Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer
Abstract Introduction Ovarian cancer has only a 17% 5‐year survival rate in patients diagnosed with late stage disease. Tumor‐associated glycoprotein‐72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody‐targeted therapy, as it is not expressed in norma...
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| Format: | Article |
| Language: | English |
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Wiley
2020-07-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.3078 |
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| author | Megan Minnix Lin Li Paul Yazaki Junie Chea Erasmus Poku David Colcher John E. Shively |
| author_facet | Megan Minnix Lin Li Paul Yazaki Junie Chea Erasmus Poku David Colcher John E. Shively |
| author_sort | Megan Minnix |
| collection | DOAJ |
| description | Abstract Introduction Ovarian cancer has only a 17% 5‐year survival rate in patients diagnosed with late stage disease. Tumor‐associated glycoprotein‐72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody‐targeted therapy, as it is not expressed in normal human adult tissues, except in the secretory endometrium. Methods Using the clinically relevant anti‐TAG72 murine monoclonal antibody CC49, we evaluated antibody drug conjugates (ADCs) incorporating the highly potent, synthetic antimitotic agent monomethylauristatin E (MMAE). MMAE was conjugated to CC49 via reduced disulfides in the hinge region, using three different types of linker chemistry, vinylsulfone (VS‐MMAE), bromoacetamido (Br‐MMAE), and maleimido (mal‐MMAE). Results The drug antibody ratios (DARs) of the three ADCs were 2.3 for VS‐MMAE, 10 for Br‐MMAE, and 9.5 for mal‐MMAE. All three ADCs exhibited excellent tumor to blood ratios on PET imaging, but the absolute uptake of CC49‐mal‐MMAE (3.3%ID/g) was low compared to CC49‐Br‐MMAE (6.43%ID/g), at 142 hours. Blood clearance at 43 hours was 38% for intact CC49, about 24% for both CC49‐VS‐MMAE and CC49‐Br‐MMAE, and 7% for CC49‐mal‐MMAE. CC49‐VS‐MMAE was not further studied due to its low DAR, while CC49‐mal‐MMAE was ineffective in the OVCAR3 xenograft likely due to its rapid blood clearance. In contrast, CC49‐Br‐MMAE treated mice exhibited an average of a 15.6 day tumor growth delay and a 40% increase in survival vs controls with four doses of 7.5 or 15 mg/kg of CC49‐Br‐MMAE. Conclusion We conclude that CC49‐Br‐MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model. |
| format | Article |
| id | doaj-art-39c08780ebd94cffa6cfb8035f48bfb8 |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2020-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-39c08780ebd94cffa6cfb8035f48bfb82024-12-20T13:05:46ZengWileyCancer Medicine2045-76342020-07-019134756476710.1002/cam4.3078Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancerMegan Minnix0Lin Li1Paul Yazaki2Junie Chea3Erasmus Poku4David Colcher5John E. Shively6Department of Molecular Imaging and Therapy Beckman Research Institute City of Hope Duarte CA USADepartment of Molecular Imaging and Therapy Beckman Research Institute City of Hope Duarte CA USADepartment of Molecular Imaging and Therapy Beckman Research Institute City of Hope Duarte CA USARadiopharmacy City of Hope Medical Center Duarte CA USARadiopharmacy City of Hope Medical Center Duarte CA USADepartment of Molecular Imaging and Therapy Beckman Research Institute City of Hope Duarte CA USADepartment of Molecular Imaging and Therapy Beckman Research Institute City of Hope Duarte CA USAAbstract Introduction Ovarian cancer has only a 17% 5‐year survival rate in patients diagnosed with late stage disease. Tumor‐associated glycoprotein‐72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody‐targeted therapy, as it is not expressed in normal human adult tissues, except in the secretory endometrium. Methods Using the clinically relevant anti‐TAG72 murine monoclonal antibody CC49, we evaluated antibody drug conjugates (ADCs) incorporating the highly potent, synthetic antimitotic agent monomethylauristatin E (MMAE). MMAE was conjugated to CC49 via reduced disulfides in the hinge region, using three different types of linker chemistry, vinylsulfone (VS‐MMAE), bromoacetamido (Br‐MMAE), and maleimido (mal‐MMAE). Results The drug antibody ratios (DARs) of the three ADCs were 2.3 for VS‐MMAE, 10 for Br‐MMAE, and 9.5 for mal‐MMAE. All three ADCs exhibited excellent tumor to blood ratios on PET imaging, but the absolute uptake of CC49‐mal‐MMAE (3.3%ID/g) was low compared to CC49‐Br‐MMAE (6.43%ID/g), at 142 hours. Blood clearance at 43 hours was 38% for intact CC49, about 24% for both CC49‐VS‐MMAE and CC49‐Br‐MMAE, and 7% for CC49‐mal‐MMAE. CC49‐VS‐MMAE was not further studied due to its low DAR, while CC49‐mal‐MMAE was ineffective in the OVCAR3 xenograft likely due to its rapid blood clearance. In contrast, CC49‐Br‐MMAE treated mice exhibited an average of a 15.6 day tumor growth delay and a 40% increase in survival vs controls with four doses of 7.5 or 15 mg/kg of CC49‐Br‐MMAE. Conclusion We conclude that CC49‐Br‐MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model.https://doi.org/10.1002/cam4.3078antibody drug conjugateovarian cancerTAG72 |
| spellingShingle | Megan Minnix Lin Li Paul Yazaki Junie Chea Erasmus Poku David Colcher John E. Shively Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer Cancer Medicine antibody drug conjugate ovarian cancer TAG72 |
| title | Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer |
| title_full | Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer |
| title_fullStr | Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer |
| title_full_unstemmed | Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer |
| title_short | Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer |
| title_sort | improved targeting of an anti tag 72 antibody drug conjugate for the treatment of ovarian cancer |
| topic | antibody drug conjugate ovarian cancer TAG72 |
| url | https://doi.org/10.1002/cam4.3078 |
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