Status: withdrawn from the market

Organizations involved:

Cytogen Corp. – Manuf.; R&D; Tech.; USA mark.; Former

EUSA Pharma Ltd. – Parent

Jazz Pharmaceuticals Inc. – Parent

CIS Bio international – Intl. Mark.; Former

Lonza Biologics plc – Manuf. other; Former

National Cancer Institute (NCI), NIH – Tech.; Former

National Institutes of Health (NIH) – Parent; Former

Cross ref: See also the entry (#313) for Satumomab Concentrate (For Further Manufacturing Use) from which this product is manufactured; and the following entry for a similar product from a different manufacturer. See the entry for Monoclonal Antibodies (#300).

Description: OncoScint CR/OV is an aqueous formulation of satumomab pendetide, an immune conjugate formed from a hybridoma cell cultured murine monoclonal antibody, CYT-099 (B72.3), with specificity for tumor-associated glycoprotein-72 (TAG-72) chemically-linked to a linker-chelator molecule, glycyl-tyrosyl-(N,N-diethylenetriaminepentaacetic acid)-lysine hydrochloride (GYK-DTPA-HCl). The CYT-099 (B72.3) monoclonal antibody is produced by in vitro hybridoma culture. Satumomab pendetide is reacted in the nuclear pharmacy with Indium-111 radioisotope prior to intravenous administration, to form the active radioimmune conjugate, Onco-Scint CR/OV-In (Indium In 111 satumomab pendetide), composed of satumomab pendetide bound to radiolabeled Indium-111 radioisotope, which is injected for radiodiagnostic imaging of tumors expressing TAG-72.

Satumomab pendetide is manufactured by Cytogen Corp. from Satumomab Concentrate (For Further Manufacturing Use) manufactured by Lonza Biologics plc. See the entry for Satumomab Concentrate (For Further Manufacturing Use) (#313). The B72.3 monoclonal antibody (Mab) concentrate is subjected to an oxidation reaction, converting the carbohydrate moieties of this immunoglobulin glycoprotein to aldehydes. The monoclonal antibody is oxidized so that it can be chemically modified with the linker/chelator moiety. Satumomab pendetide is prepared by site-specific conjugation of the tripeptide linker-chelator molecule – glycyl-tyrosyl-(N,N-diethylene-tri-amine-pentaacetic acid)-lysine hydro-chloride (GYK-DTPA HCl; CYT-063) – to the oxidized oligosaccharide side chains of B72.3 Mab. The resulting satumo-mab pendetide conjugate retains the immunoreactivity of the unconjugated monoclonal antibody, and can bind radioactive Indium 111.

The radioimmune conjugate (OncoScint CR/OV-In) is prepared locally by a nuclear pharmacy prior to use. Satumomab pendetide is used, prior to intravenous administration, to form a radioimmune conjugate composed of satumomab pendetide radiolabeled with Indium-111 radioisotope, which is injected intravenously for radiodiagnostic imaging of tumors expressing TAG-72. Sodium acetate buffer solution is added to Indium In 111 chloride solution to buffer the satumomab pendetide prior to radiolabeling. After reacting (mixing) oxidized satumomab pendetide (oxidized B72.3 Mab–GYK-DTPA HCl) with Indium-111 chloride, the resulting radiolabeled conjugate, the active immunoscin-tigraphic agent, OncoScint CR/OV-In (Indium In 111 satumomab pendetide), is formed. This is filtered through the supplied 0.22 µm filter prior to intravenous administration. The metallic radionuclides of In 111 undergo site-specific chelation with the chelator-linker component of satumomab pendetide at a location removed from the antigen binding region of the monoclonal antibody. OncoScint CR/OV-In 111 retains the immunoreactivity of the unconjugated monoclonal antibody.

OncoScint CR/OV-In 111 is used to detect high levels of TAG-72 antigen occurring on the surface of most ovarian and colorectal tumors. Scintillation cameras collect images, seen as “hot spots,” indicating where the radiolabeled antibody has bound to the TAG-72 protein in high concentrations, indicating where tumors may be located. To allow for clearance of unbound radioimmune conjugate from the blood (background noise which would interfere with imaging), gamma camera images are generally taken 48-72 hours after administration.

Each OncoScint CR/OV kit contains all of the non-radioactive ingredients needed to produce a single unit dose of OncoScint CR/OV-In (Indium In 111 satumomab pendetide) for intravenous injection. Each kit contains two vials – a single-dose vial of OncoScint CR/OV formulated with Water for Injection, containing 1 mg of satumomab pendetide in 2 mL of sodium phosphate buffered saline solution adjusted to pH 6 with hydrochloric acid; and a vial of sodium acetate buffer containing 136 mg of sodium acetate trihydrate in 2 mL of Water for Injection adjusted to pH 6 with glacial acetic acid. Neither solution contains a preservative. The sodium acetate buffer solution must be added to Indium In 111 chloride solution to buffer it prior to radiolabeling of satumomab pendetide to form OncoScint CR/OV--Indium-111 (Indium In 111 satumomab pendetide). Each kit also includes one sterile 0.22 µm Millex GV filter through which the radiolabeled product is filtered as it is administered intravenously to the patient.

Nomenclature: TAG-72 Mab–In111 radioconj./Cytogen [BIO]; OncoScint CR/OV [TR for monoclonal antibody with chelator-linker]; OncoScint CR/OV-In [TR for radioimmune conjugate]; satumomab pendetide [FDA for antibody with linker)]; Indium In 111 satumomab pendetide [FDA USAN for radioimmune conjugate]; immunoglobulin G 1 (mouse monoclonal B72.3 anti-human glycopro-tein TAG-72), disulfide with mouse monoclonal B72.3 light chain, dimer, N6-[N-[2-[[2-bis(carboxymethyl)-amino]--ethyl]-(carboxymethyl)-amino]-ethyl[-N-(carboxy-methyl)glycyl]-N2(-N-glycyl-L-tyrosyl)-lysine conjugate, Indium-111In chelate [CAS for OncoScint CR/OV-In]; 138955-27-8 [CAS RN for satumomab pendetide]; 138955-26-7 [CAS RN for OncoScint CR/OV-In]; In11 CYT-099 [SY for final radioimmune conjugate]; B72.3-GYK-DTPA-111In [SY for satumomab pendetide]; Anti-Tumor Associated Glycoprotein-72 Mab radioconjugate [SY]; GYK-DTPA-HCl.CYT-099 [SY for satumomab pendetide]; CYT-099 (MAb B72.3) murine monoclonal antibody [SY for antibody]; CYT-099 [SY for antibody]; CYT-099–GYK-DTPA.HCl [SY for satumomab pendetide]; GYK-DTPA.HCl [SY for linker-chelator]

Note, satumomab pendetide or OncoScint CR/OV, referring to the monoclonal antibody–linker conjugate, also refers to the kit for preparation of the radioimmune conjugate (OncoScint CR/OV-In; Indium In 111 satumomab pendetide). OncoScint CR/OV, satumomab pendetide, and other terms for the antibody–linker are sometimes improperly used to refer to the final radioimmune conjugate (OncoScint CR/OV-In; Indium In 111 satumomab pende-tide) administered to the patient.

Biological.: B72.3 is a murine monoclonal antibody of the IgG1, kappa subclass directed to tumor-associated glycoprotein (TAG-72), a high molecular weight glycoprotein expressed particularly by adenocarcinomas. The B72.3 monoclonal antibody was prepared by injecting mice with a membrane-enriched extract of human breast carcinoma, followed by fusion of selected splenic B-cells expressing TAG-72 anti-body with a murine myeloma cell line, forming the monoclonal antibody-expressing hybridoma. See the entry for Satumomab Concentrate (For Further Manufacturing Use) (#313).

In vitro studies have shown that B72.3 is reactive with about 83% of colorectal adenocarcinomas, 94% of common epithelial ovarian carcinomas, and the majority of breast, non-small cell lung, pancreatic, gastric, and esophageal cancers evaluated. B72.3 is generally not immunoreactive with normal adult tissues (but it is reactive with salivary gland ducts, normal post-ovulatory endometria, some benign ovarian tumors, and fetal gastrointestinal tissues).

Indium In 111 decays by electron capture with a physical half-life of 67.8 hours (2.8 days), emitting gamma electromagnetic radiation. The exposure rate constant for 37 MBq (1 mCi) of Indium In 111 is 8.3 x 104 C/kg/hr (3.21 R/hr).

Companies.: Satumomab pendetide (OncoScint CR/OV) was developed and manufactured by Cytogen Corp., CBER/FDA est. no. 1164. Laureate Pharma Inc., under contract to Cytogen, manufactures this immune conjugate from Satumomab Concentrate (For Further Manufacturing Use) manufactured by Lonza Biologics plc (formerly Celltech Biologics; see entry #313). In May 2008, EUSA Pharma completed acquisition of Cytogen for $22.6 million. In July 2012, Jazz Pharmaceuticals acquired EUSA Pharma.

OncoScint CR/OV was marketed in the U.S. and North America by Cytogen. CIS Bio international held exclusive marketing rights in Europe and the rest of the world outside of N. America. OncoScint CR/OV was originally marketed in Europe by EuroCetus (now Chiron Corp.) until a new licensing agreement was concluded in Sept. 1995 with CIS Bio. Exclusive marketing rights for Canada were reacquired by Cytogen from Faulding (Canada) Inc. in June 1999.

Cytogen discontinued OncoScint CR/OV at the end of 2002.

     In May 2008, EUSA Pharma completed acquisition of Cytogen for $22.6 million.

Manufacture: The overall manufacturing process for satumomab pendetide appears to be very similar to that of capro-mab pendetide (ProstaScint) also from Cytogen. See the entry for capromab pendetide (ProstaScint) (#312) for which more in-depth manu-facturing details are provided.

Purified bulk B72.3 monoclonal antibody (satumomab) is produced by Lonza Biologics under a shared manufacturing agreement with Cytogen. B72.3 is produced by Lonza using serum-free culture of hybridoma cells in large airlift fermentors. Purification is by sequential protein isolation and chromatographic separation procedures. See the Satumomab Concentrate (For Further Manufacturing Use) entry (#313) for further information.

Bulk frozen B72.3 shipped by Lonza is defrosted at Cytogen facilities. To prepare satumomab pendetide (Mab-linker conjugate), the Indium chelator, GYK-DTPA, is covalently attached to bulk purified B72.3 by oxidation of the carbohydrate moieties present on the B72.3 glycoprotein. This is reacted and covalently bonded to the linker molecule GYK-DTPA.HCl. The resulting satumomab pendetide immune conjugate is isolated from process reactants by a series of chromatography steps using Sephadex G-25 and Sepharose columns. Bulk product is subsequently filtered through a sterile 0.22 µm filter. The final steps of satumomab pendetide manufacture include sterile membrane filtration, aseptic filling into pre-sterilized 6 ml glass vials, stoppering with pre-sterilized rubber stoppers, and overcapping the vials. Sodium acetate solution included in the kit is manufactured by Cytogen and supplied as a sterile solution in glass vials containing 2 mL.

The manufacturing process for satumomab (B72.3) prior to chemical reactions has been validated for removal of DNA, cell culture medium additives, process reactants, and for viral inactivation/removal. Further chemical processing takes place under harsh conditions expected to eradicate or in-activate any contaminating viruses or other microorganisms. Prior to release, the final vialed satumomab pendetide is tested for immunoreactivity, protein content, radiolabeling, appearance, pH, bacterial endotoxin, sterility, and general safety.

The Summary Basis of Approval (SBA) reports the following as release specifications for satumomab pendetide: a) immunoreactivity - slope ratio 30.60 to 21.25; mucin competition IBQ (M1 and M2), 1.5 to 8.4; immunoreactivity of radiolabeled satumomab pendetide, 366% to 282%; radioisotope labeling using Indium-111, 395%; endotoxin, < 2 EU/ml; sterility (pass); general safety (pass); appearance - clear and colorless (like water), may contain translucent particles; pH, 5.7-6.2; and protein content, 1.00-1.25 mg/vial.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19921229, first approval, PLA/ELA (ref. no. 89-0600, 89-0601 and 90-0278); orphan designation (expired 12/1999); Indication = radiodiagnostic imaging of ovarian carcinoma

Date = unavailable; Indication = radiodiagnostic imaging of colorectal tumors

Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling]:

OncoScint CR/OV-In (Indium In 111 satumomab pendetide) is a diagnostic imaging agent that is indicated for determining the extent and location of extrahepatic malignant disease in patients with known colorectal or ovarian cancer. Clinical studies suggest that this imaging agent should be used after completion of standard diagnostic tests when additional information regarding disease extent could aid in patient management. The diagnostic images acquired with OncoScint CR/OV-In should be interpreted in conjunction with a review of information obtained from other appropriate tests.

OncoScint CR/OV-In is also indicated for re-administration to HAMA-negative patients who are at risk of recurrence. Ordering physicians should be aware that HAMA-positive patients have alterations in the biodistribution of the radio immuno-conjugate and in the quality of imaging. Therefore it is vital that before any repeat use of OncoScint CR/OV-In HAMA levels should be determined in pre-infusion sera. The results should be evaluated with respect to the patient’s clinical situation and the guidelines below should be followed.

Repeat OncoScint CR/OV-In should not be given to persons whose HAMA level is > 400 ng/ml because of the possibility of infusional reactions, and uniformly altered biodistribution and poor quality images. In general, if HAMA values are < 50 ng/ml most subjects will image normally. Altered biodistribution may occur in 3-4% (3/80 samples) of cases for unknown reasons unrelated to HAMA level. If HAMA values are between 50 and 400 ng/ml there is a higher incidence of subjects who will show altered biodistribution (7/13 samples) and uninformative imaging; in this range the frequency of HAMA interference with imaging has yet to be determined.

OncoScint CR/OV-In is not indicated as a screening test for ovarian or colorectal cancer.

Administration of OncoScint CR/OV-In may result in falsely elevated values from in vitro immunoassays, including tests for carcinoembryonic antigen (CEA) and CA 125. Because this interference may persist for months, the clinical laboratory should investigate for assay interference in patients who develop elevated CEA or CA 125 subsequent to imaging with OncoScint CR/OV-In (see Drug/Laboratory Test Interactions).

Status: Cytogen withdrew OncoScint from the market on Dec. 31, 2002.

OncoScint CR/OV is exempt from FDA CBER lot release requirements.

OncoScint CR/OV has not been approved by the European Union.

Tech. transfer: Cytogen Corp. exclusively licensed patents from the National Cancer Institute (NCI), National Institutes of Health (NIH; Bethesda, MD; license no. L-180-91) exemplified by U.S. 4,612,282, “Monoclonal Antibodies Reactive with Human Breast Cancer,” Sept. 16, 1986, assigned to NIH, concerning the B72.3 murine monoclonal antibody and associated hybridoma cell line with specificity for tumor associated glycoprotein-72 (TAG-72). See the Satumomab Concentrate entry (#313) for further information.

Cytogen also nonexclusively licensed from NIH patents including U.S. 4,824,986, “Method of Forming a Metal Chelate Protein Conjugate,” Gansow, O.A., NCI, April 25, 1989. This patent describes improved methods of forming metal chelate-protein and metal chelate-antibody conjugates useful to produce antibody-radioisotope conjugates (radioimmune conjugates). Prior metal chelates had limitations due to unwanted release of the metals in vivo. This metal chelate conjugation method substantially eliminates adventitiously bound radioactive metal on the protein that may be released in vivo (and concentrate and cause toxic effects in bone marrow and other tissues).

Medical: OncoScint CR/OV was the first in vivo radiodiagnostic imaging (immunoscintigraphy) agent based on monoclonal antibody technology approved by FDA. It is licensed for use in patients with known ovarian or colorectal cancer with suspected recurring or metastatic tumors. OncoScint CR/OV often enables earlier diagnosis of small tumor deposits in the abdominal cavity in patients with recurring ovarian cancer (often missed by other tests). Radiodiagnostic imaging with Onco-Scint CR/OV does not replace and is used along with computed tomography (CT) scans and other standard tests. Onco-Scint CR/OV is not effective as a screening test for ovarian or colorectal cancer.

The standard intravenous dose of OncoScint CR/OV-In is 1 mg of satumomab pendetide radiolabeled with 5 mCi of Indium In 11 chloride prior to administration. In clinical studies in patients with colorectal or ovarian carcinoma, Onco-Scint CR/OV-In (Indium In 111 satumomab pendetide) localized to primary and metastatic tumor sites. Non-antigen-dependent localization, suspected to be secondary to catabolism (metabolism of the radioimmune conjugate), was observed in the liver, spleen, and bone marrow.

OncoScint CR/OV has been shown to induce human anti-mouse antibodies (HAMA; a type of rejection) to murine IgG after single administration in about 55% of patients in tumor imaging clinical trials. HAMA levels become negative in one-third of affected patients after 6 months.

Market The 2004 Average Wholesale Price (AWP) was $1,675.00/kit (Red Book, 2004; last year listed).