- Email: [email protected]
Specific targeting of lung cancer using monoclonal antibodies
'01
and H-69) admixed in normal bone marrow. Normal bone mamxv progenitor cells were not depleted ai@fvxotly during the “purge”. A latgt scale separator suitable for clinical use was shown to be
effective as well. We intend now to use a clinical protocol for high dose chemotherapy and ABMT using mAb-purged marrow f&r oatients with SCCL. In another study. mAb-coated lioosomes were developed in order eventually to &l&r cytotoxic dru& rp&iicaUy to SCCL tumors. We have sucas.sfully conjugated both the SCCL-1 and PM-81 mAb to isotope-labelled liposomes and shown that specific localization to SCCL cell line xenografts in nude mice can be achteved after subcutaneous injection. The next step in this study will be to incorporate cytotoxic agents into the~liposomes. MAbcoated drug-loaded liposomcs could be used to deliver cytotoxic compohnds to tumors in patients with SCCL in viva while sparing normal tissues.
CHEMOSENSITIVITY OF TRANSPLANTABLE NON-SMALL CELL BRONCHIALRATTUM~URS GROWING SUBCUTANEOUSLY OR IN THE LUNG.
Berkel
D.W. van Bekkum, P.J.N. Meijnders, A.H. van of Applied Radiobiology and TNO, Rijswijk, The Netherlands.
and H.B. Kal, Institute
Immunology
Five squamous cell carcinomas of varying grades of differentiation, an adenocarcinoma and an anaplastic tumour were induced in the lungs of rats by ionizing radiation and maintained by serial subcutaneous passage in syngeneic animals for between 11 and 75 passages at the time of this
study. Responses of the tumours to a panel of cytostatic drugs were determined for tumours growing subcutaneously and for tumours from the same passage following implantation into the lung. The endpoint was growth delay as determined by direct measurements in the case of subcutaneously growing turnours or by radiography in case of intrapulmonary implants. Consistent differences were observed within each turnour cell line between the two sites in that lung implants were always less responsive than flank implants. These findings suggest that responses of subcutaneously growing bronchial cancers are “or predictive for turnours growing in the lung. This seems to be in accordance with the poor responses obtained with chemotherapeutic agents in human non-small cell cancers of the lung.
CONSlDER4TlON.S IN POPUIATION BASED SCREENINGFOR THE EARLY DETECTION OF LUNG CANCER. JAMES and Mslvyn S. Tockman Biotharapy Section, NCI-Naw Mad Oncol Br,COP,DCT,NCl,NIH. Bethesda, MD and Johns Hopkins School of Health and Hygiene. Baltimore, MD. In developing a test to detect Lund cancar at a atage in which prolongation of disease related survival could be obrrrvad. many questiona are important. What is the scientific basis for the test and how could it be expanded? What would be requlrad to validate the panarel application of such a” assay7 Further, what would be the barriers to accaptanca and utilization of a” affective early detacdon marker? The approprirtanrsa of thaaa issues la suggested by the ameroing understanding of the molecular avant8 Iasding to tha development of an invasive epithaliel cancer. A rational application of this information Is to baoin to usa this information to Identify individuals with the biochemical or mdacular changer In relevant clinical s&clmans indicative of early malignant transformation. In datectinp lung cancer, the aarliaat cellular changer occur wtthin the bronchial eplthalium. Tha some of tha transformed cells would be shod end potential recovered in the sputum. Wa have prevlou6ly publishad one approach invalving ImmunocytoloQical analysis of cell surface changes of sputum specimens from individuals at risk for lung cancer (Tockma” et al. J Clin Oncol5:1665, 19861. Knowledge of avenwal rpplicatlon of this early detection approach affects tha process of clinical svsluatlon of such tools in terms of the diagnostic precision required OFan early detection tool In regard to the pretest probability.oF positive in a taroat population. Also tha aiza of the oopulation and the required frsquency of rerlal analysis Lmpore coat considerations into the equation. Such questions might seem a bit premature, but facad with the reality of cervical cancer Fatalities years after the Oenersl rvsilablllty of an effective screening tool, such long term issya may be ralavant. Considerable research has been done on tha ax&nations For non participation in carvical cancer screening efforts. The logistics of procasr of cervical screening ara formidable and analysir of technlcal factors Involved In obtainIn& proceasing and interpreting cervical cytology have also been examined. lssuas of assay
reproduciblity and endpoint interpretation both favor approaches incorporating automated procedures. Currently no axiotino automated technologies are panerally used for routma preparation of cervical cytology and analysis of either cervical cytology or of mammography. These issues as much 8s the defining the definitive marker For early lung cancar, may ultimately impede the broad application of a lung cencar screenIn tool. Since these lxsues are different From the usual in the realm of cancer diagnostics, it may be important to consider such Issues now.
ANTIBODIES TO LUNG CANCER ANTIGENS: POTENTIALLY USEFUL REAGENTS FOR DIAGNOSIS, IMAGING AND THERAPY, Paul A. Bunn. Jr., University of Colorado Cancer Center,Denver, USA Lung cancer, the most common cancer in the USA, consists of 4 pathologic subtypes: adenocarcinoma. squamous cell carcinoma, large cell undifferentiated carcinoma and small cell carcinoma. Antibodies have been developed which recognize antigens which fall into several categories: 1) antigens predominantly expressed on epithelial neoplasms including bronchiogenic carcinomas: 2) antigens expressed primarily on one histologic type of lung cancer compared io other-lung cancer histblo&s; 3) aniigens freauentlv exoressed on luno cancer cells and less often exp’resseb oi other maligna:cies and normal cells. Antigens in the first class include cytokeratins, carcinoembryonic antigen (CEA), mucins, epidermal growth factor receptor, and blood group antigens. Antigens in the second class include neural cell adhesion molecules (NCAM), chromogramin and neuropeptide receptors for small cell lung cancers, certain mucins and surfactant associated oroteins for adenocarcinomas and certain keratins for squamous carcinomas. There are few anti ens which are expressed exclusively in lung cancer. The Parge number of antibodies recognizing anti ens on lung cancer cells has created the need to a classyY?catlon system. An international workshop has attempted to cluster over 150 antibodies, especially to small cell cancers. Thus far, the workshop has identified 6 clusters. The first of these (Cl) recognizes neural cell adhesion molecules. Future workshops and a greater understanding of the biology of lung cancer will lead to important antrbodies for the early detection, diagnosis and therapy of lung cancer.
Specific Targeting of Lung Cawer Using Monoclonal Antibodies. P. Abram*, 0. Salk, M. Fer, A. Fritzberg, P. Weiden. is the preferred radionuclide for imaging Technetium-99, due to ite ready availability, low cost, high margin of safety for patients and medical personnel, and because it provides superior resolution on both planar and tomographic (SPECT) images. The availability cf the diamide dithiolate (N,S,) ligands providee stable, gentle chelation of Tc-99m to antibodies without loss of immunoreactivity. Using an N,.?., ligand to chelate Tc-gem, we have studied the Fab fragment of an anti-4OKd. Honoclonal antibody (NR-LU10) in more than 200 patiente with lung cancer to determine whether this antibody could target primary and metaetatic lung cancer. Ninety-six (96) patients with small cell lung cancer (SCLC) received 20-30mCi Tc-99m labeled NR-Lo-10 Fab (5-10mg) in a phase III trial. Prior to receiving the labeled antibody these patients had been etaged by the standard fragment, battery of tests (CT-head, CT-chest or CXR, CT-abdomen, bane [std. battery]. scan, bone marrw aspirate and biopsy) NREighty-nine (89) patients were eligible for analysis. Lo-10 Imaging alone was virtually as accurate ae the entire std. battery in staging patients with SCLC (87 vs. 92%). NRLU-10 Imaging was the most sensitive test for establishing erteneive SCLC with a positive predictive value of 97%. HAMA was 6% and transient. Twenty-two patient= with non-SCLC (NSCLC) were evaluated pre-surg~cally~ with CT-scans and NR-LU-10 Imaging. CTscanning was found to stage patients correctly in 76% of the caees, HI-Lo-10 Imaging wee correct in 85%. and together they were accurate in all (100%) of the caeee. Rhenium-186 (Re-186) ie a beta-emitter (3.7 d half-life; 1.2 nev energy maxi 9% abundant 137 kev gamma, that ca" be chelated to antibody with the same diamide dithiolate ligand We have just begun a phase I syeteme employed for Tc-99m. etudy of Re-186 NR-IX-10 in SCLC and NSCLC, administering escalating single doses of the labeled antibody. Future plans c0netrllc!ts that are "oninclude substituting novel immunogenic for the immunogenic whole murine antibody as multiple doses. carriers for Re-186, and administering
and H-69) admixed in normal bone marrow. Normal bone mamxv progenitor cells were not depleted ai@fvxotly during the “purge”. A latgt scale separator suitable for clinical use was shown to be
effective as well. We intend now to use a clinical protocol for high dose chemotherapy and ABMT using mAb-purged marrow f&r oatients with SCCL. In another study. mAb-coated lioosomes were developed in order eventually to &l&r cytotoxic dru& rp&iicaUy to SCCL tumors. We have sucas.sfully conjugated both the SCCL-1 and PM-81 mAb to isotope-labelled liposomes and shown that specific localization to SCCL cell line xenografts in nude mice can be achteved after subcutaneous injection. The next step in this study will be to incorporate cytotoxic agents into the~liposomes. MAbcoated drug-loaded liposomcs could be used to deliver cytotoxic compohnds to tumors in patients with SCCL in viva while sparing normal tissues.
CHEMOSENSITIVITY OF TRANSPLANTABLE NON-SMALL CELL BRONCHIALRATTUM~URS GROWING SUBCUTANEOUSLY OR IN THE LUNG.
Berkel
D.W. van Bekkum, P.J.N. Meijnders, A.H. van of Applied Radiobiology and TNO, Rijswijk, The Netherlands.
and H.B. Kal, Institute
Immunology
Five squamous cell carcinomas of varying grades of differentiation, an adenocarcinoma and an anaplastic tumour were induced in the lungs of rats by ionizing radiation and maintained by serial subcutaneous passage in syngeneic animals for between 11 and 75 passages at the time of this
study. Responses of the tumours to a panel of cytostatic drugs were determined for tumours growing subcutaneously and for tumours from the same passage following implantation into the lung. The endpoint was growth delay as determined by direct measurements in the case of subcutaneously growing turnours or by radiography in case of intrapulmonary implants. Consistent differences were observed within each turnour cell line between the two sites in that lung implants were always less responsive than flank implants. These findings suggest that responses of subcutaneously growing bronchial cancers are “or predictive for turnours growing in the lung. This seems to be in accordance with the poor responses obtained with chemotherapeutic agents in human non-small cell cancers of the lung.
CONSlDER4TlON.S IN POPUIATION BASED SCREENINGFOR THE EARLY DETECTION OF LUNG CANCER. JAMES and Mslvyn S. Tockman Biotharapy Section, NCI-Naw Mad Oncol Br,COP,DCT,NCl,NIH. Bethesda, MD and Johns Hopkins School of Health and Hygiene. Baltimore, MD. In developing a test to detect Lund cancar at a atage in which prolongation of disease related survival could be obrrrvad. many questiona are important. What is the scientific basis for the test and how could it be expanded? What would be requlrad to validate the panarel application of such a” assay7 Further, what would be the barriers to accaptanca and utilization of a” affective early detacdon marker? The approprirtanrsa of thaaa issues la suggested by the ameroing understanding of the molecular avant8 Iasding to tha development of an invasive epithaliel cancer. A rational application of this information Is to baoin to usa this information to Identify individuals with the biochemical or mdacular changer In relevant clinical s&clmans indicative of early malignant transformation. In datectinp lung cancer, the aarliaat cellular changer occur wtthin the bronchial eplthalium. Tha some of tha transformed cells would be shod end potential recovered in the sputum. Wa have prevlou6ly publishad one approach invalving ImmunocytoloQical analysis of cell surface changes of sputum specimens from individuals at risk for lung cancer (Tockma” et al. J Clin Oncol5:1665, 19861. Knowledge of avenwal rpplicatlon of this early detection approach affects tha process of clinical svsluatlon of such tools in terms of the diagnostic precision required OFan early detection tool In regard to the pretest probability.oF positive in a taroat population. Also tha aiza of the oopulation and the required frsquency of rerlal analysis Lmpore coat considerations into the equation. Such questions might seem a bit premature, but facad with the reality of cervical cancer Fatalities years after the Oenersl rvsilablllty of an effective screening tool, such long term issya may be ralavant. Considerable research has been done on tha ax&nations For non participation in carvical cancer screening efforts. The logistics of procasr of cervical screening ara formidable and analysir of technlcal factors Involved In obtainIn& proceasing and interpreting cervical cytology have also been examined. lssuas of assay
reproduciblity and endpoint interpretation both favor approaches incorporating automated procedures. Currently no axiotino automated technologies are panerally used for routma preparation of cervical cytology and analysis of either cervical cytology or of mammography. These issues as much 8s the defining the definitive marker For early lung cancar, may ultimately impede the broad application of a lung cencar screenIn tool. Since these lxsues are different From the usual in the realm of cancer diagnostics, it may be important to consider such Issues now.
ANTIBODIES TO LUNG CANCER ANTIGENS: POTENTIALLY USEFUL REAGENTS FOR DIAGNOSIS, IMAGING AND THERAPY, Paul A. Bunn. Jr., University of Colorado Cancer Center,Denver, USA Lung cancer, the most common cancer in the USA, consists of 4 pathologic subtypes: adenocarcinoma. squamous cell carcinoma, large cell undifferentiated carcinoma and small cell carcinoma. Antibodies have been developed which recognize antigens which fall into several categories: 1) antigens predominantly expressed on epithelial neoplasms including bronchiogenic carcinomas: 2) antigens expressed primarily on one histologic type of lung cancer compared io other-lung cancer histblo&s; 3) aniigens freauentlv exoressed on luno cancer cells and less often exp’resseb oi other maligna:cies and normal cells. Antigens in the first class include cytokeratins, carcinoembryonic antigen (CEA), mucins, epidermal growth factor receptor, and blood group antigens. Antigens in the second class include neural cell adhesion molecules (NCAM), chromogramin and neuropeptide receptors for small cell lung cancers, certain mucins and surfactant associated oroteins for adenocarcinomas and certain keratins for squamous carcinomas. There are few anti ens which are expressed exclusively in lung cancer. The Parge number of antibodies recognizing anti ens on lung cancer cells has created the need to a classyY?catlon system. An international workshop has attempted to cluster over 150 antibodies, especially to small cell cancers. Thus far, the workshop has identified 6 clusters. The first of these (Cl) recognizes neural cell adhesion molecules. Future workshops and a greater understanding of the biology of lung cancer will lead to important antrbodies for the early detection, diagnosis and therapy of lung cancer.
Specific Targeting of Lung Cawer Using Monoclonal Antibodies. P. Abram*, 0. Salk, M. Fer, A. Fritzberg, P. Weiden. is the preferred radionuclide for imaging Technetium-99, due to ite ready availability, low cost, high margin of safety for patients and medical personnel, and because it provides superior resolution on both planar and tomographic (SPECT) images. The availability cf the diamide dithiolate (N,S,) ligands providee stable, gentle chelation of Tc-99m to antibodies without loss of immunoreactivity. Using an N,.?., ligand to chelate Tc-gem, we have studied the Fab fragment of an anti-4OKd. Honoclonal antibody (NR-LU10) in more than 200 patiente with lung cancer to determine whether this antibody could target primary and metaetatic lung cancer. Ninety-six (96) patients with small cell lung cancer (SCLC) received 20-30mCi Tc-99m labeled NR-Lo-10 Fab (5-10mg) in a phase III trial. Prior to receiving the labeled antibody these patients had been etaged by the standard fragment, battery of tests (CT-head, CT-chest or CXR, CT-abdomen, bane [std. battery]. scan, bone marrw aspirate and biopsy) NREighty-nine (89) patients were eligible for analysis. Lo-10 Imaging alone was virtually as accurate ae the entire std. battery in staging patients with SCLC (87 vs. 92%). NRLU-10 Imaging was the most sensitive test for establishing erteneive SCLC with a positive predictive value of 97%. HAMA was 6% and transient. Twenty-two patient= with non-SCLC (NSCLC) were evaluated pre-surg~cally~ with CT-scans and NR-LU-10 Imaging. CTscanning was found to stage patients correctly in 76% of the caees, HI-Lo-10 Imaging wee correct in 85%. and together they were accurate in all (100%) of the caeee. Rhenium-186 (Re-186) ie a beta-emitter (3.7 d half-life; 1.2 nev energy maxi 9% abundant 137 kev gamma, that ca" be chelated to antibody with the same diamide dithiolate ligand We have just begun a phase I syeteme employed for Tc-99m. etudy of Re-186 NR-IX-10 in SCLC and NSCLC, administering escalating single doses of the labeled antibody. Future plans c0netrllc!ts that are "oninclude substituting novel immunogenic for the immunogenic whole murine antibody as multiple doses. carriers for Re-186, and administering