Neoprobe
RIGScan CC49; CC49 tumor associated glycoprotein-72 monoclonal antibody–Indium In 111 radioimmune conjugate; CC49 Mab–I125
Status: FDA filing long on hold, being revived
Organizations involved:
Navidea Biopharmaceuticals, Inc. – R&D; Tech.; Manuf. other
Neoprobe Corp. – Former
Dow Chemical Co. – Manuf.; R&D; Tech.; Former
U.S. Surgical – World mark.; Former inv.
National Cancer Institute (NCI), NIH – R&D; Tech.; Former
National Institutes of Health (NIH) – Parent
Univ. of Nebraska Medical Center – Tech.
Cross ref: See the entry above concerning a currently marketed radiolabeled TAG-72 monoclonal antibody. See also the entry for Monoclonal Antibodies (#300).
Description: RIGScan CC49 is an injectable radioimmune conjugate of CC49, a murine tumor-associated glycoprotein-72 (TAG-72) monoclonal antibody, conjugated to Indium-111 isotope prior to use. CC49 and the CC49– Indium-111 radioimmune conjugate (RIGScan CC49) selectively localizes or binds to TAG-72 antigen found particularly on the surface of colon and breast tumor cells.
RIGScan CC49 is used as part of the RIGS system combining RIGScan CC49 with a hand-held gamma radiation detection probe and surgical methods to provide surgeons with real-time information to locate colorectal tumor deposits not detectable by conventional methods, and to assist in more thorough removal of tumors. The CC49 targeting monoclonal antibodies are labeled with a radioactive Indium-111 isotope that emits low energy gamma rays (a 27-35 KeV). Prior to surgery, patients are administered RIGScan CC49, and the radioimmune conjugate not bound to tumors is allowed to clear over a period of several weeks. In surgery, a very sensitive hand-held radiation detection instrument capable of detecting small amounts of radiation is used to localize tumors. The device emits an audible tone to direct the surgeon to targeted tissue, assisting the surgeon in the more thorough removal of tumors, leading to improved surgical treatment of the patient.
Nomenclature: TAG-72 Mab–In111 radioconj./Neoprobe [BIO]; RIGScan CC49 [TR]; CC49 tumor associated glycoprotein-72 monoclonal antibody–Indium In 111 radioimmune conjugate [SY]; CC49 Mab-In131 [SY]; CC49 Mab/I125 [SY]
Biological.: The CC49 monoclonal antibody is produced from a murine hybridoma cell line that was generated by the fusion of splenic lymphocytes from mice immunized with TAG-72 with non-immunoglobulin secreting P3-NS-1-Ag4 myeloma cells. CC49 is considered second-generation product, relative to the B72.3 monoclonal antibody used with OncoScint CR/OV (see entry above). Both Mabs are specific for tumor--associated glycoprotein-72 (TAG-72) which is highly expressed on the surface of adenocarcinomas, including colorectal, breast, ovarian, prostate, gastric and pancreatic carcinomas.
Companies.: Neoprobe began development of RIGScan in the early 1990s, with applications filed in 1996. Dow Chemical Corp. originally manufactured CC49 for Neoprobe, and collaborated with Neoprobe in development of RIGS devices. At the time, Dow was also developing radio-iodinated CC49 for cancer radiotreatment.
Neoprobe changed its name to Navidea Biopharmaceuticals, Inc. in Jan. 2012.
In Sept. 1996, Neoprobe granted exclusive worldwide rights for marketing and sales of RIGS products to U.S. Surgical Corp., now part of Tyco Healthcare. The National Cancer Institute (NCI), National Institutes of Health (NIH), assisted in the development of RIGSscan through Collaborative R&D Agreements (CRADAs) with Neoprobe and Dow Chemical. These CRADAs and, perhaps, the agreements with Dow and U.S. Surgical may have ended in the years since about 1997 when problems in gaining FDA approval caused Neoprobe to put RIGscan development on hold. Dow Chemical is now primarily involved in recombinant plant-expressed proteins, and does not appear likely to participate in the revived development of RIGScan.
Status: Neoprobe submitted a BLA to FDA and filed for European Union (EU) approval in Dec. 1996 for approval of RIGScan CR49 for the detection of metastatic colorectal cancer. Neoprobe had conducted two Phase III studies, NEO2-14 and NEO2-13, in patients with colorectal cancer. NEO2-14 was the pivotal study. Two additional studies evaluating patients with either primary or metastatic colorectal disease, NEO2-11 and NEO2-18, were included in the BLA and provided supportive proof of concept (i.e., localization and occult tumor detection) and safety data. Both FDA and EMEA (EU) responded with further questions. Both the FDA and EMEA acknowledged that the studies met the diagnostic endpoint of the Phase III clinical study, which was to provide incremental information to the surgeon regarding the location of hidden tumors. However, both agencies wanted to know how the finding of additional tumors provided clinical benefit that altered patient management or outcome. Product claims were then narrowed to the intraoperative detection of hepatic and perihepatic disease in patients with advanced colorectal cancer and patients with recurrent colorectal cancer.
The FDA determined during its review that further clinical studies of RIGScan CR49 were needed to demonstrate clinical utility, in addition to identifying additional pathology-confirmed disease. An FDA driven post hoc analysis plan was developed to limit the evaluation of RIGScan CR49 to patients with hepatic and perihepatic disease with known metastasis to the liver. Findings of “occult” disease and subsequent changes in patient management (i.e., abandoning otherwise risky hepatic resections) in this limited population would serve as a measure of patient benefit. The NEO2-14 pivotal trial was reevaluated using this criteria, but FDA found an insufficient number of evaluable patients fitting this criteria to assess clinical utility. FDA issued a not-approvable letter on Dec. 22, 1997 (and has not closed-out the application). At the time, Neoprobe lacked resources to follow-through with another Phase III trial.
In April 2004, Neoprobe met with FDA and reported that it provided FDA with new information related to a survival differential for patients whose colorectal cancer was evaluated with RIGScan CR49; FDA indicated it would consider accepting survival data from one of the two Phase III trials, NEO2-14, but not from from NEO2-13, as supportive data for a prognostic indication for colorectal cancer; FDA also clarified that two well controlled studies were required for approval; and FDA indicated that Neoprobe needed to complete an additional confirmatory Phase III study for a prognostic indication in colorectal cancer.
In recent years, various investigator-sponsored and other trials and new analyses of prior clinical trials data have renewed commercial interest in development of RIGSscan CC49. A new survival analysis of original trial patients suggests that RIGScan CR49 may be predictive of, or actually contribute to, a positive outcome when measuring survival of the patients. Reviving the product’s development will involve manufacture of new monoclonal antibody and radioimmune conjugate, including improved process development. Presuming positive feedback from FDA, Neoprobe is likely to sponsor another Phase III trial and again seek FDA and EU approvals and strategic partners.
RIGSscan CC49 received approval in South Korea in Jan. 1997. However, the product has not been commercially manufactured or marketed anywhere.
Tech. transfer: The TAG-72-specific monoclonal antibody used in RIGScan CC49 is CC49 developed by the National Cancer Institute (NCI), National Institutes of Health (NIH). In Dec. 1993, it was reported that NIH granted Neoprobe an exclusive worldwide license for use of CC49 monoclonal antibodies in RIGS (radiodiagnostic) products, while Dow Chemical retained a prior co-exclusive (with Centocor, Inc.) license for therapeutic radioimmune conjugate uses.
CC49 Mab-related patents assigned to NIH include 5,512,443, “Second Generation Monoclonal Antibodies Having Binding Specificity to TAG-72 and Human Carcinomas and Methods Employing the Same.” Although not noted in the patent upon issuance, the University of Nebraska Medical Center has been reported in the press to be a coassignee with NIH.
Medical: RIGScan CR49 is the biologic component for the RIGS system to be used in patients with colon or rectal cancer. The RIGS system is designed to be a diagnostic aid in the intraoperative detection of the extent and location of tumors in patients with colorectal cancer. Clinical trials suggest that RIGScan CR49 provides additional information outside that provided by standard diagnostic modalities (including surgical exploration) that may aid in patient management. Specifically, RIGScan CC49 used as a component of the RIGS system confirms the location of surgically suspicious metastases, evaluates the margins of surgical resection, and detects occult tumors in perihepatic (portal and celiac axis) lymph nodes.
Index Terms:
Companies involvement:
Full monograph
315 TAG-72 Mab–In111 radioconj./
Nomenclature:
TAG-72 Mab–In111 radioconj./Neoprobe [BIO]
RIGSCAN CC49 [TR]
CC49 Mab---Indium I 125 radioimmune conjugate [SY]
CC49 Mab-In131 [SY]
CC49 tumor Associated Glycoprotein-72 monoclonal antibody–Indium In 111 radioimmune conjugate [SY]
tumor Associated Glycoprotein-72 monoclonal antibody–Indium In 111 radioimmune conjugate [SY]
FDA Class: Biologic BLA
biopharmaceutical products
conjugates
monoclonal antibodies
murine (mouse) materials used
murine (mouse) monoclonal antibodies
radioimmune conjugates<!-- radioconjugates -->
catheter clearance
mammalian cell culture
murine (mouse) hybridoma cells
murine myeloma cells
myeloma cells, murine
p-nitrophenyl-beta-D-glucopyranoside
rodent cells <!-- rodentcells -->
tumor necrosis factor-2 receptor (TNFR2)
indium-111 radioisotope
murine monoclonal antibody, carcinoembryonic antigen
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US002 FDA application pending
EM999 Not Available/Not Marketed in EU
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