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 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.

• Authors: Megan Minnix, Lin Li, Paul Yazaki, Junie Chea, Erasmus Poku, David Colcher, John E Shively
• Journal: Cancer medicine (Cancer Med) Vol. 9 Issue 13 Pg. 4756-4767 (07 2020) ISSN: 2045-7634 [Electronic] United States
• PMID: 32368864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Acetates
• Antibodies, Neoplasm
• Antigens, Neoplasm
• B72.3 antibody
• Immunoconjugates
• Immunologic Factors
• Oligopeptides
• Sulfones
• tumor-associated antigen 72
• divinyl sulfone
• bromoacetate
• monomethyl auristatin E

Topics

• Acetates (chemistry)
• Animals
• Antibodies, Neoplasm (blood, metabolism, therapeutic use)
• Antigens, Neoplasm (immunology, metabolism)
• Cell Line, Tumor
• Female
• HT29 Cells
• Humans
• Immunoconjugates (therapeutic use)
• Immunologic Factors (pharmacokinetics, therapeutic use)
• Mice
• Oligopeptides (blood, chemistry, metabolism, therapeutic use)
• Ovarian Neoplasms (blood, diagnostic imaging, metabolism, therapy)
• Positron-Emission Tomography
• Random Allocation
• Sulfones (chemistry)