Tumor Immunoscintigraphy by Means of Radiolabeled Monoclonal Antibodies

[CANCER RESEARCH (SUPPL.) 50, 899s-903s. February I. 1990] Tumor Immunoscintigraphy by Means of Radiolabeled Monoclonal Antibodies: Multicenter Studies of the Italian National Research Councilâ€”Special Project "BiomÃ©dicalEngineering"l

Antonio G. Siccardi Dipartimento di Biologia e Genetica per le Scienze Mediche, UniversitÃ di Milano, Via Viotti 3/5, 20133 Milan, Italy

Abstract configuration(s); and (d) pilot studies on tumor imaging, spec Four radioimmunopharmaceuticals ("'""Ir- and "'In-labeled anti-mel ificity tests, and comparisons between differently labeled re anoma and '"In- and 13ll-labeled anti-carcinoembryonic antigen I (ali')., agents. Stage 1 required the collaboration of several groups: S. Ferrane and coworkers at the Department of Microbiology and fragments derived from monoclonal antibodies 225.28S and F023C5) Immunology, New York Medical College, Valhalla, NY; M. were developed by means of a collaborative effort coordinated by the Italian National Research Council, Special Project "Biomedicai Engi Dovis and coworkers at the Research Center of Sorin Biome neering." After appropriate pilot studies, the radioimmunopharmaceuti dica; and P. G. Natali and coworkers at the Istituto Tumori cals, prepared by Sorin Biomedica (Saluggia, Italy), were distributed to Regina Elena, Rome, Italy. Stages 2, 3, and 4 were carried out 31 Nuclear Medicine departments in Italy and in 10 other European by L. Callegaro, G. Deleide, and coworkers at the Research countries within the framework of three immunoscintigraphy multicenter Center of Sorin Biomedica, Saluggia, Italy; by G. Mariani and studies. A total of 1245 patients were studied, 898 of whom carried 1725 coworkers at the CNR Institute of Clinical Physiology, Pisa, documented tumor lesions; 1596 of 2193 tumor lesions (468 of which Italy; by G. L. Buraggi and coworkers at the Istituto Nazionale were previously unknown) were imaged by immunoscintigraphy in 785 of Tumori, Milan, Italy; and by P. Riva and coworkers at the 990 lesion-bearing patients. Among the occult lesions, 173 were imaged in 92 patients admitted to the study as lesion-free patients. The results Ospedale Bufalini, Cesena, Italy. G. A. Scassellati of Sorin have been analyzed in terms of the reliability, reproducibility, and diag Biomedica coordinated the industrial side of the program. This report summarizes the results of three multicenter stud nostic usefulness of the method and of each immunoradiopharmaceutical. ies, the first of which, the Italian section of "ISG of Human Melanoma," was completed in 1985 (15); the second, "ISG of Introduction CEA-secreting Carcinomas" was completed in 1987 (16); and The aim of the Special Project "Biomedicai Engineering" the third, the European section of the melanoma study, was (1982-1987; directed by L. Donato) was to promote product- completed in 1988(17). The principal investigators of the 31 Nuclear Medicine de oriented research in collaboration with Italian industries oper ating in the biomedicai area. Tumor ISG,2 in its pioneering partments involved in the multicenter studies were: A. Abbati stages in 1982 (1-3), was included in the project as a potential (Ospedale Maggiore, Bologna, Italy), M. Bestagno (Spedali field of development. A coordinated program was set up to (a) Civili, Brescia, Italy), D. Bockisch (Institut fÃ¼rKlinische und Experimentelle Nuklearmedizin der UniversitÃ¤t, Bonn, West evaluate the feasibility and the effectiveness of the method in Germany); K. E. Britton (St. Bartholomew's Hospital, London, pilot studies, (b) develop standardized reagents (IRP) of indus trial quality suitable for routine clinical use, and (c) perform United Kingdom), U. Bull (Klinikum Aachen, Aachen, West Germany), G. L. Buraggi (Istituto Nazionale Tumori, Milan, multicenter studies in Italy and other countries, in order to Italy), V. Caputo (UniversitÃ "La Sapienza," Rome, Italy), A. evaluate the reproducibility and reliability of the developed Centi Colella (Policlinico "Umberto I," Rome, Italy), T. Cerny products and their clinical diagnostic usefulness. Industrial IRPs derived from two monoclonal antibodies, the and S. Owens (Christie Hospital and Holt Radium Institute, anti-melanoma 225.28S and the anti-CEA F023C5, were de Manchester, United Kingdom), A. Crespo Diez (Centra Ramon veloped by Sorin Biomedica, Saluggia, Italy, with the collabo Y Cajal, Madrid, Spain), R. Dudczak (Medizinische Universi ration of several University and National Research Council tÃ¤tklinik,Wien, Austria), J. J. Duque (Hospital de Cruces de laboratories, the Nuclear Medicine Department of the Istituto Barcaldo, Bilbao, Spain), M. FÃ¼zy(National Institute of On Nazionale Tumori of Milan, and other institutions (4-14). The cology, Budapest, Hungary), G. Galli (Policlinico Gemelli, products were distributed to 31 Nuclear Medicine departments UniversitÃ Cattolica, Rome, Italy), D. Garcia Sous (Hospital in Italy and other countries and evaluated extensively in terms Universitario Virgen del RociÃ³, Seville, Spain), J. Y. Herry of diagnostic application and usefulness on more than 1200 (Centre Eugene Marquis, Rennes, France), A. T. Irvine (The patients. Royal Marsden Hospital, London, United Kingdom), K. Liew- The research stages to be undertaken prior to the evaluation endahl (Department of Clinical Chemistry, University of Hel of IRPs in large-scale clinical trials are common to all projects sinki, Finland), M. Martinez-Paredes (CÃ¡tedra de Radiologia, of this kind: (a) the choice of suitable, well-characterized anti Facultad de Medicina, Universidad de CÃ³rdoba, CÃ³rdoba, gen-antibody systems; (b) immunochemical and radiochemical Spain), R. Masi (Ospedale Careggi, Florence, Italy), A. No- studies to prepare various types of immunoglobulin fragments gueira (Instituto PortuguÃ©sde Oncologia Francisco Gentil, labeled with a number of radioisotopes; (c) biodistribution Lisboa, Portugal), E. Pittelkow (Klinikum der UniversitÃ¤t,Hei studies in animals and humans to choose the most appropriate delberg, West Germany), M. Rentsch (Institut fÃ¼rMedizinische Onkologie der UniversitÃ¤t, Inselspital, Bern, Switzerland), P. 1Presented at the "Second Conference on Radioimmunodetection and Ra- dioimmunotherapy of Cancer." September 8-10, 1988, Princeton. NJ. Riva (Ospedale Bufalini, Cesena. Italy), M. Salvatore (Istituto 2The abbreviations used are: ISG. immunoscintigraphy; CEA, carcinoem- Pascale, Naples, Italy), M. Sanguineti (Ospedali Galliera. bryonic antigen; CT, computerized tomography; F(ab');, bivalent fragments of Genoa, Italy), K. Scheidhauer (Klinikum Grosshadern, Univ antibodies obtained by papain digestion: HMW-MAA, high molecular weight melanoma-associated antigen: Mab, monoclonal antibody; IRP, immunoradi ersitÃ¤t,Munich, West Germany), B. Siwek (Zaklad Medycyny opharmaceutical; US, ultrasound tomography: i.d.. intradermally. Nuklearnej, Lublin, Poland), I. SzilvÃ¡si (Department of Ra- 899s

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. TUMOR IMMUNOSCINTIGRAPHY WITH RADIOLABELED Mabs diology, Postgraduate Medical School, Budapest, Hungary), G. The localization of radiolabeled reagents in tumor lesions L. Turco (UniversitÃ di Torino, Turin, Italy), and P. Zaniol was demonstrated to be antigen specific, since it was shown to (UniversitÃ di Modena, Modena, Italy). More than 100 physi be quite different from the distribution of radiolabeled frag cians, in the above departments, were actively involved in the ments of monoclonal antibody 4C4 (reactive with an irrelevant multicenter studies. viral antigen) in all patients investigated; 15 melanoma patients and 12 carcinoma patients were subjected to this kind of "dou ble-tracer" ISG specificity test. Materials and Methods In other cases, the anti-melanoma IRP were used as specific Monoclonal Antibodies. The anti-melanoma Mab 225.28S, reactive ity control in carcinoma patients and vice versa. A representative with the high molecular weight melanoma associated antigen (HMW- example (14) follows. Four patients, who had shown positive MAA) was developed by Wilson et al. (18) and characterized extensively imaging of carcinoma lesions by the '"In-labeled anti-CEA (see Ref. 14 for a collection of the relevant references). Its applications F(ab')2, were injected, after 3 weeks, with equal amounts of in ISG have been reported (4-7). The anti-CEA Mab F023C5, reactive '"In-labeled (in 2 cases) or "Tc-labeled (in 2 cases) F(ab')2 with the protein portion of CEA and unreactive with human granulo- fragments of the anti-melanoma monoclonal antibody. No im cytes, was developed by Dovis and collaborators and has been exten aging of carcinoma lesions with the melanoma-specific IRPs sively described, also for its ISG applications (8-14). The anti-hepatitis B virus surface antigen Mab 4C4 (19) was used as a specificity control. was observed; conversely, no imaging of melanoma lesions by the CEA-specific IRP was observed in a complementary study, Immunoradiopharmaceuticals. The following products were devel oped and produced by Sorin Biomedica: (a) kit for instant labeling carried out on four melanoma patients. F (ab')2 fragments of Mab 225.28S with 99nTc; (o) kit for instant A correlation close to 100% between positive ISG imaging labeling F(ab')2 fragments of Mab 225.28S with "'In; (c) kit for instant and the immunocytochemical detection of the relevant tumor- labeling F(ab')2 fragments of Mab F023C5 with '"In; (d) F(ab')2 associated antigen on biopsied tumor tissues was demonstrated. fragments of Mab F023C5 labeled with I31I;(e) F(ab')2 fragments of The converse correlation (negative imaging versus negative im- Mab 4C4 labeled with '"I. Appropriate specific activity and immuno- munocytochemistry) was better in the case of CEA carcinoma reactivity controls were carried out on each lot of the reagents, as (10 of 16 ISG-negative lesions were also CEA negative immu- reported (15, 16). nocytochemically) than in the case of melanoma (6 of 12 ISG- Immunoscintigraphy Protocol. Before i.v. administration of IRP, negative lesions were immunocytochemically HMW-MAA pos patients were tested for hypersensitivity to mouse immunoglobulins by injecting 1-3 pg of cold F(ab')2 fragments i.d. Routine clinical analyses itive). to evaluate hematopoietic, hepatic, pancreatic, and renal functions were In 23 melanoma patients and in 19 carcinoma patients the performed before IRP administration and were repeated during the ISG procedure was performed more than once, either with the subsequent 2 weeks. No adverse reactions were observed. IRP solutions same reagent or with the other radiolabel. In most cases, the (approximately 5 ml; containing 2-3 mCi of ml or '"In or 10-30 mCi same lesions were visualized in the repetition(s), although dif of 99mTc/0.5 mg of F(ab')2 fragments) were injected i.v. over a 2-min ferences in image quality and in the relative intensities of period. Scans were obtained at 6 and 24 h (for the 99mTc-labeledanti- radiolabel accumulations were observed, with the exception of melanoma IRP) or at 48, 72, or 96 h after administration (for the other some liver lesions in carcinoma patients which were imaged by IRP) utilizing large field-of-view gamma cameras connected to dedi the "'I-IRP, but not by the "'In-IRP. cated computers for data processing. F(ab')2 fragment doses, radiolabel-specific activities, and optimal False-positive radiolocalizations were very rare (less 0.5% of the total positive images) and included abscesses, granuloma- times for scanning were chosen on the basis of the results obtained in pilot studies (4-14). tous masses, and inflammatory processes. The scans were read by one or two physicians who did not know the patient's case. Their findings were then compared with preexisting evidence from other diagnostic techniques. Known tumor localizations Radioimaging of Melanoma Lesions were classified as true-positive or false-negative in ISG; "unexpected" Results of the Italian Multicenter Study (15). A total of 262 radiolocalizations were investigated, whenever possible, by other diag melanoma patients, 191 of whom carried 412 known tumor nostic techniques, such as clinical examination. CT, US, planar radiog raphy (X-ray), and biopsy and either confirmed immediately after the lesions, were investigated by 10 Italian Nuclear Medicine de partments. The same ISG protocol was used in all departments. ISG study or followed up for up to 3 years. The "Tc-IRP was used in 182 patients, while the '"In-IRP was used in the remaining 80 patients: (a) No clinical or Results chemical toxicity was detected during or following the studies. Specificity Controls and Reproducibility (b) Positive ISG results were obtained in 174 of 206 (84.5%) patients [i.e., 174 of 206 patients (191 carrying known lesions In all the patients investigated there was a nonspecific accu and 15 carrying only occult lesions, detected for the first time mulation of radioactivity in the liver (especially with ' "In-IRPs) by ISG and then confirmed by other means)]; in 118 (57%) of and spleen; with 99mTc-IRPs a remarkable accumulation of these patients 283 of 283 lesions were imaged, in 56 (27%), 94 radioactivity in the kidneys was also found. The detection of of 200 lesions were imaged, and in 32 (15%) 0 of 56 lesions tumor lesions in these sites was severely limited and could often were imaged. The percentage of ISG-positive patients was be achieved only with the aid of "subtraction" methods or of higher with the 99mTc-IRP; such a difference in sensitivity is single photon emission computerized tomography. Other, less close to statistical significance (P = 0.058). (c) The percentage marked, nonspecific accumulations of radioactivity were ob of melanoma lesions visualized by ISG was 70%; 377 lesions served in the cardiac area and in the lungs (especially, given were visualized of a total of 539 (412 already documented at their earlier scanning times, with "Tc-IRPs), in the urinary the time of the study and 127 previously occult, revealed by bladder, in bone marrow, occasionally in the scrotum, in uterine ISG). (d) A total of 162 documented melanoma lesions (30%) fibromas, and in recent surgical scars; these nonspecific accu were not visualized by ISG in a total of 88 patients; about 70% mulations of radioactivity, however, did not affect the detection of the ISG-negative lesions were of small size, (e) The mela of specific uptake by known tumors. noma nature of 87 of the 127 ISG-positive occult lesions was 900s

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. TUMOR IMMUNOSCINTIGRAPHY WITH RADIOLABELED Mabs confirmed by clinical criteria and/or additional laboratory tests positive cases (79%) were found. In the latter group, 273 of 324 at the time of the ISG study; another 14 lesions, which could patients (67%) had all their known lesions correctly imaged by not be detected by other diagnostic means, were confirmed in ISG, whereas in the remaining 51 patients (12%) in whom one the follow-up of the patients (by the appearance of pleural or or more lesions were imaged, at least one known lesion was not peritoneal effusions or by the subsequent positivization of other imaged, (c) No significant difference in overall sensitivity was diagnostic tests, such as X-ray, CT, or US). observed between '"I- and '"In-IRP. (d) Tumor imaging was The large number of patients and lesions investigated pro obtained in 82% of the CEA-seropositive and in 69.0% of the vided an opportunity for the analysis of the influence of several CEA-seronegative patients, (e) The fraction of documented variables on the outcome of immunoscintigraphy. Several of lesions imaged was 73% in CEA-seropositive patients and 54% the observed differences are statistically significant: (a) the in CEA-seronegative patients. (/) A large number (218) of percentage of visualized lesions was significantly higher (P = "unexpected" radiolocalizations were recorded. Follow-up stud 0.00057) with 99mTc-IRP than with the "'In-IRP (74 and 59%, ies unambiguously demonstrated that 139 of 183 of these respectively); (b) the percentage of visualized lesions showed localizations were in fact previously occult tumor lesions. (#) significant differences (P = 0.0023) from organ to organ. The Taking into account the occult lesions detected by immunoscin anatomic distribution of ISG-negative lesions was found to be tigraphy, the fraction of imaged lesions becomes 80% for CEA- significantly different (P = 0.0049) from that of ISG-positive seropositive patients and 63% for CEA-seronegative patients. lesions (skin, 31 and 21%, respectively; superficial lymph nodes, (ft) While the sensitivity of the method for extrahepatic lesions 25 and 34%, respectively); (c) the difference in imaging fre is 83% in CEA-seropositive patients, the detection of liver quency due to the size of tumor lesions was highly significant mÃ©tastasesis severely hampered, especially with '"In-IRP, a (P = 0.0000026). high nonspecific uptake of radioactivity. (/) The major cause of Results of the European Multicenter Study. A total of 493 negative ISG results in a lack of CEA in the tumor lesion, as melanoma patients, 363 of whom carried 605 known tumor documented by the immunohistochemistry of surgically re lesions, were investigated by 20 European Nuclear Medicine moved tumors, (f) Lesion size is also important since the departments (17). The same 1RP (99mTc-labeled) and the same sensitivity is 64% for lesions up to 2 cm in diameter and 84% ISG protocol were used in all departments, (a) No clinical or for larger lesions. chemical toxicity was detected during or following the studies. (b) Positive ISG results were obtained in 287 of 363 (79%) Discussion patients (321 carrying known lesions and 42 carrying only occult lesions, detected for the first time by ISG and then The aim of the Immunoscintigraphy Program of the Italian confirmed by other means): in 247 (68%) of these patients, 402 National Research Council was to investigate the applicability of 402 lesions were imaged; in 52 (14%), 108 of 204 lesions and clinical usefulness of tumor immunoscintigraphy and to were imaged, and in 76 (21%), 0 of 122 lesions were imaged. promote the development, in Italy, of industrial products for (c) The percentage of melanoma lesions visualized by ISG was routine clinical use. Both anti-melanoma and anti-CEA mono 70%; 510 lesions were visualized of a total of 728 (605 already clonal antibodies were used in ISG as F(ab')2 fragments. Both documented at the time of the study and 123 previously occult, reagents were developed also in the form of instant labeling but revealed by ISG). (d) A total of 218 documented melanoma kits, to allow the routine preparation of well standardized lots lesions (30%) were not visualized by ISG in a total of 128 of larger size and for a more convenient use of the reagents by patients; about 70% of the ISG-negative lesions were of small Nuclear Medicine departments. size, (e) The melanoma nature of 92 of the 123 ISG-positive The results of the three multicenter studies are summarized occult lesions was confirmed by clinical criteria and/or addi in Table 1. The following points are worth noting, (a) The tional investigations either immediately or in follow-up studies results obtained in 19 departments with the anti-melanoma which lasted for up to 3 years. reagents and in 11 departments with the anti-CEA reagents are No significant differences in sensitivity between this study comparable (i.e., no significant differences were observed and the Italian Multicenter Study could be detected at any level among the results obtained by departments which investigated (patient ISG classification, single lesion detection, and organ 20 or more cases). This finding indicates that ISG with these distribution). reagents is a reliable procedure, (b) The concordance of the results obtained when ISG was repeated on two or more occa sions (in 56 patients) indicates that the procedure is reproduc Radioimaging of Adenocarcinoma Lesions: Results of the Mul ible, (c) The frequent finding of "unexpected" radiolocalizations ticenter Study (16) (a total of 468) which turn out to be previously occult tumor A total of 509 patients, 386 of whom carried 711 known lesions is the most appealing feature of ISG in terms of diag tumor lesions, were investigated by 11 Nuclear Medicine de nostic usefulness. In fact, in 92 patients this finding contributed partments (10 in Italy and 1 in Germany). The same ISG to the early diagnosis of tumor recurrences. Although our protocol was used in all departments. The '"I-IRP was used in multicenter studies documented only a few false-positive re 283 patients, while the '"In-IRP was used in the remaining sults, and none among unexpected radiolocalizations, the rate 226 patients. The patient population included 284 gastrointes of confirmation of unexpected radiolocalizations as tumor le tinal cancer cases, 204 nongastrointestinal adenocarcinoma sions shows a significant variation in relation to different ana cases, and 21 controls. Serum CEA levels were studied in 285 tomic districts, (d) The specificity of the method has been patients and were elevated in 169. The following results are experimentally proved to be close to 100%, by "double tracer" worth emphasizing, (a) No adverse reactions or evidence of tests in 25 patients and by the immunohistochemical study of toxicity were observed, (b) Among the 410 patients carrying biopsied ISG-positive tumor tissues. Nonspecific radioactivity tumor lesions (375 with previously known tumor lesions, plus accumulations are reasonably constant in terms of both location 35 admitted as lesion free but in whom ISG detected previously and size for both IRPs and, provided they are recognized as occult lesions), 86 false-negative cases (21%) and 324 true- such, do not impair the specificity of the method, (e) The 901s

Table l Summary of immunoscintigraphy results of the three multicenter studies patientsMulticenter ISG classification of lesionsPositive491 in -le sion-free" studyCEA URL218127 patients79 (II NMD) in 35 MELAIT. (10 NMD) 48125Known 250387Negative217 162 32 in 15 MELA EU. (19 NMD)TP"324174 287FN8632 76TN88 218Total 123URL 62 in 42 Â°TP.true-positive; FN, false-negative; TN, true-negative: URL, unexpected radiolocalization; NMD, Nuclear Medicine departments; MELA IT.. Italian melanoma study: MELA EU., European melanoma study. evaluation of the sensitivity of the method requires some spec patients and which contributed to the early detection of tumor ification; the probability that a given lesion will be imaged recurrences in seven CEA-seronegative patients admitted to the should be calculated as the percentage of ISG-positive tumor study as lesion-free patients. lesions among those already known at the time of the study. In conclusion, the bulk of the information drawn from the The figures would be 63% for anti-melanoma reagents and 69% multicenter studies, which essentially confirms the capacity of for anti-CEA reagents, respectively. If occult lesions are in the tested reagents to image known lesions and indicates their cluded in the calculation, sensitivity rises to 70 and 77%, potential in detecting otherwise occult lesions, provides an respectively. appropriate basis on which to approach the problem of the The major cause of ISG-negative results is probably the practical, clinical value of immunoscintigraphy. This is the absence or poor expression of the relevant tumor-associated definition of its suitability in detecting occult tumor lesions in antigen in a fraction of metastatic lesions. Immunohistochem- the early stages of disease. Prospective studies in apparently ical data indicate that about 10% of melanoma mÃ©tastasesmay lesion-free patients, in follow-up after surgical removal of the be HMW-MAA negative (20, 21) and that adenocarcinoma primary tumor, are now under way (e.g., at the Istituto Nazion lesions are CEA positive to various extents (40-89%), depend ale Tumori and at Ospedale Bufalini) with encouraging prelim ing on the site of origin and the organ in which the metastasis inary results; these studies will provide a better evaluation of is located (15). the clinical importance of immunoscintigraphy in diagnostic Besides the radioisotope used as a label, the anatomic site of oncology. the tumor and its antigen content, several other factors were shown to influence significantly the outcome of ISG, i.e., the sensitivity of the method at the level of the single lesion. These Acknowledgments include the size of the lesion, the blood flow in tumor tissue This work was supported by a number of grants from the Italian and, in the case of melanoma, the clinical stage of the patient. National Research Council. Special Project "BiomÃ©dicalEngineering." Mariani et al.* have used the multicenter study database in The help of the multicenter studies' secretary, S. Spedalini, in handling order to carry out a comparison between the diagnostic sensi the computer archive and in generating the databases is gratefully tivity of ISG and of other noninvasive diagnostic techniques, acknowledged. such as standard X-ray, CT, and US; 200 patients (131 gas trointestinal and 69 lung cancer patients) were found to be suitable for such comparison. Statistically significant differ ences in sensitivity were found between ISG and X-ray and References between ISG and US, but not between ISG and CT, although ISG performed better. In particular, significant differences were 1. Goldenberg, D. M.. DeLand, F., Kim, E.. Bennett, S., Primus, F. J., Van shown by patients carrying lesions smaller than 2 cm. Analo Nagell. J. R., Estes, N., De Simone, P.. and Rayburn. P. Use of radiolabeled gous data were obtained by Buraggi and collaborators.4 antibodies to carcinoembryonic antigen for the detection and localization of diverse cancer by external photoscanning. N. Engl. J. Med., 298: 1384-1388, The statistical analysis of a large number of cases should 1978. provide the elements necessary for defining the best indication 2. Mach. J. P.. Buchegger, F., Forni. M., Ritshard, J.. Berche, C., Lumbroso, J. D.. Screyer. M., Giradet, C., Accolla, R. S., and Carrel, S. Use of for ISG diagnostic procedures, i.e., the conditions in which a radiolabeled monoclonal anti-CEA antibodies for the detection of human given IRP can perform at its best. For example, since in the carcinoma by external photoscanning and tomoscintigraphy. Immunol. To case of melanoma, the "Tc-IRP performs significantly better day, 2: 239-249, 1981. 3. Epenetos, A. A., Britton, K. E., Mather. S., Sheperd, J., Granowska, M., than the '"In-IRP in all anatomic sites and since stage IV Taylor-Papadimitriou, J.. Nimmon, C. C., Durbin. H., Hawkins, L. R., patients show a significantly higher frequency of false-negative Malpas, J., and Bodmcr, W. F. Targeting of iodine-123-labeled tumor- associated monoclonal antibodies to ovarian, breast, and gastrointestinal results, we could take into consideration the subpopulation of tumors. Lancet. 2: 999-1004. 1982. patients of stages I to III studied with the "Tc-IRP; the 4. Buraggi. G. L., Callegaro, L., Turrin, A., Cascinelli. N., Aitili. A., Emanuelli, fraction of ISG-positive patients would become 78 of 84 (93%) H., Gasparini. M., Deleide, G.. Plassio, G.. Dovis, M., Mariani. G.. Natali, P. G., Scassellati. G. A.. Rosa. U., and Ferrane, S. Immunoscintigraphy with and the fraction of ISG-positive lesions would become 146 of iÂ¡j| Wl"Tcand '"In-labeled F(ab'); fragments of monoclonal antibodies to 185 (79%). This rÃ©Ã©valuationwouldbe legitimate, since in human high molecular-weight melanoma-associated antigen. J. NucÃ.Med. Allied Sci., 2Â«:283-295. 1984. clinical practice the diagnosis of further lesions in stage IV 5. Buraggi. G. L., Callegaro, L., Mariani, G., Turrin, A., Cascinelli, N., Aitili, patients is irrelevant. In the case of anti-CEA reagents, perform A.. Bombardieri. E., Terno, G.. Plassio, G., Dovis, M., Mazzucca. N., Natali, ance could be maximized by restricting its indication to CEA- P. G., Scassellati. G. A., Rosa. U., and Ferrane. S. 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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. Tumor Immunoscintigraphy by Means of Radiolabeled Monoclonal Antibodies: Multicenter Studies of the Italian National Research Council−−Special Project ''Biomedical Engineering''

Antonio G. Siccardi

Cancer Res 1990;50:899s-903s.

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