Colorectal cancer is the third most common cause of cancer death. Surgery is the most common treatment method for this disease. However, due to the lack of accurate assessment of surgical margins and abnormal lymph nodes involved in the disease, it is very challenging for the surgeon to detect and remove all tumor tissues in patients. Thus, more than 40% of colorectal cancer patients will ultimately have fatal outcome because of cancer recurrence in other organs after surgery. Clearly, new tumor detection methods in surgery need to be sought to achieve surgical success.
RadioImmunoGuided Surgery (RIGS) was utilized to improve tumor detection and surgical precision. RIGS combines radioactive-labeled monoclonal antibodies (anti-TAG-72 antibodies in this thesis study) and a hand-held gamma probe, to identify tumor tissues for resection in colorectal cancer patients. In order to predict the optimal time for surgery after antibody administration, the population pharmacokinetics of 125I-HuCC49ΔCH2 and 125I-CC49 were characterized in 55 patients with colorectal cancers (Chapter 2). A two-compartment linear model was used to fit the data. It was found that the clearance of humanized HuCC49ΔCH2 antibody almost doubled compared to murine CC49 antibody due to the truncated size and deletion of CH2 domain. Body weight (BW) was the only identified covariate in the selected population to explain the inter-patient variability of PK parameters. Visula Predictive Check (VPC) demonstrated the wide interval of surgery time for the patients; necessitating the individualization of surgery time.
Different clinical trial designs were further evaluated by simulation in combination with Bayesian estimation method to predict the optimal time for surgery (Chapter 3). Clinical trial designs with at least three measurements of antibody disposition were found to be better than an empirical direct observation method for the optimal surgery time prediction. This will revolutionize the future clinical trial designs in which daily sampling is not required to predict the surgery time.
However, when surgery is impossible for patients with advanced tumors, the tumor-localized antibody is retained in the tumors without therapeutic benefit. Therefore, we intend to take advantage of the tumor-localized antibody to deliver a drug activation enzyme to site-specifically activate prodrug in tumors as in antibody-directed enzyme prodrug therapy (ADEPT). In Chapter 4, HuCC49ΔCH2 and β-galactosidase were chemically conjugated and tested for binding specificity and enzymatic activity in vitro for ADEPT. It was validated that the HuCC49ΔCH2-β-galactosidase conjugates preserved enzymatic activity for prodrug activation with specific binding affinity.
In vivo non-invasive fluorescence imaging was utilized for visualizing the ADEPT process and for tumor detection in Chapter 5. The conjugate of antibody HuCC49ΔCH2 and β-galactosidase was tested in LS174T colorectal cancer cell xenograft model. The biodistribution of HuCC49ΔCH2-β-galactosidase conjugates and prodrug activation were further explored in tumor-bearing nude mice in Chapter 6. These in vivo results demonstrated that HuCC49ΔCH2-β-galactosidase could specifically bind to tumor antigen TAG-72 with well-preserved enzymatic activity, while the undesired binding to normal tissues (background noise) was minimal.
A physiologically based pharmacokinetic model (PBPK) approach was applied to understand the complicated ADEPT and optimal therapy regimen was suggested in Chapter 7. Based on the proposed optimal ADEPT system, the dose of conjugate and time interval between conjugate and prodrug administration were suggested to be 1/10 of Bmax and 5 days, respectively. While the optimal dose of prodrug was determined by the active drug’s efficacy and the prodrug’s maximum tolerable toxicity.
Altogether, the objective of the current thesis is to integrate tumor detection in surgery and targeted drug therapy into one system with the same tumor targeting antibody, HuCC49ΔCH2. To our best knowledge, this is the first time to apply fluorescent imaging to visualize the antibody-directed enzyme prodrug therapy (ADEPT) process. In addition, PBPK approach is used for the first time to predict ADEPT. Further in vivo ADEPT studies are necessary to confirm the current studies.
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Antibody, Cancers, Clinical pharmacokinetics, Colorectal, Detection, Drug, Humanized, Pharmacodynamics and antibody-directed enzyme prodrug therapy, Targeting, Therapy, Tumor|
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