David Kukis - Academia.edu (original) (raw)

Papers by David Kukis

Research paper thumbnail of Are Radiometal-Labeled Antibodies Better Than Iodine-131–Labeled Antibodies: Comparative Pharmacokinetics and Dosimetry of Copper-67–, Iodine-131–, and Yttrium-90–Labeled Lym-1 Antibody in Patients with Non-Hodgkin's Lymphoma

Clinical Lymphoma Myeloma, 2000

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has... more Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu-and 131 I-labeled Lym-1 or 111 In-and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y-2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.

Research paper thumbnail of Imaging and Pharmacokinetics of 64 Cu-DOTA-HB22.7 Administered by Intravenous, Intraperitoneal, or Subcutaneous Injection to Mice Bearing Non-Hodgkin's Lymphoma Xenografts

Mol Imaging Biol, 2009

The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistrib... more The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistribution of (64)Cu-DOTA-HB22.7 when administered to xenograft-bearing mice intravenously (IV), intraperitoneally (IP), and subcutaneously (SQ). Mice bearing human non-Hodgkin's lymphoma (NHL) xenografts were injected IV, IP, or SQ with (64)Cu-DOTA-HB22.7. Xenograft targeting was evaluated by micro positron emission tomography (microPET) and confirmed by organ biodistribution studies. Blood measurements of (64)Cu were performed to determine the pharmacokinetics and clearance of (64)Cu-DOTA-HB22.7. (64)Cu-DOTA-HB22.7 demonstrated equivalent tumor targeting within 24-48 h, regardless of the route of administration. Organ biodistribution confirmed tumor-specific targeting. Blood pharmacokinetics demonstrated that (64)Cu-DOTA-HB22.7 accessed the bloodstream after IP and SQ administration to a similar degree as IV administration, albeit at a slower rate. These findings establish (64)Cu-DOTA-HB22.7 as a potential radioimmunotherapeutic and/or NHL-specific imaging agent. These findings provide evidence that IP and SQ administration can achieve results equivalent to IV administration and may lead to more efficient, reproducible treatment plans for antibody-based therapeutics.

Research paper thumbnail of Effect of the extent of substitution on the immunoreactivity of 21T-BAT-LYM-1 immunoconjugate

J Nucl Med, 1994

... BAT-Lym-1 is prepared by conjugating the bifunctional macrocyclic chealting agent 6-[p-(bromo... more ... BAT-Lym-1 is prepared by conjugating the bifunctional macrocyclic chealting agent 6-[p-(bromoacetamido)benzyl]-TETA (BAT) to murine anti-lymphoma lgG{sub 2a} Lym-1 via 2-iminothiolane (2IT). The specific activity of Cu-67 used for radiolabeling is as low as 1 mCi/{ ...

Research paper thumbnail of Metabolite production in patients with lymphoma after radiometal-labeled antibody administration

Journal of Nuclear Medicine, Sep 1, 2001

Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies,... more Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111 In-and 90 Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,NЈ,N Љ,N ٞ-tetraacetic acid-Lym-1 ( 111 In/ 90 Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111 In-and 90 Y-2IT-BAD-Lym-1; 111 In was used as a surrogate tracer for 90 Y, which emits no ␥-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111 In in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111 In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111 In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90 Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111 In-2IT-BAD-m170, 91% and 94% of 111 In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111 In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111 In/ 90 Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111 In/ 90 Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111 In/ 90 Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

Research paper thumbnail of Yttrium-90-Labeled Monoclonal Antibody for Therapy: Labeling by a New Macrocyclic Bifunctional Chelating Agent

Journal of Nuclear Medicine Official Publication Society of Nuclear Medicine, Apr 1, 1990

Research paper thumbnail of Optimized conditions for chelation of yttrium-90-DOTA immunoconjugates

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1998

Radioimmunotherapy (RIT) with 90Y-labeled immunoconjugates has shown promise in clinical trials. ... more Radioimmunotherapy (RIT) with 90Y-labeled immunoconjugates has shown promise in clinical trials. The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) binds 90Y with extraordinary stability, minimizing the toxicity of 90Y-DOTA immunoconjugates arising from loss of 90Y to bone. However, reported 90Y-DOTA immunoconjugate product yields have been typically only < or =50%. Improved yields are needed for RIT with 90Y-DOTA immunoconjugates to be practical. (S) 2-[p-(bromoacetamido)benzyl]-DOTA (BAD) was conjugated to the monoclonal antibody Lym-1 via 2-iminothiolane (2IT). The immunoconjugate product, 2IT-BAD-Lym-1, was labeled in excess yttrium in various buffers over a range of concentrations and pH. Kinetic studies were performed in selected buffers to estimate radiolabeling reaction times under prospective radiopharmacy labeling conditions. The effect of temperature on reaction kinetics was examined. Optimal radiolabeli...

Research paper thumbnail of A clinical trial of radioimmunotherapy with 67Cu-2IT-BAT-Lym-1 for non-Hodgkin's lymphoma

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1999

Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's... more Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's lymphoma (NHL), this phase I/II clinical trial of 67Cu-2IT-BAT-Lym-1 was conducted in an effort to further improve the therapeutic index of Lym-1-based radioimmunotherapy. Lym-1 is a mouse monoclonal antibody that preferentially targets malignant lymphocytes. 67Cu has beta emissions comparable to those of 131I but has gamma emissions more favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid binds 67Cu tightly to form a stable radioimmunoconjugate in vivo. All 12 patients had stage III or IV NHL that had not responded to standard therapy; 11 had intermediate- or high-grade NHL. At 4-wk intervals, patients received up to four doses of 67Cu-2IT-BAT-Lym-1, 0.93 or 1.85-2.22 GBq/m2 (25 or 50-60 mCi/m2), with the lower dose used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging ...

Research paper thumbnail of Strategies for enhancement of radioimmunotherapy

International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991

Two new strategies for increasing tumor uptake have been investigated. First the effect of interl... more Two new strategies for increasing tumor uptake have been investigated. First the effect of interleukin-2 (IL-2) on tumor uptake of 125I-Lym-1 antibody in nude mice was investigated. Secondly, the use of 67Cu-labeled Lym-1 was evaluated in patients. In nude mice implanted with Raji human lymphoma, a greater than 2-fold enhancement of tumor uptake of 125I-Lym-1 was observed after administration of PEG-interleukin-2 (PEG-IL-2). The macrocycle 1,4,8,11-tetraazacylcotetradecane-N,N',N",N"'-tetraacetic acid (TETA), synthesized specifically for copper chelation, has been conjugated to Lym-1 for 67Cu labeling of the monoclonal antibody (MoAb). There was no evidence for bone or normal marrow uptake and the residence time in the tumor was prolonged. Surprisingly, a dose of 4.4 mCi that was intended for imaging induced substantial tumor regression in a patient.

Research paper thumbnail of A smart and versatile theranostic nanomedicine platform based on nanoporphyrin

Nature Communications, 2014

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promi... more Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;all-in-one&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.

Research paper thumbnail of Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and90yttrium-DOTA-peptide-ChL6

The Prostate, 2002

Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-C... more Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-ChL6 (5.55 MBq;150 microCi) has resulted in durable responses. To make radioimmunotherapy (RIT) more effective, the radiation-enhancing drugs Taxol (paclitaxel) and Taxotere (docetaxel) were tested for synergy with 90Y-DOTA-peptide-ChL6. Nude mice bearing human prostate cancer PC3 xenografts were treated with 90Y-DOTA-peptide-ChL6 (2.78 MBq; 75 microCi) and after 24 hr, paclitaxel (300 or 600 microg), or docetaxel (300 microg). Tumor size, survival, blood counts, and pharmacokinetics were monitored to assess efficacy and toxicity. Docetaxel plus RIT had a 67% cure rate, whereas no mice were cured among the RIT alone, chemotherapy alone, or untreated controls. Paclitaxel (600 microg) plus RIT produced a 100% response rate with 20% cures. Average tumor volume was reduced to a greater degree in the combined modality radioimmunotherapy (CMRIT) groups compared to controls and the anti-tumor response was durable. Myelotoxicity in the combined modality groups (RIT plus paclitaxel or RIT plus docetaxel) were similar to groups receiving the same dose of RIT alone. In the PC3-tumor nude mouse model, addition of paclitaxel or docetaxel to 90Y-DOTA-peptide-ChL6, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.

Research paper thumbnail of Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

Proceedings of the National Academy of Sciences, 1997

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 m... more Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90 Y-labeled DOTA-peptide-ChL6 ( 90 Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N,N ؆,N ٟ-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90 Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90 Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before 90 Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90 Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90 Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90 Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90 Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90 Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.

Research paper thumbnail of Imaging and Pharmacokinetics of 64Cu-DOTA-HB22.7 Administered by Intravenous, Intraperitoneal, or Subcutaneous Injection to Mice Bearing Non-Hodgkin’s Lymphoma Xenografts

Molecular Imaging and Biology, 2009

The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistrib... more The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistribution of (64)Cu-DOTA-HB22.7 when administered to xenograft-bearing mice intravenously (IV), intraperitoneally (IP), and subcutaneously (SQ). Mice bearing human non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma (NHL) xenografts were injected IV, IP, or SQ with (64)Cu-DOTA-HB22.7. Xenograft targeting was evaluated by micro positron emission tomography (microPET) and confirmed by organ biodistribution studies. Blood measurements of (64)Cu were performed to determine the pharmacokinetics and clearance of (64)Cu-DOTA-HB22.7. (64)Cu-DOTA-HB22.7 demonstrated equivalent tumor targeting within 24-48 h, regardless of the route of administration. Organ biodistribution confirmed tumor-specific targeting. Blood pharmacokinetics demonstrated that (64)Cu-DOTA-HB22.7 accessed the bloodstream after IP and SQ administration to a similar degree as IV administration, albeit at a slower rate. These findings establish (64)Cu-DOTA-HB22.7 as a potential radioimmunotherapeutic and/or NHL-specific imaging agent. These findings provide evidence that IP and SQ administration can achieve results equivalent to IV administration and may lead to more efficient, reproducible treatment plans for antibody-based therapeutics.

Research paper thumbnail of CMR 2007: 4.03: High-throughputin vivo screening of targeted molecular imaging agents using PET

Contrast Media & Molecular Imaging, 2007

Research paper thumbnail of Are Radiometal-Labeled Antibodies Better Than Iodine-131–Labeled Antibodies: Comparative Pharmacokinetics and Dosimetry of Copper-67–, Iodine-131–, and Yttrium-90–Labeled Lym-1 Antibody in Patients with Non-Hodgkin's Lymphoma

Clinical Lymphoma, 2000

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has... more Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu-and 131 I-labeled Lym-1 or 111 In-and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y-2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.

Research paper thumbnail of Cleavable Linkers to Enhance Selectivity of Antibody-Targeted Therapy of Cancer

Cancer Biotherapy & Radiopharmaceuticals, 2001

Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to r... more Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to radionuclides to deliver radiation selectively to tumors. However, radiolabeled proteins deposit radioactivity in normal organs that metabolize or conserve proteins and peptides, primarily liver and kidneys. To accelerate the clearance of radioactivity from normal tissues, linkers between the antibody or antibody fragment and the radioactive moiety have been designed for cleavage in the liver and kidneys, to liberate low molecular weight radioactive species for rapid excretion. Modest success in improving the tumor-to-liver and tumor-to-kidney radiation dose ratios have been achieved in preclinical studies. Such changes when taken to clinical studies have suggested useful impact on therapeutic work. Recent advances in the development of cleavable linkers are described.

Research paper thumbnail of Radioimmunotherapy of Acquired Immunodeficiency Syndrome (AIDS) Associated Lymphoma

Cancer Biotherapy & Radiopharmaceuticals, 1999

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunothera... more Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.

Research paper thumbnail of Combined Modality Radioimmunotherapy with Taxol and 90 Y-LYM-1 for Raji Lymphoma Xenografts

Cancer Biotherapy & Radiopharmaceuticals, 1998

Despite effective therapies for non-Hodgkin&#39;s lymphoma (NHL), the majority of patients ar... more Despite effective therapies for non-Hodgkin&#39;s lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt&#39;s lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.

Research paper thumbnail of Enhancement of 67Cu‐2IT‐BAT‐LYM‐1 therapy in mice with human burkitt's lymphoma (Raji) using interleukin‐2

Cancer, 1997

Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice ... more Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts. 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N&#39;, N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2. In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2. 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.

Research paper thumbnail of Comparative toxicity studies of yttrium-90 mx-dtpa and 2-it-bad conjugated monoclonal antibody (bre-3)

Cancer, 1994

BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Be... more BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N&#39;,N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid (BAD). Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.

Research paper thumbnail of A comparative study of copper-67 radiolabeling and kinetic stabilities of antibody-macrocycle chelate conjugates

Cancer, 1994

The development of new chelating agents and radiolabeling protocols is essential to progress in r... more The development of new chelating agents and radiolabeling protocols is essential to progress in radioimmunotherapy with antibody-chelate conjugates. Immunoconjugates of four polyazamacrocycles with N-bonded acetate groups were prepared by conjugation via 2-iminothiolane to Lym-1, a murine antilymphoma immunoglobulin G2a MoAb. To optimize 67Cu radiolabeling, complexation conditions were explored. The kinetic stabilities in vitro in human serum of four 67Cu labeled immunoconjugates were investigated. Lym-1-2IT-6-BAT-67Cu, the chelate conjugate of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N&#39;,N&#39;&#39;N&#39;&#39;&#39;-tetraacetic acid, exhibited excellent kinetic stability in human serum, while Lym-1-2IT-2-BAT-67Cu, prepared from the structural isomer 2-[p-(bromoacetamido)benzyl]-1,4,8,11- tetraazacyclotetradecane-N,N&#39;,N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid, exhibited a markedly higher rate of loss of radiometal. It was observed that the radiolabeling ratio of Lym-1-2IT-6-BAT-67Cu, in mCi per mg immunoconjugate, was limited solely by the specific activity of the radiometal, which varied significantly from lot to lot. This ratio for a given lot of 67Cu can be predicted by a preliminary titration. The preparation of 67Cu labeled immunoconjugates of therapeutic quality has been improved by the determination of optimum radiolabeling conditions, and by development of a titration protocol which rapidly and accurately predicts the radiolabeling ratio in mCi per mg immunoconjugate. The surprising difference in the properties of 6-BAT and 2-BAT shows the exquisite dependence of kinetic stability on structure.

Research paper thumbnail of Are Radiometal-Labeled Antibodies Better Than Iodine-131–Labeled Antibodies: Comparative Pharmacokinetics and Dosimetry of Copper-67–, Iodine-131–, and Yttrium-90–Labeled Lym-1 Antibody in Patients with Non-Hodgkin's Lymphoma

Clinical Lymphoma Myeloma, 2000

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has... more Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu-and 131 I-labeled Lym-1 or 111 In-and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y-2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.

Research paper thumbnail of Imaging and Pharmacokinetics of 64 Cu-DOTA-HB22.7 Administered by Intravenous, Intraperitoneal, or Subcutaneous Injection to Mice Bearing Non-Hodgkin's Lymphoma Xenografts

Mol Imaging Biol, 2009

The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistrib... more The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistribution of (64)Cu-DOTA-HB22.7 when administered to xenograft-bearing mice intravenously (IV), intraperitoneally (IP), and subcutaneously (SQ). Mice bearing human non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma (NHL) xenografts were injected IV, IP, or SQ with (64)Cu-DOTA-HB22.7. Xenograft targeting was evaluated by micro positron emission tomography (microPET) and confirmed by organ biodistribution studies. Blood measurements of (64)Cu were performed to determine the pharmacokinetics and clearance of (64)Cu-DOTA-HB22.7. (64)Cu-DOTA-HB22.7 demonstrated equivalent tumor targeting within 24-48 h, regardless of the route of administration. Organ biodistribution confirmed tumor-specific targeting. Blood pharmacokinetics demonstrated that (64)Cu-DOTA-HB22.7 accessed the bloodstream after IP and SQ administration to a similar degree as IV administration, albeit at a slower rate. These findings establish (64)Cu-DOTA-HB22.7 as a potential radioimmunotherapeutic and/or NHL-specific imaging agent. These findings provide evidence that IP and SQ administration can achieve results equivalent to IV administration and may lead to more efficient, reproducible treatment plans for antibody-based therapeutics.

Research paper thumbnail of Effect of the extent of substitution on the immunoreactivity of 21T-BAT-LYM-1 immunoconjugate

J Nucl Med, 1994

... BAT-Lym-1 is prepared by conjugating the bifunctional macrocyclic chealting agent 6-[p-(bromo... more ... BAT-Lym-1 is prepared by conjugating the bifunctional macrocyclic chealting agent 6-[p-(bromoacetamido)benzyl]-TETA (BAT) to murine anti-lymphoma lgG{sub 2a} Lym-1 via 2-iminothiolane (2IT). The specific activity of Cu-67 used for radiolabeling is as low as 1 mCi/{ ...

Research paper thumbnail of Metabolite production in patients with lymphoma after radiometal-labeled antibody administration

Journal of Nuclear Medicine, Sep 1, 2001

Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies,... more Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111 In-and 90 Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,NЈ,N Љ,N ٞ-tetraacetic acid-Lym-1 ( 111 In/ 90 Y-2IT-BAD-Lym-1). Methods: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111 In-and 90 Y-2IT-BAD-Lym-1; 111 In was used as a surrogate tracer for 90 Y, which emits no ␥-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111 In in organs and tumors. Results: Metabolites and complexes were observed in the plasma of every patient who received 111 In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111 In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90 Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111 In-2IT-BAD-m170, 91% and 94% of 111 In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111 In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111 In/ 90 Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. Conclusion: Metabolites of 111 In/ 90 Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111 In/ 90 Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

Research paper thumbnail of Yttrium-90-Labeled Monoclonal Antibody for Therapy: Labeling by a New Macrocyclic Bifunctional Chelating Agent

Journal of Nuclear Medicine Official Publication Society of Nuclear Medicine, Apr 1, 1990

Research paper thumbnail of Optimized conditions for chelation of yttrium-90-DOTA immunoconjugates

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1998

Radioimmunotherapy (RIT) with 90Y-labeled immunoconjugates has shown promise in clinical trials. ... more Radioimmunotherapy (RIT) with 90Y-labeled immunoconjugates has shown promise in clinical trials. The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) binds 90Y with extraordinary stability, minimizing the toxicity of 90Y-DOTA immunoconjugates arising from loss of 90Y to bone. However, reported 90Y-DOTA immunoconjugate product yields have been typically only < or =50%. Improved yields are needed for RIT with 90Y-DOTA immunoconjugates to be practical. (S) 2-[p-(bromoacetamido)benzyl]-DOTA (BAD) was conjugated to the monoclonal antibody Lym-1 via 2-iminothiolane (2IT). The immunoconjugate product, 2IT-BAD-Lym-1, was labeled in excess yttrium in various buffers over a range of concentrations and pH. Kinetic studies were performed in selected buffers to estimate radiolabeling reaction times under prospective radiopharmacy labeling conditions. The effect of temperature on reaction kinetics was examined. Optimal radiolabeli...

Research paper thumbnail of A clinical trial of radioimmunotherapy with 67Cu-2IT-BAT-Lym-1 for non-Hodgkin's lymphoma

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1999

Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's... more Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's lymphoma (NHL), this phase I/II clinical trial of 67Cu-2IT-BAT-Lym-1 was conducted in an effort to further improve the therapeutic index of Lym-1-based radioimmunotherapy. Lym-1 is a mouse monoclonal antibody that preferentially targets malignant lymphocytes. 67Cu has beta emissions comparable to those of 131I but has gamma emissions more favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid binds 67Cu tightly to form a stable radioimmunoconjugate in vivo. All 12 patients had stage III or IV NHL that had not responded to standard therapy; 11 had intermediate- or high-grade NHL. At 4-wk intervals, patients received up to four doses of 67Cu-2IT-BAT-Lym-1, 0.93 or 1.85-2.22 GBq/m2 (25 or 50-60 mCi/m2), with the lower dose used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging ...

Research paper thumbnail of Strategies for enhancement of radioimmunotherapy

International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991

Two new strategies for increasing tumor uptake have been investigated. First the effect of interl... more Two new strategies for increasing tumor uptake have been investigated. First the effect of interleukin-2 (IL-2) on tumor uptake of 125I-Lym-1 antibody in nude mice was investigated. Secondly, the use of 67Cu-labeled Lym-1 was evaluated in patients. In nude mice implanted with Raji human lymphoma, a greater than 2-fold enhancement of tumor uptake of 125I-Lym-1 was observed after administration of PEG-interleukin-2 (PEG-IL-2). The macrocycle 1,4,8,11-tetraazacylcotetradecane-N,N',N",N"'-tetraacetic acid (TETA), synthesized specifically for copper chelation, has been conjugated to Lym-1 for 67Cu labeling of the monoclonal antibody (MoAb). There was no evidence for bone or normal marrow uptake and the residence time in the tumor was prolonged. Surprisingly, a dose of 4.4 mCi that was intended for imaging induced substantial tumor regression in a patient.

Research paper thumbnail of A smart and versatile theranostic nanomedicine platform based on nanoporphyrin

Nature Communications, 2014

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promi... more Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;all-in-one&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.

Research paper thumbnail of Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and90yttrium-DOTA-peptide-ChL6

The Prostate, 2002

Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-C... more Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-ChL6 (5.55 MBq;150 microCi) has resulted in durable responses. To make radioimmunotherapy (RIT) more effective, the radiation-enhancing drugs Taxol (paclitaxel) and Taxotere (docetaxel) were tested for synergy with 90Y-DOTA-peptide-ChL6. Nude mice bearing human prostate cancer PC3 xenografts were treated with 90Y-DOTA-peptide-ChL6 (2.78 MBq; 75 microCi) and after 24 hr, paclitaxel (300 or 600 microg), or docetaxel (300 microg). Tumor size, survival, blood counts, and pharmacokinetics were monitored to assess efficacy and toxicity. Docetaxel plus RIT had a 67% cure rate, whereas no mice were cured among the RIT alone, chemotherapy alone, or untreated controls. Paclitaxel (600 microg) plus RIT produced a 100% response rate with 20% cures. Average tumor volume was reduced to a greater degree in the combined modality radioimmunotherapy (CMRIT) groups compared to controls and the anti-tumor response was durable. Myelotoxicity in the combined modality groups (RIT plus paclitaxel or RIT plus docetaxel) were similar to groups receiving the same dose of RIT alone. In the PC3-tumor nude mouse model, addition of paclitaxel or docetaxel to 90Y-DOTA-peptide-ChL6, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.

Research paper thumbnail of Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

Proceedings of the National Academy of Sciences, 1997

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 m... more Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90 Y-labeled DOTA-peptide-ChL6 ( 90 Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N,N ؆,N ٟ-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90 Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90 Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before 90 Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90 Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90 Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90 Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90 Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90 Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.

Research paper thumbnail of Imaging and Pharmacokinetics of 64Cu-DOTA-HB22.7 Administered by Intravenous, Intraperitoneal, or Subcutaneous Injection to Mice Bearing Non-Hodgkin’s Lymphoma Xenografts

Molecular Imaging and Biology, 2009

The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistrib... more The aim of the study is to compare the tumor-specific targeting, pharmacokinetics, and biodistribution of (64)Cu-DOTA-HB22.7 when administered to xenograft-bearing mice intravenously (IV), intraperitoneally (IP), and subcutaneously (SQ). Mice bearing human non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma (NHL) xenografts were injected IV, IP, or SQ with (64)Cu-DOTA-HB22.7. Xenograft targeting was evaluated by micro positron emission tomography (microPET) and confirmed by organ biodistribution studies. Blood measurements of (64)Cu were performed to determine the pharmacokinetics and clearance of (64)Cu-DOTA-HB22.7. (64)Cu-DOTA-HB22.7 demonstrated equivalent tumor targeting within 24-48 h, regardless of the route of administration. Organ biodistribution confirmed tumor-specific targeting. Blood pharmacokinetics demonstrated that (64)Cu-DOTA-HB22.7 accessed the bloodstream after IP and SQ administration to a similar degree as IV administration, albeit at a slower rate. These findings establish (64)Cu-DOTA-HB22.7 as a potential radioimmunotherapeutic and/or NHL-specific imaging agent. These findings provide evidence that IP and SQ administration can achieve results equivalent to IV administration and may lead to more efficient, reproducible treatment plans for antibody-based therapeutics.

Research paper thumbnail of CMR 2007: 4.03: High-throughputin vivo screening of targeted molecular imaging agents using PET

Contrast Media & Molecular Imaging, 2007

Research paper thumbnail of Are Radiometal-Labeled Antibodies Better Than Iodine-131–Labeled Antibodies: Comparative Pharmacokinetics and Dosimetry of Copper-67–, Iodine-131–, and Yttrium-90–Labeled Lym-1 Antibody in Patients with Non-Hodgkin's Lymphoma

Clinical Lymphoma, 2000

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has... more Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu-and 131 I-labeled Lym-1 or 111 In-and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y-2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.

Research paper thumbnail of Cleavable Linkers to Enhance Selectivity of Antibody-Targeted Therapy of Cancer

Cancer Biotherapy & Radiopharmaceuticals, 2001

Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to r... more Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to radionuclides to deliver radiation selectively to tumors. However, radiolabeled proteins deposit radioactivity in normal organs that metabolize or conserve proteins and peptides, primarily liver and kidneys. To accelerate the clearance of radioactivity from normal tissues, linkers between the antibody or antibody fragment and the radioactive moiety have been designed for cleavage in the liver and kidneys, to liberate low molecular weight radioactive species for rapid excretion. Modest success in improving the tumor-to-liver and tumor-to-kidney radiation dose ratios have been achieved in preclinical studies. Such changes when taken to clinical studies have suggested useful impact on therapeutic work. Recent advances in the development of cleavable linkers are described.

Research paper thumbnail of Radioimmunotherapy of Acquired Immunodeficiency Syndrome (AIDS) Associated Lymphoma

Cancer Biotherapy & Radiopharmaceuticals, 1999

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunothera... more Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.

Research paper thumbnail of Combined Modality Radioimmunotherapy with Taxol and 90 Y-LYM-1 for Raji Lymphoma Xenografts

Cancer Biotherapy & Radiopharmaceuticals, 1998

Despite effective therapies for non-Hodgkin&#39;s lymphoma (NHL), the majority of patients ar... more Despite effective therapies for non-Hodgkin&#39;s lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt&#39;s lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.

Research paper thumbnail of Enhancement of 67Cu‐2IT‐BAT‐LYM‐1 therapy in mice with human burkitt's lymphoma (Raji) using interleukin‐2

Cancer, 1997

Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice ... more Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts. 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N&#39;, N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2. In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2. 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.

Research paper thumbnail of Comparative toxicity studies of yttrium-90 mx-dtpa and 2-it-bad conjugated monoclonal antibody (bre-3)

Cancer, 1994

BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Be... more BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N&#39;,N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid (BAD). Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.

Research paper thumbnail of A comparative study of copper-67 radiolabeling and kinetic stabilities of antibody-macrocycle chelate conjugates

Cancer, 1994

The development of new chelating agents and radiolabeling protocols is essential to progress in r... more The development of new chelating agents and radiolabeling protocols is essential to progress in radioimmunotherapy with antibody-chelate conjugates. Immunoconjugates of four polyazamacrocycles with N-bonded acetate groups were prepared by conjugation via 2-iminothiolane to Lym-1, a murine antilymphoma immunoglobulin G2a MoAb. To optimize 67Cu radiolabeling, complexation conditions were explored. The kinetic stabilities in vitro in human serum of four 67Cu labeled immunoconjugates were investigated. Lym-1-2IT-6-BAT-67Cu, the chelate conjugate of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N&#39;,N&#39;&#39;N&#39;&#39;&#39;-tetraacetic acid, exhibited excellent kinetic stability in human serum, while Lym-1-2IT-2-BAT-67Cu, prepared from the structural isomer 2-[p-(bromoacetamido)benzyl]-1,4,8,11- tetraazacyclotetradecane-N,N&#39;,N&#39;&#39;,N&#39;&#39;&#39;-tetraacetic acid, exhibited a markedly higher rate of loss of radiometal. It was observed that the radiolabeling ratio of Lym-1-2IT-6-BAT-67Cu, in mCi per mg immunoconjugate, was limited solely by the specific activity of the radiometal, which varied significantly from lot to lot. This ratio for a given lot of 67Cu can be predicted by a preliminary titration. The preparation of 67Cu labeled immunoconjugates of therapeutic quality has been improved by the determination of optimum radiolabeling conditions, and by development of a titration protocol which rapidly and accurately predicts the radiolabeling ratio in mCi per mg immunoconjugate. The surprising difference in the properties of 6-BAT and 2-BAT shows the exquisite dependence of kinetic stability on structure.