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10.1245/ASO.2004.05.010
Annals of Surgical Oncology 11:197-202 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Pilot Study Using a Humanized CC49 Monoclonal Antibody (HuCC49{Delta}CH2) to Localize Recurrent Colorectal Carcinoma

Doreen M. Agnese, MD, Shahab F. Abdessalam, MD, William E. Burak, Jr., MD, Mark W. Arnold, MD, Denise Soble, RN, George H. Hinkle, RPh, Donn Young, PhD, M.B. Khazaeli, PhD and Edward W. Martin, Jr., MD

From the Divisions of Surgical Oncology (DMA, SFA, WEB, DS, EWM) and General Surgery, Department of Surgery (MWA), Department of Pharmacy (GHH), and Department of Biostatistics (DY), The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio; and Department of Radiation Oncology (MBK), University of Alabama at Birmingham, Birmingham, Alabama.

Correspondence: Address correspondence and reprint requests to: Edward W. Martin, Jr., MD, Doan N911, 410 West 10th Avenue, Columbus, OH 43210; Fax: 614-293-3465; E-mail: martin-4{at}medctr.osu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: CC49 is a monoclonal antibody directed against a pancarcinoma antigen (TAG-72) expressed by colorectal cancers. The use of murine CC49 in radioimmunoguided surgery (RIGS) was problematic because of the human anti-mouse antibodies (HAMA) generated. This study was designed to assess the clearance, safety, and effectiveness of localization of a complimentarity determining region (CDR)-grafted humanized domain-deleted antitumor CC49 antibody (HuCC49{Delta}CH2).

Methods: After thyroid blockade, 1 mg of HuCC49{Delta}CH2 radiolabeled with 2 mCi of iodine-125 was administered. All patients subsequently underwent traditional exploration followed by a survey with the gamma-detecting probe. In five patients, exploration was performed 10 to 24 days after injection, when precordial counts were sufficiently low (<30 counts per 2 seconds [cp2s]). Traditionally suggestive and probe-positive tissue was biopsied or excised and examined for the presence of carcinoma, when considered appropriate by the operating surgeon. Serum was assessed for HAMA.

Results: Seventeen sites were identified as suggestive of carcinoma on traditional exploration and 21 by RIGS. Of these, pathologic correlation was obtained in 15. The sensitivity of RIGS was 92%, and the positive predictive value was 100%. None of the patients expressed significant HAMA.

Conclusions: This initial study indicates that the HuCC49{Delta}CH2 monoclonal antibody, when used with RIGS, is safe and sensitive in detecting recurrent intra-abdominal colon cancer.

Key Words: RIGS • Colorectal carcinoma • Recurrent • Monoclonal antibody


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Over the past 15 years, many antitumor monoclonal antibodies (mAbs) have been used in vivo for the clinical diagnosis and treatment of cancer.1 The results, although initially promising, have not yet fulfilled expectations. Successful tumor imaging has been reported in some studies,2 but false-negative and false-positive results have been noted in many others.3 The most widely used mAbs are of murine origin. The use of such antibodies can lead to a human response to the murine component, which can further limit their clinical usefulness.4,5 Even chimeric, humanized, or human mAbs6–8 have limited effectiveness because of their large size. For an ideal diagnostic agent, fast, accurate, and clear visualization of the region of interest is required.

TAG-72 is an antigen expressed in several epithelial-derived cancers, including most colonic adenocarcinomas,7,8 invasive ductal carcinomas of the breast,9,10 non–small cell lung carcinomas,11,12 common epithelial ovarian carcinomas,13 and most pancreatic, gastric, and esophageal cancers evaluated.14 The TAG-72 antigen has been used as an immunogen to generate mAbs. Because the source of purified TAG-72 was a human colon cancer xenograft, these mAbs have been given a colon cancer designation. Twenty-eight colon cancer mAbs, including CC49, have been generated. Initial studies with murine CC49 showed the antibody to be effective in localizing tumor.15–17 In a phase I study performed at our institution to determine the optimal dose of both antibody and isotope, significant human anti-mouse antibody (HAMA) formation was noted in 63% of the patients (unpublished data). This study was designed to assess the clearance, safety, and effectiveness of localization of a complimentarity determining region (CDR)-grafted humanized domain-deleted antitumor CC49 antibody (HuCC49{Delta}CH2).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Enrollment
Patients with suspected recurrent colorectal cancer who were acceptable candidates for surgical exploration were enrolled in this institutional review board–approved phase I study. All of the subjects were adults (age >18 years) with a history of histologically confirmed colorectal carcinoma with clinically evident (computed tomography or positron emission tomography determined) metastatic disease suitable for either resection or placement of a hepatic arterial infusion pump. Adequate organ function (creatinine <2.0 mg/dL; bilirubin <2.0 mg/dL; AST/ALT <4 times the institutional upper limit of normal; WBC >3500/mm3 or absolute neutrophil count >1500/mm3; platelets >125,000/mm3; and hemoglobin >10 g/dL) and performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were required. Previous chemotherapy was permitted only if three or more weeks had passed since completion of therapy.

Exclusion criteria included pregnancy; clinically significant cardiac disease; significant pulmonary disease that would contraindicate or increase the risk of operative complications; serious infection requiring treatment with antibiotics; corticosteroid use; active CNS tumor involvement; concurrent therapy with nonstudy chemotherapy, radiotherapy, or immunotherapy; other malignancies in the 5 years before enrollment, excluding basal cell carcinoma of the skin; prior exposure to murine antibody; and iodine allergy. All subjects signed written consent approved by the Human Subjects Review Board at the Ohio State University.

Radiolabeled Antibody
CH2 domain-deleted CC49 mAb was obtained from Neoprobe (Dublin, OH) as a sterile, nonpyrogenic form suitable for clinical use. Injection consisted of 1 mg of HuCC49{Delta}CH2 mAb labeled with 2.0 mCi of iodine-125 (125I). HuCC49 {Delta}CH2 was labeled with 125I by using the 1,3,4,6-tetrachloro-3{alpha},6{alpha}-diphenylglycouril (IODO-GEN; Pierce Chemical, Rockford, IL) method. Unbound 125I was removed from the mixture by size exclusion chromatography. Quality-assessment tests were performed before administration to patients. Saturated solution of potassium iodide (10 drops by mouth daily) was started 2 days before injection and continued for 2 weeks to minimize active uptake by the thyroid gland. Operations were performed at varying intervals from 3 to 24 days after injection; the fist cohort of three patients had surgery performed at an interval of 3 days. In five patients, exploration was after the precordial counts measured by the gamma-detecting probe had decreased to <30 counts per 2 seconds, indicating optimal clearance from the blood background.

Operative Procedure
The surgical procedures were performed through a midline laparotomy incision. On entering the peritoneal cavity, thorough adhesiolysis was performed. The traditional exploration was then performed by careful visual and manual inspection of the entire gastrointestinal tract, retroperitoneum, and pelvis. Intraoperative ultrasound of the liver was performed. Traditionally suspicious sites, defined as areas that, in the opinion of the operating surgeon, contained recurrent malignant tissue, were recorded by the protocol nurse.

Immediately after the traditional exploration, a radioimmunoguided surgery (RIGS) exploration was performed with the handheld gamma-detecting probe. A systematic survey (2-second counts in triplicate) was conducted of the entire gastrointestinal tract, retroperitoneum, and pelvis. In addition, 2-second counts were performed in triplicate for each site considered suspicious by traditional exploration and for the normal-appearing adjacent tissue. Tumor:normal tissue ratios of >3:1 were considered RIGS positive. These finding were recorded by the protocol nurse.

When considered appropriate by the operating surgeon, traditionally suspicious or probe-positive tissue was either biopsied or excised and examined for the presence of carcinoma. This tissue was evaluated by the surgical pathologist, both grossly and microscopically, by using standard hematoxylin and eosin staining techniques. No tissue was resected or biopsied until both the traditional and RIGS explorations were complete. Specially designed data sheets were used to record all intraoperative data.

After operation, all patients had routine postoperative management. Any complications related to the administration of the radiolabeled antibody and adverse events were recorded.

Measurement of HAMA
Human antibody to murine mAb was assayed as previously described.18 Briefly, 100 µL of patient serum was incubated with a mAb-coated bead (Precision Plastic Balls, Chicago, IL) for 1 hour at room temperature with shaking. After incubation, the beads were washed with phosphate-buffered saline, pH 7.2, and incubated with 200 ng of 125I-labeled mAb (approximately 200,000 counts per minute) for 1 hour at room temperature. The beads were again washed with phosphate-buffered saline, and bead-associated radioactivity was determined on a Micromedic (Horsham, PA) automatic gamma counter. The mean counts per minute bound per 100 µL of serum was converted to nanograms of 125I mAb, and the results were expressed as nanograms of mAb bound per milliliter of patient serum. Values were obtained at baseline and at 4 to 6 weeks and 12 weeks after administration of the HuCC49{Delta}CH2 mAb. Values >2 times the pretreatment level and 3 SD above the mean of healthy donors (>10 ng/mL) were considered positive.19

Statistics
To evaluate the effectiveness of traditional surgical exploration and radiolabeled CH2 domain-deleted CC49 mAb in localizing tumor, the data were analyzed, and a sensitivity and positive predictive value were calculated for each modality.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty patients with recurrent colorectal cancer consented to this protocol. Five of these patients underwent exploration when the precordial counts were sufficiently low (<30 cp2s), when distinction of truly positive tissue from background counts was possible. These patients comprised the study group. There were four men and one woman in this group, with a mean age of 59 years (range, 55–66 years). The primary tumor site was rectal in two patients, sigmoid in two patients, and appendiceal in one.

Seventeen sites were identified as suggestive of carcinoma on traditional exploration. These are shown in Fig. 1 and Table 1. Of these 17, 10 were examined by using conventional histological methods. Nine of these actually contained tumor. No tumor was identified by pathologic examination of one site believed to be suggestive of disease (an area in the retroperitoneum believed to be consistent with a lymph node involved with metastatic disease).



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  		FIG. 1. Location of 17 sites considered suggestive of disease by traditional surgical exploration (n = 5 patients). H&E, hematoxylin and eosin.

 

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  		TABLE 1. Sites of RIGS-positive tissue
 
Twenty-one sites suggestive of disease were identified by using the RIGS system. These are shown in Fig. 2 and Table 1. Of these 21 areas, 15 were sampled. All 14 sites assessed pathologically contained tumor. Six sites not identified by traditional exploration were identified by RIGS. Five of these were sampled pathologically, and all contained tumor. Only one site discovered by traditional exploration and found to contain tumor on pathologic assessment was RIGS negative.



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  		FIG. 2. Location of 21 radioimmunoguided surgery–positive sites (n = 5 patients). H&E, hematoxylin and eosin.

 
The sensitivity of traditional exploration for identifying recurrent adenocarcinoma in this cohort of patients was 64%. The positive predictive value of traditional exploration was 90%. In contrast, RIGS exploration had a 92% sensitivity and a 100% positive predictive value for identifying intra-abdominal metastases in this group of patients.

None of the patients expressed significant HAMA after exposure to the humanized antibody. Results of the HAMA assay are listed in Table 2.


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  		TABLE 2. Results of human anti-mouse antibody (HAMA) assay
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Relatively few therapeutic options offer a prolongation in survival for patients with recurrent or metastatic colorectal cancer. Chemotherapy can provide response rates ranging from 15% to 35%, but there is a minimal effect on overall survival.20–23 The addition of newer strategies, such as a mAb to vascular endothelial growth factor, may improve response rates and result in a modest improvement in overall survival23; however, surgery remains the optimal treatment modality, offering 5-year survival rates of up to 30% in well-selected patients.24

Traditionally, physicians have relied on radiographical studies to determine which patients might benefit from surgical intervention. These studies, although helpful in determining extra-abdominal disease that might preclude successful surgical resection, are limited in their ability to accurately predict the extent of intra-abdominal disease. Although abdominal computed tomography is frequently used as a staging tool, its sensitivity is only approximately 50% in detecting all sites of abdominal and retroperitoneal tumor.25

Once in the operating room, the surgeon generally relies on clinical judgment to select patients best suited for resection. This may involve the use of frozen sections of areas suggestive of disease, which are difficult to differentiate from fibrosis, especially in the setting of prior radiotherapy. Frozen-section analysis of these suspicious tissues often prolongs the operative procedure. Ultrasonography, although useful in assessing the extent of hepatic involvement, is of limited use in localizing extrahepatic disease. Radioimmunolocalization is being investigated as a useful technique to more accurately identify intra-abdominal disease.26

Because of the difficulties described previously, RIGS was developed as an intraoperative tool. RIGS allows the surgeon to detect occult tumor, guides the resection to allow better margins, and helps differentiate fibrosis from carcinoma. The safety of this technique has been previously established.27 Its effectiveness has improved over time because of the development of improved mAbs. The use of CC49 has been associated with good tumor localization; however, the generation of HAMA has been problematic. As such, a minimally immunogenic variant of humanized anticarcinoma mAb CC49 has been developed.28,29

On one occasion, RIGS was unsuccessful in localizing disease believed to be suspicious on traditional exploration. Although we do not have an explanation for this occurrence, it is possible that the background counts were not low enough to allow the differentiation of a truly positive site from tissue from which the antibody had not yet cleared.

This study demonstrated success in the initial application of this antibody to RIGS. RIGS surgery with HuCC49{Delta}CH2 mAb was associated with a 92% sensitivity in detecting disease at surgical exploration. In addition, a 100% positive predictive value was demonstrated. Although the number of patients is small,5 the initial results are encouraging. More importantly, no significant HAMA was generated in any of the patients enrolled. Further clinical trials are needed to assess the use of this antibody in a larger population of patients with metastatic and recurrent colorectal carcinomas. In addition, further study is needed to determine the role of RIGS surgery with HuCC49{Delta}CH2 mAb in patients with primary colorectal carcinoma.


   FOOTNOTES
 
This pilot study investigated the clearance, safety and effectiveness of a humanized CC49 monoclonal antibody. Radioimmunoguided surgery (RIGS) using this antibody was well tolerated and sensitive in detecting recurrent intraabdominal colon cancer without generation of significant human anti-HuCC49{Delta}CH2 antibody.

Received for publication May 12, 2003. Accepted for publication September 22, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Epenettos AA, Kosmas C. Monoclonal antibodies for imaging and therapy. Br J Cancer 1989; 59: 152–5.[Medline]
  2. Halpern SE, Abdel-Nabi H, Murray L. Radioimmunoimaging. Quo vadis? Toward the imaging of tumor. J Nucl Med 1990; 31: 1436–43.[Free Full Text]
  3. Epenetos AA, Snook D, Durbin H, Johnson PM, Taylor-Papadimitriou J. Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res 1986; 46: 3183–91.[Abstract/Free Full Text]
  4. Courtenay-Luck NS, Epenetos AA, Moore R, et al. Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms. Cancer Res 1986; 46: 6489–94.[Medline]
  5. Schroff RW, Foon KA, Beatty SM, Oldham RK, Morgan AC. Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 1995; 45: 879–85.
  6. Boulianne GL, Hozumi N, Shulman M. Production of functional chimaeric mouse/human antibody. Nature 1984; 312: 643–6.[CrossRef][Medline]
  7. Hird V, Verheyen M, Badley RA, et al. Tumour localization with a radioactively labeled reshaped human monoclonal antibody. Br J Cancer 1991; 64: 911–4.[Medline]
  8. Boven E, Haisma JH, Bril H, et al. Tumour localization with 131-I labelled human IgM monoclonal antibody 16.88 in advanced colorectal cancer patients. Eur J Cancer 1991; 27: 1430–6.[Medline]
  9. Buchsbaum DJ, Hanna DE, Randall BC. Radiolabelling of monoclonal antibody against carcinoembryonic antigen with 88Y and biodistribution studies. Int J Nucl Med Biol 1985; 12: 79–82.[CrossRef][Medline]
  10. Martin EW Jr, Thurston MO. The use of monoclonal antibodies (MAbs) and the development of an intraoperative hand-held probe for cancer detection. Cancer Invest 1996; 14: 560–71.[Medline]
  11. Kalofonos HP, Sivolapenko GB, Courtenay-Luck NS, et al. Antibody guided targeting of non-small cell lung cancer using 111In-labeled HMFG1 F(ab')2 fragments. Cancer Res 1988; 48: 1977–84.[Abstract/Free Full Text]
  12. Huston JS, Levinson D, Mudgett-Hunter M, et al. Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci U S A 1988; 85: 5879–83.[Abstract/Free Full Text]
  13. Swallow DM, Gendler S, Griffiths B, et al. The human tumour-associated epithelial mucins are codes by an expressed hypervariable gene locus PUM. Nature 1987; 328: 82–4.[CrossRef][Medline]
  14. Sivolapenko GB, Douli V, Epenetos AA, et al. Breast cancer imaging with radiolabeled peptide from complementarity-determining region of antitumour antibody. Lancet 1995; 346: 1662–6.[CrossRef][Medline]
  15. Bakalakos EA, Young DC, Martin EW Jr. Radioimmunoguided surgery for the patients with liver metastases secondary to colorectal carcinoma. Ann Surg Oncol 1998; 5: 590–4.[Abstract]
  16. Schneebaum S, Troitsa A, Haddad R, et al. Immunoguided lymph node dissection in colorectal cancer: a new challenge? World J Surg 2001; 25: 1495–8.[Medline]
  17. Arnold MW, Hitchcock CL, Young DC, Burak WE, Bertsch DJ, Martin EW Jr. Intra-abdominal patterns of disease dissemination in colorectal cancer identified using radioimmunoguided surgery. Dis Colon Rectum 1996; 39: 509–13.[CrossRef][Medline]
  18. Khazaeli MB. Quantitation of mouse monoclonal antibody and human anti-mouse antibody response in serum of patients. Hybridoma 1989; 8: 231–9.[Medline]
  19. Forero A, Meredith RF, Khazaeli MB, et al. A novel monoclonal antibody design for radioimmunotherapy. Cancer Biother Radiopharm 2003; 18: 751–9.[CrossRef][Medline]
  20. Hine KR, Dykes PW. Prospective randomized trial of early cytotoxic therapy for recurrent colorectal carcinoma detected by serum CEA. Gut 1984; 25: 682–8.[Abstract/Free Full Text]
  21. Ahn JH, Kim TW, Lee JH, et al. Oral doxifluridine plus leucovorin in metastatic colorectal cancer: randomized phase II trial with intravenous 5-fluorouracil plus leucovorin. Am J Clin Oncol 2003; 26: 98–102.[CrossRef][Medline]
  22. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 2003; 21: 807–14.[Abstract/Free Full Text]
  23. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21: 60–5.[Abstract/Free Full Text]
  24. Drebin JA, Niederhuber JE. Cancer of the lower gastrointestinal tract. In: Niederhauber JE, ed. Current Therapy in Oncology. St. Louis: Mosby-Year Book, Inc., 1992: 426–31.
  25. Cohen AM, Martin EW Jr, Lavery I, et al. Radioimmunoguided surgery using iodine 125 B72.3 in patients with colorectal cancer. Arch Surg 1991; 126: 349–52.[Abstract]
  26. Goel A, Baranowska-Kortylewicz J, Hinrichs SH, et al. 99mTc-labeled divalent and tetravalent CC49 single-chain Fv’s: novel imaging agents for rapid in vivo localization of human colon carcinoma. J Nucl Med 2001; 42: 1519–27.[Abstract/Free Full Text]
  27. Martin DT, Hinkle GH, Tuttle S, et al. Intraoperative radioimmunodetection of colorectal tumor with a hand-held radiation detector. Am J Surg 1985; 150: 672–5.[CrossRef][Medline]
  28. Slavin-Chiorini DC, Kashmiri SV, Lee HS, et al. A CDR-grafted (humanized) domain-deleted antitumor antibody. Cancer Biother Radiopharm 1997; 12: 305–16.[Medline]
  29. Kashmiri SV, Iwahashi M, Tamura M, Padlan EA, Milenic DE, Schlom J. Development of a minimally immunogenic variant of humanized anti-carcinoma monoclonal antibody CC49. Crit Rev Oncol Hematol 2001; 38: 3–16.[Medline]



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