Cancer Biology & Therapy

2008

DOI: 10.4161/cbt.7.7.6197

|View full text |Cite

|

Sign up to set email alerts

|

Pre-clinical evaluation and efficacy studies of a melanin-binding IgM antibody labeled with 188Re against experimental human metastatic melanoma in nude mice

Ekaterina Dadachova

¹

,

Ekaterina Revskaya

²

,

³

et al.

Abstract: We have developed radiolabeling and quality control procedures for melanin-binding (188)Re-6D2 mAb which made possible currently an on-going Phase I clinical trial in patients with metastatic melanoma.

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Discussion2

Methods1

Citation Types

Supporting

2

Mentioning

51

Contrasting

0

Year Published

2009

2009

2019

2019

Publication Types

Select...

Article6

Book1

Relationship

Self Cite0

Independent7

Authors

Journals

Cited by 47 publications

(53 citation statements)

References 18 publications

Supporting

2

Mentioning

51

Contrasting

0

Order By: Relevance

“…Hence, the Interestingly, from day 18 post-treatment, administration of ''cold'' 11B11 modestly inhibited the increase in tumor volume in comparison with untreated controls. The same effect was previously observed for ''cold'' 6D2 in both MNT1 and A2048-melanoma bearing mice (7,10). A possible explanation for this could be the induction of proinflammatory effects by murine IgM, which is a potent activator of the complement system (17).…”

Section: Discussionsupporting

confidence: 58%

“…A similar effect on the amount of extracellular melanin was noted in a prior study that analyzed histology after RIT (10).…”

Section: Discussionmentioning

confidence: 48%

“…Antibodies and melanin ELISA mAb 6D2 was produced by Goodwin Biotechnology and purified using a multicolumn purification system (10). Purity of the 6D2 from this process was >95% via high-performance liquid chromatographysize exclusion chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, this strategy is attractive because melanin in normal tissues is not accessible to the antibody by virtue of its intracellular location. Additional preclinical development of melanin-binding 188 Re-6D2 mAb, including pharmacokinetics, efficacy, and acute hematologic toxicity studies in a metastatic human melanoma model in mice (10), preceded recently completed phase I trial in patients with metastatic melanoma (11) that has shown targeting of 188 Re-6D2 mAb to the tumors, thus providing encouragement for further trials of RIT with melaninbinding mAbs.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Radioimmunotherapy of Experimental Human Metastatic Melanoma with Melanin-Binding Antibodies and in Combination with Dacarbazine

²

,

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and (b) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin. Experimental Design: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with 188 Re (6D2 and 11B11). We compared the efficacy of RIT with 188Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice. Results: Therapeutic efficacy of 188 Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RITrevealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RITwas more effective than either modality alone. Conclusions: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.

“…Hence, the Interestingly, from day 18 post-treatment, administration of ''cold'' 11B11 modestly inhibited the increase in tumor volume in comparison with untreated controls. The same effect was previously observed for ''cold'' 6D2 in both MNT1 and A2048-melanoma bearing mice (7,10). A possible explanation for this could be the induction of proinflammatory effects by murine IgM, which is a potent activator of the complement system (17).…”

Section: Discussionsupporting

confidence: 58%

“…A similar effect on the amount of extracellular melanin was noted in a prior study that analyzed histology after RIT (10).…”

Section: Discussionmentioning

confidence: 48%

“…Antibodies and melanin ELISA mAb 6D2 was produced by Goodwin Biotechnology and purified using a multicolumn purification system (10). Purity of the 6D2 from this process was >95% via high-performance liquid chromatographysize exclusion chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, this strategy is attractive because melanin in normal tissues is not accessible to the antibody by virtue of its intracellular location. Additional preclinical development of melanin-binding 188 Re-6D2 mAb, including pharmacokinetics, efficacy, and acute hematologic toxicity studies in a metastatic human melanoma model in mice (10), preceded recently completed phase I trial in patients with metastatic melanoma (11) that has shown targeting of 188 Re-6D2 mAb to the tumors, thus providing encouragement for further trials of RIT with melaninbinding mAbs.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Radioimmunotherapy of Experimental Human Metastatic Melanoma with Melanin-Binding Antibodies and in Combination with Dacarbazine

²

,

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and (b) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin. Experimental Design: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with 188 Re (6D2 and 11B11). We compared the efficacy of RIT with 188Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice. Results: Therapeutic efficacy of 188 Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RITrevealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RITwas more effective than either modality alone. Conclusions: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.

“…To test this hypothesis, we used data on biodistribution of 188 Re-labeled antibody to melanin in athymic melanoma xenograft-bearing mice (6,7).…”

mentioning

confidence: 99%

New Approaches for Modeling Radiopharmaceutical Pharmacokinetics Using Continuous Distributions of Rates

¹

,

²

2015

View full text Add to dashboard Cite

Radiopharmaceutical pharmacokinetics are usually approximated by sums of discrete first-order rates, using 3 or more parameters. We hypothesized that pharmacokinetic processes can be modeled even better by continuous probability distributions (CPD) of rates, using only 1-2 parameters. Methods: To test this hypothesis, we used biodistribution data for 188 Re-labeled melanin-specific antibody in blood, kidneys, liver, bone marrow, and lungs of melanoma xenograft-bearing mice. We used 3 discrete-rate models (monoexponential, monoexponential with constant, and biexponential) and 4 CPD models (stretched-exponential, modified stretched-exponential, simplified versions of stretched-exponential, and modified stretched-exponential). They were compared by sample-size-corrected Akaike information criterion. Total time integrals of radioactivity were computed for each model and averaged across all models. Results: The ratio of weights of evidence for CPD versus discrete-rate models was high for blood (12.2) and lungs (2.7), almost unity (0.99) for bone marrow, and slightly lower for kidneys (0.81) and liver (0.73). In all organs or tissues except lungs, model-averaged time integrals were 12.7%-54.0% higher than biexponential model estimates. Conclusion: Simple CPD models often outperform more complex discrete-rate models on pharmacokinetic data. Radioactivity time integrals are more robustly estimated by multimodel inference than using any single model. Phar macokinetics of radiopharmaceuticals (e.g., radioimmunotherapy agents) are assumed to follow first-order kinetics and are, therefore, approximated by the sum of discrete rates (1-3). However, the existence of first-order kinetics does not necessarily imply the existence of only a few discrete rates. Instead, complex decay patterns may result from a continuous probability distribution (CPD) of first-order rates (4,5). "Depending on the level of precision, a decay can be fitted with a sum of 2 or 3 exponentials with satisfactory x 2 values and weighted residuals despite the existence of an underlying distribution" (5).We hypothesized that pharmacokinetic processes can be modeled even better by CPDs of rates using only 1-2 parameters than by sums of discrete rates using 3 or more parameters. To test this hypothesis, we used data on biodistribution of 188 Re-labeled antibody to melanin in athymic melanoma xenograft-bearing mice (6,7).We used 7 models to fit the data. Three of them assumed discrete pharmacokinetic rates, and 4 assumed CPDs. We compared the performances of these models, and their predictions for the total time integral of radioactivity (which is needed for radiopharmaceutical dosimetry), using information theoretic methods. Our results provide new insight into modeling of radiopharmaceutical pharmacokinetics. MATERIALS AND METHODS DatasetsThe biodistribution studies analyzed here were published (6) and are described in the supplemental data (supplemental materials are available at http://jnm.snmjournals.org). Briefly, athymic mice (maintained in accordance wi...

Evaluation of novel highly specific antibodies to cancer testis antigen Centrin‐1 for radioimmunoimaging and radioimmunotherapy of pancreatic cancer

¹

,

²

,

³

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

Background Pancreatic ductal adenocarcinoma (PDAC) accounts for >90% of pancreatic malignancies, and has median survival of <6 months. There is an urgent need for diagnostic and therapeutic options for PDAC. Centrin1 (CETN1) is a novel member of Cancer/Testis Antigens, with a 25‐fold increase of CETN1 gene expression in PDX from PDAC patients. The absence of selective anti‐CETN1 antibodies is hampering CETN1 use for diagnosis and therapy. Here we report the generation of highly specific for CETN1 antibodies and their evaluation for radioimmunoimaging and radioimmunotherapy (RIT) of experimental PDAC. Methods The antibodies to CETN1 were generated via mice immunization with immunogenic peptide distinguishing CETN1 from CETN2. Patient tumor microarrays were used to evaluate the binding of the immune serum to PDAC versus normal pancreas. The antibodies were tested for their preferential binding to CETN1 over CETN2 by ELISA. Mice bearing PDAC MiaPaCa2 xenografts were imaged with microSPECT/CT and treated with 213 Bi‐ and 177 Lu‐labeled antibodies to CETN1. Results Immune serum bind to 50% PDAC cases on patient tumor microarrays with no specific binding to normal pancreas. Antibodies demonstrated preferential binding to CETN1 versus CETN2. Antibody 69‐11 localized to PDAC xenografts in mice in vivo and ex vivo. RIT of PDAC xenografts with 213 Bi‐labeled antibodies was effective, safe, and CETN1‐specific. Conclusions The results demonstrate the ability of these novel antibodies to detect CETN1 both in vitro and in vivo; as well, the RIT treatment of experimental PDAC when radiolabeled with 213 Bi is highly efficient and safe. Further evaluation of these novel reagents for diagnosis and treatment of PDAC is warranted.

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Product

Browser Extension Assistant by scite Citation Statement Search Reference Check Visualizations Dashboards Explore Journals Explore Organizations Explore Funders Embedding Badge Embedding Citation Search Pricing

Resources

Blog Help & FAQ Accessibility Statement API Terms For Universities & Governments For Researchers For Publishers For Corporate, Pharma & Enterprise Author Marketing Become an Affiliate Get an organization trial or quote scite Data & Services

About

News & Press Careers Read our Paper Coverage

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Copyright © 2024 scite LLC. All rights reserved.

Made with 💙 for researchers

Part of the Research Solutions Family.