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Otto C Boerman - One of the best experts on this subject based on the ideXlab platform.
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optimizing lutetium 177 anti carbonic anhydrase ix radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model
Molecular Imaging, 2014Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti–carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 ( 177 Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 mg of G250 labeled with 10 MBq indium 111 ( 111 In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177 Lu-DOTA-G250, a control group received 13 MBq nonspecific 177 Lu-MOPC21, and the second control group was not treated and received 20 MBq 111 In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 mg G250. Treatment with 13 MBq 177 Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49–53 days, p 5 .015), indicating that RIT has potential in this metastatic ccRCC model.
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monitoring lutetium 177 anti caix radioimmunotherapy with in 111 anti caix spect in an intraperitoneal clear cell renal cell carcinoma xenograft model
The Journal of Nuclear Medicine, 2013Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:116 Objectives Radioimmunotherapy (RIT) with radiolabeled anti-carbonic anhydrase IX (CAIX) antibody G250 is a new approach in the treatment of clear cell renal cell carcinoma (ccRCC). Potentially the efficacy of Lu-177-anti CAIX RIT can be monitored with In-111-anti-CAIX SPECT. Here the potential of this theranostics approach was studied in mice with intraperitoneal ccRCC. Methods Mice with intraperitoneally growing SK-RC-52 tumor lesions (3 weeks after tumor cell inoculation) were treated with 13 MBq Lu-177-G250 (n=10), a control group received 13 MBq Lu-177-labeled irrelevant antibody MOPC21 (n=10) and the second control group was not treated. Tumor growth in the three groups was monitored with SPECT/CT with In-111-G250 at 3 week intervals. Primary endpoints were overall survival and toxicity. Results The optimal G250 protein dose to target ccRCC in this model was 10 μg G250. Tumor uptake 48 h p.i. was 54.9±3.5 % ID/g, with a tumor-to-blood ratio of 5.3:1. The median survival of the mice in the control groups was 53 days after inoculation, whereas treatment with Lu-177-G250 resulted median survival of >100 days. Survival was significantly longer in the group treated with Lu-177-G250 (log-rank test, p=0.002). Tumor progression over time could be monitored noninvasively with SPECT. Conclusions This is the first RIT study with radiolabeled G250 in mice with i.p. growing ccRCC. The optimal dose for in vivo targeting and monitoring of ccRCC in this model was 10 μg/mouse. RIT with Lu-177-G250 significantly improved median survival. This model is suitable to further investigate the potential of RIT of ccRCC.
Egbert Oosterwijk - One of the best experts on this subject based on the ideXlab platform.
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optimizing lutetium 177 anti carbonic anhydrase ix radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model
Molecular Imaging, 2014Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti–carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 ( 177 Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 mg of G250 labeled with 10 MBq indium 111 ( 111 In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177 Lu-DOTA-G250, a control group received 13 MBq nonspecific 177 Lu-MOPC21, and the second control group was not treated and received 20 MBq 111 In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 mg G250. Treatment with 13 MBq 177 Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49–53 days, p 5 .015), indicating that RIT has potential in this metastatic ccRCC model.
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monitoring lutetium 177 anti caix radioimmunotherapy with in 111 anti caix spect in an intraperitoneal clear cell renal cell carcinoma xenograft model
The Journal of Nuclear Medicine, 2013Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:116 Objectives Radioimmunotherapy (RIT) with radiolabeled anti-carbonic anhydrase IX (CAIX) antibody G250 is a new approach in the treatment of clear cell renal cell carcinoma (ccRCC). Potentially the efficacy of Lu-177-anti CAIX RIT can be monitored with In-111-anti-CAIX SPECT. Here the potential of this theranostics approach was studied in mice with intraperitoneal ccRCC. Methods Mice with intraperitoneally growing SK-RC-52 tumor lesions (3 weeks after tumor cell inoculation) were treated with 13 MBq Lu-177-G250 (n=10), a control group received 13 MBq Lu-177-labeled irrelevant antibody MOPC21 (n=10) and the second control group was not treated. Tumor growth in the three groups was monitored with SPECT/CT with In-111-G250 at 3 week intervals. Primary endpoints were overall survival and toxicity. Results The optimal G250 protein dose to target ccRCC in this model was 10 μg G250. Tumor uptake 48 h p.i. was 54.9±3.5 % ID/g, with a tumor-to-blood ratio of 5.3:1. The median survival of the mice in the control groups was 53 days after inoculation, whereas treatment with Lu-177-G250 resulted median survival of >100 days. Survival was significantly longer in the group treated with Lu-177-G250 (log-rank test, p=0.002). Tumor progression over time could be monitored noninvasively with SPECT. Conclusions This is the first RIT study with radiolabeled G250 in mice with i.p. growing ccRCC. The optimal dose for in vivo targeting and monitoring of ccRCC in this model was 10 μg/mouse. RIT with Lu-177-G250 significantly improved median survival. This model is suitable to further investigate the potential of RIT of ccRCC.
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a phase ii trial of chimeric monoclonal antibody g250 for advanced renal cell carcinoma patients
British Journal of Cancer, 2004Co-Authors: Ivar Bleumer, Egbert Oosterwijk, Cor H J Lamers, Alexander Knuth, Rainer Hofmann, Z Varga, Wim H J Kruit, S Melchior, C Mala, S UllrichAbstract:Chimeric monoclonal antibody G250 (WX-G250) binds to a cell surface antigen found on >90% of renal cell carcinoma (RCC). A multicentre phase II study was performed to evaluate the safety and efficacy of WX-G250 in metastatic RCC (mRCC) patients. In all, 36 patients with mRCC were included. WX-G250 was given weekly by intravenous infusion for 12 weeks. Patients with stable disease (SD) or response were eligible to receive additional treatment for 8 weeks. None of the 36 enrolled patients experienced any drug-related grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. In all, 10 patients had SD and received extended treatment. One complete response and a significant regression was observed during the follow-up of the treatment. Five patients with progressive disease at study entry were stable for more than 6 months after study entry. The median survival after treatment start was 15 months. The weekly schedule of WX-G250 was well tolerated. With a median survival of 15 months after the start of this treatment and two late clinical responses, WX-G250 seems to be able to modulate mRCC. To improve the activity of WX-G250-specific antibody-dependent cellular cytotoxicity and the clinical response rate, currently combinations of WX-G250 with cytokines are in phase II trials.
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the renal cell carcinoma associated antigen g250 encodes a human leukocyte antigen hla a2 1 restricted epitope recognized by cytotoxic t lymphocytes
Cancer Research, 1999Co-Authors: Joost L M Vissers, Egbert Oosterwijk, I J M De Vries, Marco W J Schreurs, Linda P H Engelen, Carl G Figdor, G J AdemaAbstract:Evidence has accumulated that the immune system can play a significant role in the defense against tumors in humans. Especially melanoma and renal cell carcinoma (RCC) are considered immunogenic tumors. In contrast to melanoma, hardly any RCC-associated antigens have been identified as targets for RCC-reactive T cells. Here, we report the identification of a human leukocyte antigen (HLA)-A2.1-restricted T-cell epitope within the G250 antigen. This antigen is expressed in 85% of RCCs but not by neighboring normal kidney tissue and has recently been molecularly defined and shown to be identical to MN/CA IX. Computer-aided motif prediction revealed the presence of 60 potential HLA-A2.1-binding peptides within the G250 antigen. Subsequent binding analysis showed that 13 of these peptides bound to HLA-A2.1 with high-to-intermediate affinity. Analysis of their immunogenicity in HLA-A2.1K b transgenic mice indicated that 4 of the 13 peptides gave rise to cytotoxic T lymphocytes (CTLs) capable of lysing peptide-loaded target cells. However, only the G250 peptide 254–262 induced CTLs that recognized target cells that endogenously expressed the G250 antigen. Similarly, we were also able to raise human CTLs against the G250 peptide 254–262, which lysed target cells that endogenously expressed the G250 antigen. These findings and the high prevalence of this antigen in RCC patients makes G250 a potential target for anti-RCC immunotherapy.
Constantijn H J Muselaers - One of the best experts on this subject based on the ideXlab platform.
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optimizing lutetium 177 anti carbonic anhydrase ix radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model
Molecular Imaging, 2014Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti–carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 ( 177 Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 mg of G250 labeled with 10 MBq indium 111 ( 111 In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177 Lu-DOTA-G250, a control group received 13 MBq nonspecific 177 Lu-MOPC21, and the second control group was not treated and received 20 MBq 111 In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 mg G250. Treatment with 13 MBq 177 Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49–53 days, p 5 .015), indicating that RIT has potential in this metastatic ccRCC model.
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monitoring lutetium 177 anti caix radioimmunotherapy with in 111 anti caix spect in an intraperitoneal clear cell renal cell carcinoma xenograft model
The Journal of Nuclear Medicine, 2013Co-Authors: Constantijn H J Muselaers, Egbert Oosterwijk, Desiree Bos, Wim J G Oyen, Peter F A Mulders, Otto C BoermanAbstract:116 Objectives Radioimmunotherapy (RIT) with radiolabeled anti-carbonic anhydrase IX (CAIX) antibody G250 is a new approach in the treatment of clear cell renal cell carcinoma (ccRCC). Potentially the efficacy of Lu-177-anti CAIX RIT can be monitored with In-111-anti-CAIX SPECT. Here the potential of this theranostics approach was studied in mice with intraperitoneal ccRCC. Methods Mice with intraperitoneally growing SK-RC-52 tumor lesions (3 weeks after tumor cell inoculation) were treated with 13 MBq Lu-177-G250 (n=10), a control group received 13 MBq Lu-177-labeled irrelevant antibody MOPC21 (n=10) and the second control group was not treated. Tumor growth in the three groups was monitored with SPECT/CT with In-111-G250 at 3 week intervals. Primary endpoints were overall survival and toxicity. Results The optimal G250 protein dose to target ccRCC in this model was 10 μg G250. Tumor uptake 48 h p.i. was 54.9±3.5 % ID/g, with a tumor-to-blood ratio of 5.3:1. The median survival of the mice in the control groups was 53 days after inoculation, whereas treatment with Lu-177-G250 resulted median survival of >100 days. Survival was significantly longer in the group treated with Lu-177-G250 (log-rank test, p=0.002). Tumor progression over time could be monitored noninvasively with SPECT. Conclusions This is the first RIT study with radiolabeled G250 in mice with i.p. growing ccRCC. The optimal dose for in vivo targeting and monitoring of ccRCC in this model was 10 μg/mouse. RIT with Lu-177-G250 significantly improved median survival. This model is suitable to further investigate the potential of RIT of ccRCC.
Eric Ferrandis - One of the best experts on this subject based on the ideXlab platform.
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quinazolinone based anticancer agents synthesis antiproliferative sar antitubulin activity and tubulin co crystal structure
Journal of Medicinal Chemistry, 2018Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Fabrice Jourdan, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed we...
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Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
2017Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Fabrice L. Jourdan, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template
Wolfgang Dohle - One of the best experts on this subject based on the ideXlab platform.
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tetrahydroisoquinoline sulfamates as potent microtubule disruptors synthesis antiproliferative and antitubulin activity of dichlorobenzyl based derivatives and a tubulin cocrystal structure
ACS Omega, 2019Co-Authors: Wolfgang Dohle, Gregory Menchon, Andrea E Prota, Ernest Hamel, Michel O Steinmetz, Barry V L PotterAbstract:Tetrahydroisoquinoline (THIQ) 6-O-sulfamate-based anticancer agents, inspired by the endogenous steroid 2-methoxyestradiol and its sulfamate derivatives, are further explored for antiproliferative and microtubule disruptor activity. Based on recently designed C3-methyl C7-methoxy-substituted THIQ derivatives, compounds with mono- and dichloro-substitutions on the pendant N-benzyl ring were synthesized and evaluated. Although improved antiproliferative activity was observed, for example, 4a versus 4b and 4b versus 8c, it was relatively modest. Compound 8c, a 2′,5′-dichlorobenzyl derivative was, however, identified as a promising antiproliferative agent with in vitro activities exceeding that of the parent steroid (e.g., GI50 90 nM in DU-145 cells) and was highly potent against a range of tumor cell lines (e.g., GI50 26 nM for OVCAR-3). 8c inhibited the polymerization of tubulin in vitro with an IC50 only twofold less potent than combretastatin A-4 and inhibited colchicine binding to tubulin. Tubulin polyme...
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quinazolinone based anticancer agents synthesis antiproliferative sar antitubulin activity and tubulin co crystal structure
Journal of Medicinal Chemistry, 2018Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Fabrice Jourdan, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed we...
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Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
2017Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Fabrice L. Jourdan, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template