Abstract
IntroductionOvarian 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.MethodsUsing 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).ResultsThe 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.ConclusionWe conclude that CC49‐Br‐MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model.
Highlights
Ovarian cancer has only a 17% 5-year survival rate in patients diagnosed with late stage disease
More than 70% of patients will relapse after first-line treatment of surgery and chemotherapy[2] with less than a 20% survival rate in patients diagnosed with the later stage diseases
Overexpression of Tumor-associated glycoprotein-72 (TAG72) occurs in 88% of all stages of ovarian cancer with a good correlation between expression and patient prognosis, while normal TAG72 expression is limited to endometrial tissues during the secretory phase.[3,4,5,6,7]
Summary
Ovarian cancer is the fifth most common cause of death in women due to cancer, with minimal improvement in firstline therapies.[1]. Overexpression of TAG72 occurs in 88% of all stages of ovarian cancer with a good correlation between expression and patient prognosis, while normal TAG72 expression is limited to endometrial tissues during the secretory phase.[3,4,5,6,7] Importantly, radiolabeled B72.3, a first generation anti-TAG72 specific monoclonal antibody was approved for imaging ovarian tumors as the product Oncoscint.[8] CC49 a second generation, TAG72 specific monoclonal antibody, recognizes an epitope comprising both carbohydrates and protein,[4] but has no antitumor activity of its own, unlike some anti-mucin antibodies that target purely carbohydrate epitopes.[9] To overcome this limitation, beta-emitting radionuclide-labeled CC49 agents have been used in several radioimmunotherapy (RIT) trials, but results were disappointing due to lack of significant clinical responses and/or dose limiting bone marrow toxicity.[10,11,12] In this study, we investigated alternative cytotoxic payloads attached to CC49 in order to improve upon the in vivo efficacy and to maintain high tumor targeting. We found that the linker with the most stable chemical attachment of the drug to the antibody exhibited the best in vitro and in vivo cytotoxicity and antitumor effects
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