society (ACS) ; 2010
    In:  Bioconjugate Chemistry Vol. 21, No. 7 ( 2010-07-21), p. 1225-1238
    Details
    In: Bioconjugate Chemistry, American Chemical Society (ACS), Vol. 21, No. 7 ( 2010-07-21), p. 1225-1238
    Type of Medium: Online Resource
    ISSN: 1043-1802 , 1520-4812
    URL: Article
    DOI: 10.1021/bc100030q
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2010
    detail.hit.zdb_id: 1500067-9
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  • 6
    Online Resource
    Online Resource
    Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 22 ( 2016-11-15), p. 6669-6679
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 22 ( 2016-11-15), p. 6669-6679
    Abstract: Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P & lt; 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P & lt; 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. Cancer Res; 76(22); 6669–79. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-0571
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Therapeutics Vol. 19, No. 12 ( 2020-12-01), p. 2575-2584
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 19, No. 12 ( 2020-12-01), p. 2575-2584
    Abstract: Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (% ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1,200 μCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all nontreated controls required euthanasia because of tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen, 9.0 ± 1.5% ID/g and bone marrow, 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs ( & lt;0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 μCi) of 90Y-DOTA-biotin had a survival advantage compared with untreated leukemic mice (median, 43 vs. 30 days, respectively; P & lt; 0.0001). These data suggest bispecific antibody–mediated PRIT may be highly effective for leukemia therapy and translation to human studies.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-20-0306
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies
    American Society of Hematology ; 2018
    In:  Blood Vol. 131, No. 6 ( 2018-02-08), p. 611-620
    Details
    In: Blood, American Society of Hematology, Vol. 131, No. 6 ( 2018-02-08), p. 611-620
    Abstract: A novel bispecific antibody against CD38 eradicates MM and NHL tumors in murine models. CD38-bispecific antibody pretargeting addresses limitations associated with radioimmunotherapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2017-09-807610
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    Bulk production and evaluation of high specific activity 186gRe for cancer therapy using enriched 186WO3 targets in a proton beam
    Elsevier BV ; 2017
    In:  Nuclear Medicine and Biology Vol. 49 ( 2017-06), p. 24-29
    Details
    In: Nuclear Medicine and Biology, Elsevier BV, Vol. 49 ( 2017-06), p. 24-29
    Type of Medium: Online Resource
    ISSN: 0969-8051
    URL: Article
    DOI: 10.1016/j.nucmedbio.2017.02.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1498538-X
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Glypican-3 targeted delivery of 89Zr and 90Y as a theranostic radionuclide platform for hepatocellular carcinoma
    Springer Science and Business Media LLC ; 2021
    In:  Scientific Reports Vol. 11, No. 1 ( 2021-02-12)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-02-12)
    Abstract: Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 ( 89 Zr) and yttrium-90 ( 90 Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89 Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90 Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUV max by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP ( R 2  = 0.90). Serum AFP was significantly lower 30 days after RIT in 90 Y-αGPC3 treated animals compared to those untreated ( p  = 0.01) or treated with non-radiolabeled αGPC3 ( p  = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT ( R 2  = 0.87), and GTV of animals treated with 90 Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89 Zr and 90 Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-021-82172-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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