Cytogen
Capromab Pendetide - ProstaScint; prostate tumor monoclonal antibody–Indium In111 radioimmune conjugate
Status: approved; marketed
Organizations involved:
Cytogen Corp. – Manuf.; R&D; Tech.; World mark.
EUSA Pharma Ltd. – Parent
Jazz Pharmaceuticals Inc. – Parent
Bard Inc., C.D. – USA mark.
GE Medical Systems – USA mark.
Laureate Pharma, Inc. – Manuf.
Immunomedics, Inc. – Patent Dispute
National Cancer Institute (NCI) – Tech.
National Institutes of Health (NIH) – Parent org.
CELLEX BIOSICENCES, Inc. – Tech.
Cross ref: See the entry for Monoclonal Antibodies (#300).
Description: ProstaScint is an aqueous formulation of a murine hybridoma cell cultured IgG1 kappa subclass (IgG1k) monoclonal antibody, 7E11-C5.3 (capromab; CYT-351), chemically conjugated to a linker-chelator peptide group – glycyl-tyrosyl-(N,N-diethylenetriamine-penta-ace-tic acid)-lysine hydrochloride (GYK-DTPA-HCl) – forming capromab pendetide, which is reacted with Indium In111 to form Indium In111 capromab pendetide. The 7E11-C5.3 monoclonal antibody (capromab) has specificity for a glycoprotein, Prostate Specific Membrane Antigen (PSMA), expressed by prostate epithelial cells including prostate tumors. Capromab pendetide (ProstaScint; GYK-DTPA-HCl.CYT-063) is reacted in the nuclear pharmacy prior to administration to form a radioimmune conjugate composed of capromab pendetide radiolabeled with Indium In 111 radioisotope, which is injected for radiodiagnostic imaging of prostatic tissues, including metastatic prostatic tumors.
The capromab (7E11-C5.3) monoclonal antibody is produced by in vitro serum-free culture of murine hybridoma cells, and purified by sequential protein isolation and chromatographic separation procedures. Capromab pendetide (CYT-356) is prepared by Cytogen by site-specific modification of carbohydrate side chains of the 7E11-C5.3 (CYT-351) monoclonal antibody glycoprotein, by covalent binding to a tri-peptide linker-chelator molecule, glycyl-tyrosyl-(N-epsilon-diethylenetriamino-penta--acetic acid)-lysine hydrochloride (CYT-063; GYK-DTPA-HCl), to form the immune conjugate, capromab pendetide (GYK-DTPA--HCl.CYT-351; CYT-356). The linker-chelator group functions to further bind the radioisotope Indium In 111, forming the final radioimmune conjugate immuno-scinti-graphic agent – Indium In 111 capromab pendetide (Indium In 111 ProstaScint). Radiolabeling is performed on-site or locally in a nuclear pharmacy by reaction of capromab pendetide with Indium In 111 Chloride. The metallic Indium radionuclides undergo site-specific chelation with the linker portion of capromab pendetide at a location removed from the antigen-binding region of the monoclonal antibody, and the final molecule retains the PSMA specificity of the original monoclonal antibody.
Capromab pendetide is packaged in kits containing two vials with all of the non-radioactive ingredients needed to produce a single unit of Indium In 111 ProstaScint for administration by intravenous injection. The ProstaScint vial contains 0.5 mg of capromab pendetide in 1 mL of sodium phosphate buffered saline solution adjusted to pH 6. Another vial contains 82 mg of sodium acetate in 2 mL of Water for Injection adjusted to pH 5-7 with glacial acetic acid. This is added to sterile, non-pyrogenic, high purity Indium In 111 Chloride solution to buffer it prior to mixing and radiolabeling with Capromab Pendetide. Neither solution contains a preservative. Each kit also includes one sterile 0.22 µm Millex GV filter and two identification labels. The dating period for Prosta-Scint is 24 months from the date of manufacture, defined as the date of final sterile filtration of the formulated product. Cytogen may store bulk capromab antibody for up to 36 months at 2-8˚C (refrigerated) or frozen at -70˚C.
Nomenclature: TAG-72 Mab–In111 radioconj./Cytogen [BIO]; ProstaScint [TR for capromab pendetide immune conjugate]; Indium In 111 ProstaScint [TR for radioimmune conjugate]; capromab pendetide [FDA USAN for ProstaScint]; Kit for the Preparation of Indium In 111 Capromab Pendetide [FDA for kit]; Indium In 111 Capromab Pendetide [FDA for radioimmune conjugate]; Capromab [INN for monoclonal antibody]; Immunoglobulin G 1 (mouse monoclonal 7E11-C5.3 anti-human prostatic carcinoma cell), disulfide with mouse monoclonal 7E11-C5.3 light chain, dimer, N6-(N-[2-[[2-(bis(carboxy-methyl)-amino]ethyl](-carboxymethyl)-amino)ethyl]-N-(carboxy-methyl)glycyl]-N2-(N-glycyl-L-tyrosyl)-L-lysine conjugate [CAS for capromab pendetide]; 145464-28-4 [CAS RN for capromab pendetide]; anti-(human prostatic carcinoma cell) immunoglobulin G1 (mouse monoclonal 7E11-C5.3 chain) disulfide with mouse monoclonal 7E11-C5.3 light chain, dimer [CAS for capromab]; 151763-64-3 [CAS RN for capromab]; CYT-356 [SY for capromab pendetide]; 111In-CYT-356 [SY for capromab pendetide]; 7E11-C5.3-GYK-DTPA [SY for capromab pendetide]; 7E11-C5 [SY for monoclonal antibody]; GYK-DTPA.HCl [SY for linker-chelator]; GYK-DTPA-HCl.CYT-356 [SY for capromab pendetide]; CYT-351 [SY for monoclonal antibody]; In-111-Capromab Pendetide [SY for radioimmune conjugate]; CYT-063 [SY for linker-chelator]; glycyl-tyrosyl-(N-epsilon-diethylenetriamino-penta-acetic acid-lysine hydrochloride [SY for linker-chelator]; NDC 57902-817-01 [NDC for kit]
Biological.: In 1987, Horoszewicz, et al., developed a murine IgG1kappa monoclonal antibody designated 7E11-C5 (capromab; designated CYT-351 by Cytogen) secreted by a hybridoma cell line formed by fusion of P3x63Ag8.653 myeloma cells with spleen cells from BALB/c mice immunized with whole cells and membrane extracts of the human prostate adenocarcinoma cell line LNCaP. Capromab reacts with high specificity with prostate-specific membrane antigen (PSMA), a membrane glycoprotein with a molecular weight of about 100 kDa found in both normal and hypertrophic adult male prostate tissue. The antigenic epitope recognized by capromab is located in the cytoplasmic domain of PSMA, localized to both the internal region of the plasma membrane and certain cytoplasmic organelles. Expression of the PSMA glycoprotein has not been demonstrated on any other adenocarcinomas or transitional cell cancers tested, i.e., ProstaScint is specific for prostate tissue, including metastatic tumors of prostatic tissue origin. Indium In 111 Capromab Pendetide (ProstaScint) has demonstrated reactivity with 90-100% of primary and metastatic prostatic carcinoma cell lines in in vitro testing. Capromab, the immune conjugate (capromab pendetide), and the final radio-immune conjugate have greatest reactivity for malignant prostatic cells, followed by benign prostatic hypertrophic, and then normal prostate cells.
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.: ProstaScint was developed and is manufactured by Cytogen Corp., CBER/FDA est. no. 1164. ProstaScint is co-marketed in the U.S. by Cytogen and C.D. Bard Inc. Cytogen primarily promotes ProstaScint to imaging specialists (nuclear medicine specialists), while Bard’s urological division promotes it to office- and hospital-based urologists. Exclusive marketing rights for Canada were reacquired by Cytogen from Faulding (Canada) Inc. in June 1999. Development of ProstaScint was at least partially funded by CytoRad (a Cytogen limited partnership or other special purpose funding/investment entity).
In June 2003, Cytogen and GE Medical Systems formed a collaboration for development and marketing of GE’s Infinia Hawkeye imaging system for use with ProstaScint. GE handles installation and customer service, and Cytogen provides technical support.
ProstaScint has been manufactured in Laureate’s cGMP manufacturing facility in Princeton, NJ for more than 10 years. In Sept. 2004, Cytogen entered contracted with Laureate Pharma, Inc. for manuacture of capromab (ProstaScint ) for a single manufacturing campaign, expected to provide enough capromab to satisfy commercial requirements for approximately the next four years, based upon current sales levels. In Oct. 2006, Laureate Pharma renewed its agreement with Cytogen for the cGMP manufacture of ProstaScint. Laureate will continue to provide cGMP protein production, purification, conjugation of Cytogen’s proprietary linker chelator and aseptic filling services.
In May 2008, EUSA Pharma completed acquisition of Cytogen for $22.6 million. In July 2012, Jazz Pharmaceuticals acquired EUSA Pharma
Manufacture: Master and manufacturer’s Working Cell Banks for the hybridoma cell line were established following the FDA “Points to Consider in the Characterization of Cell Lines Used for the Production of Biologicals,” and are free of microbial, fungal, and adventitious viral contamination. According to the Summary Basis of Approval (SBA), the monoclonal antibody (CYT-351) was originally manufactured by unspecified (FDA redacted/censored) methods. Subsequently, it was manufactured by two different methods, termed Process B and C, with Process C is currently used for product manufacture. Rele-vant sections of the SBA are heavily redacted, but Process B involved expansion of cells in an unspecified bioreactor system using EMEM/NCTC medium supplemented with calf serum and weaned into serum-free DMEM/NCTC/Biotin production medium. Purification involved sequential chromatography in Protein A, DEAE-Sepharose and S-Seprarose columns.
Process C, currently employed for commercial manufacture of the capromab monoclonal antibody, uses AcuSyst-XCell hollow fiber perfusion cell culture bioreactors from CELLEX Biosciences, Inc. The bioreactors are reported to produce 60-200 grams of monoclonal antibody per month per incubator. A vial from the Master Working Cell Bank is used as inoculum for the bioreactors. Serum-free CMM1 medium (Cytogen) is used as the production medium. Harvested culture medium containing the monoclonal antibody is clarified by filtration and stored at 2-8˚C (refrigerated). Harvests are periodically checked for antibody titer, endotoxin, bioburden, and immunoreactivity. Prior to purification, pooled harvest samples are tested for antibody concentration, mycoplasma, and sterility, and tested for viral contamination by reverse transcriptase (for retroviruses), XC plaque (for ectopic viruses), S+L-Focus, and other in vitro viral testing.
Purification is performed in six steps, including four chromatography steps: 1) filtration, clarification and concentration of pooled harvests; 2) gel filtration chromatography on Sepha-dex G-25 column(s); 3) affinity chromatography on Protein A column(s); 4) anion exchange chromatography on DAEA-Sepharose column(s); 5) cation exchange chromatography on S-Sepharose column(s); and 6) sterile filtration through a 0.22 µM filter.
A CYT-351 Standard (for the monoclonal antibody) has been established. Product testing (vs. the Standard) includes: immunoreactivity, electrophoretic mobility, isoelectric focusing, monomer content, N-terminal amino acid sequencing, isotype, and appearance. Capromab is further characterized for potency, purity, and freedom from process contaminants and adventitious agents by assays including: S+L Focus assay, XC plaque assay (for ectopic viruses), reverse transcrip-tase in the presence of Mn+2 and Mg+2 (for retroviruses), sterility, mycoplasma, pH, electrophoretic mobility, isolectric focusing, monomer content (by size exclusion HPLC), isotype, immunoreactivity, appearance, and for levels of Protein A content, transferrin, bovine serum albumin, DNA, insulin-like growth factor-1, and bacterial endotoxin.
Lot release specifications for the monoclonal antibody include: protein concentration (5-11 mg/ml); immunoreactivity (slope ratio 65-120%); isotype (IgG1k); isoform profile (comparable to standard); electrophoretic mobility (comparable to standard); monomeric IgG (> 95%); appearance; pH (5.7-6.3); bacterial endotoxin (<1.0 EU/mg); DNA (probe hybridization; < 20 pg/mg); insulin-like growth factor-1 (< 5 ppm); bovine transferrin concentration (< 25 ppm); bovine serum albumin concentration (< 25 ppm); sterility (21CFR610.12f; no growth); and Protein A concentration (< 25 ppm).
Studies of viral removal/inactivation during manufacture using spiked crude monoclonal antibody bulk have shown the following total log10 reductions:> 9.2 log for E-MuLV; > 16.3 log for X-MuLV; > 14.2 log for SV-40; 18.9 log for herpes simplex virus type 1 (HSV-1); and 4.4 log for poliovirus. In infectivity assays prior to approval, no X-MuLV or other viruses were present in any of the conditioned media from production runs.
The glycyl-tyrosyl-(N-epsilon-diethylenetriamino-penta-acetic acid)-lysine hydrochloride linker-chelator (GYK-DTPA.HCl; CYT-063) can be synthesized or recovered from previous conjugation processes. The linker-chelator is manufactured for Cytogen by an unspecified contractor. The phosphate buffered saline (PBS; 10 mM sodium phosphate, 0.15 M sodium chloride; pH 6) is prepared by Cytogen. The sodium acetate solution part of the kit, used to buffer 111-In prior to labeling of the monoclonal antibody, is manufactured and packaged in glass vials by Cytogen.
Bulk CYT-356 immune conjugate (capromab pendetide) is manufactured by covalent linkage (oxidation) of the carbohydrate moieties of the purified CYT-356 (capromab) monoclonal antibody (immunoglobulin G) to aldehydes by reaction of the CYT-356 with sodium metaper-oxidate. Excess peroxidate is removed by Sephadex G25 gel filtration chromatography, and the oxidized glycoprotein is allowed to react with the CYT-063 linker-chelator. This resulting immune conjugate is concentrated and purified by chromatography on Superose 12. The product is collected, diluted with phosphate buffered saline (PBS) to a concentration of 0.55-0.60 mg/ml, and filtered through a 0.22 µm filter into a sterile polystyrene container.
The resulting CYT-356 immune conjugate (capromab pendetide) is subjected to in-process and final testing, including assay of monomer content, protein concentration, cyanide content, and excess GYK-DTPA (residual linker-chelator). Final release specifications for ProstaScint include appearance; electrophoretic mobility (SDS-PAGE equivalent to standard); radiolabeling of CYT-356 (>90%); immunoreactivity (>70%); affinity (0.5-5.0 µM-1); protein content (0.50-0.63 mg/vial); pH (5.7-6.3); rabbit pyrogen (non-pyrogenic; dose of 3.0 mg/kg/rabbit); sterility; general safety; chelator ratios (23.0, CYT-063/CYT-356), and bacterial endotoxin.
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Approval Date = 19961028, first approval, BLA ref. no. 95-0041 and 95-0087
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling]:
Indium In 111 ProstaScint (Capromab Pendetide) is indicated as a diagnostic imaging agent in newly-diagnosed patients with biopsy-proven prostate cancer, thought to be clinically-localized after standard diagnostic evaluation (e.g., chest x-ray, bone scan, CT scan, or MRI), who are at high-risk for pelvic lymph node metastases (see CLINICAL PHARMACOLOGY, Imaging Performance in Newly-Diagnosed Patients). It is not indicated in patients who are not at high risk. Indium In 111 ProstaScint is also indicated as a diagnostic imaging agent in post-prostatectomy patients with a rising PSA and a negative or equivocal standard metastatic evaluation in whom there is a high clinical suspicion of occult metastatic disease. The imaging performance of Indium In 111 ProstaScint following radiation therapy has not been studied.
The information provided by Indium In 111 ProstaScint imaging should be considered in conjunction with other diagnostic information. Scans that are positive for metastatic disease should be confirmed histologically in patients who are otherwise candidates for surgery or radiation therapy unless medically contraindicated. Scans that are negative for metastatic disease should not be used in lieu of histological confirmation.
ProstaScint is not indicated as a screening tool for carcinoma of the prostate nor for readministration for the purpose of assessment of response to treatment.
Status: ProstaScint is exempt from CBER/FDA lot release requirements. Capromab pendetide was the first injectable biopharmaceutical product to receive approval produced using hollow fiber perfusion culture technology (for monoclonal antibody production).
ProstaScint has not received centralized European Union approval, with no application apparently ever filed.
Tech. transfer: ProstaScint (capromab pendetide) is covered in whole or partially by at least the following U.S. patents: 4,671,958; 4,741,900 and 5,162,504. U.S. patent 5,162,504, “Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients,” by J.S. Horoszewicz, is assigned to Cytogen. The official abstract states, “Monoclonal antibodies to prostatic cells, are produced by a hybridoma formed by fusing mouse lymphocytes and mouse myeloma cells. The monoclonal antibodies show specificity for a non-soluble, membrane associated, organ specific antigenic determinant limited in its distribution to normal and neoplastic, human prostate epithelial cells. The monoclonal antibodies, specifically 7E11-C5 monoclonal antibodies, may be suitable for diagnostic uses.” Hybridoma cell line 7E11-C5 was deposited as ATCC HB 10494.
Due to the time ProstaScint spent in FDA regulatory review (under 35 USC §156), the expiration date of 5,162,504 was extended 352 days to Oct. 28, 2010.
Cytogen has nonexclusively licensed patents from the National Cancer Institute (NCI), National Institutes of Health (NIH; Bethesda, MD) including U.S. 4,824,986, “Method of Forming a Metal Chelate Protein Conjugate,” O.A. Gansow, assigned to NIH. This 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 (which concentrates and causes toxic effects in bone marrow and other tissues).
In Feb. 2000, Immunomedics, Inc. filed a patent infringement suit gainst Cytogen Corp. and C.D. Bard, alleging that Prosta-Scint infringes its U.S. patent 4,460,559, by M.D. Goldenberg, “Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers,” a continuation of 4,361,544. These patents broadly cover aspects of radioimmune conjugates and their use for tumor imaging and treatment. In spring 2003, the U.S. District Court granted a summary judgement of non-infringement. In June 2004, the U.S. Court of Appeals for the Federal Circuit (CAFC) ruled that ProstaScint does not infringe Immunomedics’ U.S. 4,460,559; agreed with the District Court ruling that ProstaScint does not literally infringe; but reversed the District Court ruling that ProstaScint does not infringe 4,460,559 under the doctrine of equivalents, and remanded this issue back to the District Court. In Oct. 2004, the companies settled this dispute, with Immunomedics paying a one-time undisclosed settlement payment to Cytogen and C.R. Bard Inc., without any admission of fault or liability.
Trials: In June 2005, new results concerning seven-year outcome clinical data strengthened evidence of the independent prognostic value of Prostascint. Over-expression of PSMA in primary prostate cancer not only correlated with other adverse traditional prognostic factors, but was shown to independently predict a higher incidence and shorter time to disease recurrence. Prostascint imaging to non-invasively identify and target areas of PSMA over-expression with higher doses of radiation in prostate cancer patients undergoing brachytherapy treatment resulted in significant disease-free survival rates. Prostascint imaging was performed prior to brachytherapy treatment in 239 prostate cancer patients. Brachytherapy consisted of either iodine-125 or palladium-103 radioactive “seed” implants. Seven-year outcomes were evaluated based on American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria as well as more stringent criteria involving prostate-specific antigen (PSA) cut-offs of 1.0 ng/ml and 0.5 ng/ml. For the entire group, biochemical disease free survival (bDFS) at seven-years was 88.0% by the ASTRO criteria, 82.1% by the PSA < 1.0 ng/ml criteria and 80.4% by the PSA < 0.5 ng/ml criteria. These rates of bDFS exceed those previously published by centers using standard treatment planning methods without dose escalation to BTVs, particularly for patients with intermediate- and high-risk features associated with their cancer. For patients in whom Prostascint imaging demonstrated uptake confined to the prostate gland and/or seminal vesicles, the overall seven-year bDFS was 85.8% to 90.6%; whereas for the 22 patients where the images showed uptake in lymph nodes the corresponding rates of bDFS were only 43.8-66.1%.
In June 2006, Cytogen and Philips Electronics reported significantly improved resolution and quality of ProstaScint images using Philips’ unique Astonish image processing tools and SPECT detectors, allowing physicians to visualize in greater detail the location and extent of disease, from both an anatomical and physiological perspective.
Medical: Indium In 111 ProstaScint is indicated for use in immunoscintigraphy in patients with biopsy-proven prostate carcinoma who are at high risk for pelvic lymph node meta-stases. After intravenous administration, the Indium In 111 capromab pendetide selectively localizes in the prostate and primary and metastatic prostate tumor sites. Two SPECT (single photon emission computed tomography) imaging sessions are performed. The first, about 30 minutes after infusion of Indium In 111 capromab pendetide, is used to obtain a blood pool (background) image of the pelvis. The second SPECT imaging session, performed between 72 and 120 hours after infusion, involves both the pelvis and abdomen, for the detection of benign and malignant prostate tissues.
Indium In 111 ProstaScint has been shown to induce human anti-mouse antibodies (HAMA), a type of immune rejection to murine IgG, infrequently and with low peak levels after single administration. In trials, HAMA levels were detected (at >8 ng/mL) by RIA after single infusion in 8% (20/239) of patients, while 1% of patients had levels greater than 100 ng/mL. In addition, serum HAMA levels were detected by RIA after repeat infusion in 19% (5/27) of patients.
The National Comprehensive Cancer Network (NCCN) added ProstaScint in its Practice Guidelines for Prostate Cancer in March 2000. NCCN guidelines are the most widely recognized guidelines in U.S. cancer care.
In Jan. 2007, the National Comprehensive Cancer Network (NCCN) included Prostascint in its updated clinical practice guidelines for recurrent prostate cancer. This expanded inclusion in the NCCN’s guidelines further reinforces the value of Prostascint for evaluation of prostate cancer in patients suspected of having locally recurrent disease.
Trials: In May 2006, Cytogen reported seven-year outcomes data from ProstaScint studies. The study evaluated the use of fusion imaging to assess disease in 239 newly diagnosed prostate cancer patients prior to undergoing brachytherapy with either iodine-125 or palladium-103 radioactive seed implants. Fusion imaging with ProstaScint, or hybrid imaging, is an in vivo diagnostic technique that combines anatomic images with functional images. Anatomical information derived from either computed tomography (CT) or magnetic resonance (MR) imaging can be fused (or co-registered) with functional information obtained using single-photon emission computed tomography (SPECT) and novel molecular imaging agents, such as ProstaScint. SPECT imaging focuses on metabolic abnormalities that may be present earlier than the anatomical changes otherwise seen with CT or MR imaging alone. Co-registering (aligning) anatomic and functional images provides an anatomic context for areas of enhanced or abnormal uptake, helping physicians identify areas of disease and enabling them to better plan an individualized treatment protocol for patients.
Seven-year outcomes for patients in the study were evaluated based on American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria as well as more stringent criteria involving prostate-specific antigen (PSA) cut-offs of 1.0 ng/mL and 0.5 ng/mL. For the entire group (217 patients with local disease, 22 patients with extraprostatic disease), biochemical disease free survival (bDFS) at seven years for patients in whom the ProstaScint scan showed disease confined to the prostate as opposed to those who had uptake outside the peri-prostatic region (including uptake in lymph nodes) was 91% vs. 66% by the ASTRO criteria (p=0.0003), 87% vs. 46% by the PSA <1.0 criteria (p<0.0001) and 86% vs. 44% by the PSA <0.5 criteria (p<0.0001). For the hormonal naive sub-population (171 localized, 18 extraprostatic), the seven-year bDFS was 92% vs. 64% (p=0.0004), 88% vs. 31% (p<0.0001), and 87% vs. 30% (p<0.0001) with the same criteria. Hazard ratios for patients with ProstaScint uptake outside the prostate were 3-fold higher for the entire group and four-fold higher for the hormonal naive subgroup. These differences were noted across all risk categories, particularly for those patients with intermediate and high risk features associated with their cancer.
Disease: Prostate cancer is the second leading cause of death from cancer in males in the United States. The American Cancer Society estimated there were 184,500 new cases of prostate cancer in the U.S. in 1998. The disease is most common in males over 60 and accounts for over 40,000 deaths annually.
Market Total ProstaScint sales were $91.1 million in 2006; $7.4 million in 2005; $7.2 million in 2004; $6.5 million in 2003, $7.92 million in 2002, and $7.64 million in 2001
The 2005 Average Wholesale Price (AWP) is $2,963.52/kit ($2,307.50 in 2004) (Red Book, 2005).
Starting in 2004, the Centers for Medicare & Medicaid Services (CMS) increased the Medicare hospital outpatient prospective payment system (HOPPS) reimbursement for ProstaScint. Cytogen believes this will help encourage hospitals to increase use of ProstaScint.
R&D: In May 2005, Cytogen and Dow Chemical formed a collaboration for development of a radiolabeled antibody to treat prostate and other cancers. This will combine Dow’s MeO-DOTA bifunctional chelant technology for attaching radioisotopes and Cytogen’s 7E11 monoclonal antibody against intracellular epitope of prostate-specific membrane antigen (PSMA).
Companies involvement:
Full monograph
312 TAG-72 Mab–In111 radioconj./
Nomenclature:
Prostate Mab–In 111 radioconj. [BIO]
ProstaScint [TR (for Capromab Pendetide immunoconjugate)]
Indium In 111 ProstaScint [TR (for final radioimmune conjugate)]
Capromab Pendetide [FDA USAN (for immunoconjugate)]
Indium In 111 Capromab Pendetide [FDA (for final radioimmune conjugate)]
Kit for the Preparation of Indium In 111 Capromab Pendetide [FDA (for final radioimmune conjugate preparation kit)]
Capromab [INN (for monoclonal antibody)]
Immunoglobulin G 1 (mouse monoclonal 7E11-C5.3 anti-human prostatic carcinoma cell), disulfide with mouse monoclonal 7E11-C5.3 light chain, dimer, N6-(N-[2-[[2-(bis(carboxymethyl)amino]ethyl](-carboxymethyl)-amino)ethyl]-N-(carboxymethyl)glycyl]-N2-(N-glycyl-L-tyrosyl)-L-lysine conjugate [CAS (for immunoconjugate)]
145464-28-4 [CAS RN (for final radioimmune conjugate)]
111In-CYT-356 [SY (for monoclonal antibody with linker)]
7E11-C5 [SY (for monoclonal antibody)]
7E11-C5.3-GYK-DTPA [SY (for monoclonal antibody with linker)]
CYT-351 [SY (for monoclonal antibody)]
CYT-356 [SY (for monoclonal antibody with linker)]
GYK-DTPA-HCl.CYT-356 [SY (for monoclonal antibody with linker)]
GYK-DTPA.HCl [SY (for CYT-063 tripeptide linker-chelator)]
In-111-Capromab Pendetide [SY (for final radioimmune conjugate)]
CYT-063 [SY (for tripeptide linker-chelator or GYK-DTPA-HCl)]
glycyl-tyrosyl-(N-epsilon-diethylenetriaminopentaacetic acid)-lysine hydrochoride [SY (for CYT-063 tripeptide linker-chelator)]
NDC 57902-817-01 [NDC for Capromab Pendetide kit]
FDA Class: Biologic BLA
Year of approval (FDA) = 1996
Date of 1st FDA approval = 19961028
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
bovine materials used<!-- bovinesource -->
conjugates
human materials used<!-- humansource -->
monoclonal antibodies
murine (mouse) materials used
murine (mouse) monoclonal antibodies
radioimmune conjugates<!-- radioconjugates -->
7E11-C5.3 murine hybridoma cells
ACUSYST perfusion bioreactors
albumin, bovine
ATCC HB 10494
BALB/c mice
bioreactors, 10,000 Liter
bovine serum
bovine serum albumin (BSA)
bovine transferrin
CMM1 (Cytogen), serum-free medium
CYT-063 monoclonal antibody
CYT-351 monoclonal antibody
Dulbecco's Modified Eagles Medium (DMEM)
EMEM/NCTC medium
human P3x63Ag8.653 myeloma cells
mammalian cell culture
P3x63Ag8.653 myeloma cells
perfusion bioreactors
rodent cells <!-- rodentcells -->
transferrin, bovine
Capromab
chelation
glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)-lysine hydrochloride (GYK-DTPA-HCl)
GYK-DTPA-HCl
indium-111 radioisotope
monoclonal antibody 7E11-C5.3
monoclonal antibody CYT-351
monoclonal antibody, Prostate Specific Membrane Antigen
phosphate buffered saline (PBS)
Prostate Specific Membrane Antigen (PSMA) monoclonal antibody
Protein A affinity chromatography
Sephadex
Sepharose
sodium acetate
sodium chloride
sodium metaperoxidate
sodium phosphate
Sterile Water for Injection
Superose 12
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
Park-William no. 8, Corynebacterium diphtheriae
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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