Vaeth JM, Meyer JL (eds): The Present and Future Role of Monoclonal Antibodies in the Management of Cancer. Front Radiat Ther mcii. Basel, Karger, 1990, vol 24, pp 247-259
The Present and Future Role of Monoclonal Antibodies in the Management of Cancer Summary Luther W. Brady 1, Arnold M. Markoe, David V. Woo Department of Radiation Oncology and Nuclear Medicine, Hahnemann University, Philadelphia, Pa., USA
With the development of the hyb doma technique by Kohler and Milstein [ 1 ] in 1975, multiple areas of research have been pursued attracting a wide variety of disciplines. Realization of the full potential of labeled antibodies for increasing the selectivity of cancer cell identification and destruction requires continued persistent efforts by researchers in tumor cell biology, immunology, pharmacology, radiopharmaceutical and protein chemistry as well as in clinical medicine. Although there has been much work with monoclonal antibodies, presently there is no one monoclonal antibody that has entered routine clinical use in the treatment of any given cancer. The theoretical versus the practical applications of monoclonal antibodies have not always agreed with each other. For this reason, the practical advantages and limitations of monoclonal antibodies need to be further explored to clarify whether greater effort and resources are necessary for any given use of monoclonal antibodies in cancer treatment. Because radioisotopes offer certain advantages in labeling monoclonal antibodies, many diagnostic and therapeutic studies have been performed with a variety of radiolabels and monoclonal antibodies. Perhaps the Hylda Cohn/American Cancer Society Professor 0f Clinical Oncology and ChairDownloaded by: Université de Paris 193.51.85.197 - 2/5/2020 11:16:26 PM
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easiest approach to evaluating the biodistribution and kinetics of monoclonal antibodies in vivo is through the use of the nuclear gamma camera [2-10]. In humans, this method has yielded important information concerning the specificity of the radiolabeled antibody for the target tumor compared to other tissues [4, 5, 8, 11-15]. However, in many of these studies, just what is considered to be specific uptake and what is nonspecific is still not well defined. From the standpoint of diagnostic application, the basic major indications for tumor imaging are directed toward detection of the presence of the tumor, the localization of the sites of the disease and in the follow-up of the patient's course in terms of assessment of the effects of the administered therapy, prediction of early treatment failure as well as new sites of disease and to reinforce a sense of patient well-being in those individuals where there is no clinical evidence of recurrence. Using monoclonal antibodies developed by Koprowski et al. [ 16] to react specifically with colorectal tumor antigens and labeled with iodine131, Mach et al. [8] reported a cancer detection rate of 41 % using conventional images which slightly improve to 51 % using single photon emission, computed tomography (SPECT). Because background radioactivity was relatively high and partially obscured the image of the tumor particularly with iodine-131 emissions, digital enhancement techniques have slightly improved the detection rate of the lesions. This procedure has been fairly common to deal with the low target to nontarget uptake as observed with radiolabeled antibodies [7, 17]. In addition, the detection rate could be further improved as cited by Mach et al. [8] to 61 % by using a modified form of the monoclonal antibody, namely an F(ab')2 fragment. Furthermore, if it were possible to note precisely that the target tumor antigen existed in preselected patients, the detection rate might significantly improve as Larson et al. [6] reported with an 88 % detection rate for antimelanoma IgG specific for the P-97 antigen. In contrast to these studies, studies by Goldenberg et al. [ 17] reported a 91 % detection rate for polyclonal anti-CEA antibodies in patients with colorectal cancer. In other studies, Chatal et al. [4] evaluated two iodine-131-labeled monoclonal antibodies called 17-1A and 19-9 F(ab')2 fragments by scintigraphy of patients with colon cancer. They observed for 17-1 A that 59% of the known colorectal cancer sites were detected while for 19-9, 66% were detected. Both are monoclonal antibodies specific for colorectal tumors; however, their target antigens are different. Also, the 17-1A anti-
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gen is not shed by the tumor while the 19-9 antigen is shed into the bloodstream. When combinations of these two antibodies are co-administered, the detection rate was increased to 77 % of patients with colon cancer. More recently, improved chemical modification of tumor-specific monoclonal antibodies have allowed radionuclide metal atoms to be stably attached resulting in better image detection and less overall radiation dose. In studies by Hnatowich et al. [13], a total of 14 patients were imaged with indium-111-labeled 19-9 F(ab')2 and whole body clearance kinetics were determined. Nine of these patients had identifiable sites of metastatic disease from colorectal cancers (8 patients), pancreatic (2 patients), ovarian (3 patients), and small cell lung cancer (1 patient). The detection rate in this study was 67 % of the patients who were externally imaged 48-72 h after injection, results similar to those obtained by Chatal et al. [4]. The successful detection of malignant melanoma in patients using an indium-111-labeled 96.5 monoclonal antibody reported by Halpern et al. [5] indicated detection rates of 61 % without digital subtraction techniques. In addition, prolonging serum half-time by increasing the mass dose of the antibody appeared to improve tumor detection. The detection rates observed in the various studies highlight some of the problems in the application of monoclonal antibodies as diagnostic imaging agents. The overall accuracy appears to average somewhere between 40 and 70 % depending upon the specific monoclonal antibody, the radiolabel, and the type of imaging. The criteria used for selection of patients should be more precisely identified, the known cross-reactívítíes of the specific monoclonal antibodies used for diagnostic purposes should be known, whether the patient has specific antigen present should be identified, and the appropriate imaging technique defined. These are only a few of the questions that need to be addressed before monoclonal antibodies can be used as diagnostic imaging agents. Goldenberg [ 18] in his presentation identified the various tumor serum markers that might be used for diagnostic purposes. With the development of a broad, new array of tumor-associated antibodies through hybridoma technology, new innovative areas for tumor targeting have been open for exploration. Even though the initial studies were done with iodine-131, better imaging agents are now available with radionuclides of lower energy such as iodine-123, indium-111, and technetium-99m. With
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the significant progress made in the development of technetium-99mlabeling methods and the use of short-lived isotopes such as iodine-123 and technetium-99 rapid targeting agents such as bivalent or monovalent antibody fragments have been pursued. Using both F(ab')2 and F(ab') fragments of a CEA monoclonal antibody accurate imaging of CEA-producing tumors has been achieved using both iodine-123 and technetium99 with both planar and SPECT imaging. With this technology known cancer sites can be identified with an accuracy of at least 85%, including the demonstration of new lesions. Goldenberg [18] has pointed out that technetium-99 conjugated by new direct methods appears to be the preferred agent allowing for rapid clinical application. The major advantages offered by the ability to generate gram quantities of very pure and monospecific antibodies to a particular tumor-associated antigen as well as avoidance of cross-reactivity, dealing with the variability and antigen expression and the potential problem of circulating serum antigens, clinical work with radiolabeled antitumor antibodies has made remarkable progress in the last several years. As tumor imaging techniques are refined using radionuclides, the oncologist will push for earlier detection of even smaller tumor cell masses. The advent of new technology will allow the achievement of scintographic techniques to meet these morphological constraints of cancer medicine. Conceivably, monoclonal antibodies, if measured in quantitative terms proportional to a tumor mass, may reflect their degree of cellular differentiation or antiplasticity. Thus, the advent of diagnostic application of labeled monoclonal antibodies offers an exciting method to examine the behavior of tumors as well as to record their presence. Ehrlich and co-workers recognized the therapeutic potential of antitumor antibodies as carriers of toxic substances that could be selectively targeted to tumor cells. Although the concept of specific antibodies reacting with specific antigens on the surface of the tumor cell but not normal cells is easily appreciated, its realization is not without problems. Antibodies to tumor-associated antigens have proved to be valuable research tools and have moved rapidly from the laboratory into the clinic. The application of antibodies as a major therapeutic modality is still in the early developmental stages. There is much hope for monoclonal antibodies to be carriers of cytotoxic drugs and radioisotopes. Yet, the same problems associated with imaging such as tumor uptake and specificity still exist with approaches to radioimmunotherapy. In addition, the radiation dose to normal tissues
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and tumor becomes a major factor in evaluating the efficacy of treatment in cancer patients. A variety of radioisotopes are suitable for delivering a significant radiobiological dose to kill cells. Radioactive iodine-131 which is used for diagnostic imaging can also be used for therapy because of its numerous beta emissions. Its advantages include easy radiolabeling, high radiation dose per unit of activity, and the ability of most monoclonal antibodies to still bind to their target antigen after incorporation of the label. Numerous clinical studies reported by Order and co-workers [19-23] using iodine-131 to labeled tumor-associated polyclonal antibodies (antifemtin) resulted in fairly good success in the treatment of primary liver cancers. Monoclonal antibodies (antiferritin) have been developed and are presently being evaluated by the same group. The method of attachment of the radioiodine is generally applicable to all proteins containing accessible tyrosine residues and has seen major use as the first isotope to label monoclonal antibodies. However, there are major problems associated with the use of iodine-131 as a potential radionuclide for treatment. Although radiotagging iodine-131 to antibodies provides a reasonably stable attached label without significant loss of antibody activity, in vivo administration of iodinated antibodies into animals or humans has resulted in significant loss of radiolabel through dehalogenation. As much as 75 % of the radioactivity can be found in the urine at 24 h after injection [5, 24]. Moreover, the free iodide ion may be sequestered by the thyroid and excreted by the kidney resulting in an appreciable radiation dose to nontarget organs. It now appears that dehalogenation of the radioactive iodine occurs primarily in normal tissues as well as in the tumor. However, dehalogenation is not a problem for circulating antibodies since both indium-111- and iodine-131-labeled monoclonal antibodies have been found to show similar blood clearance curves. With better coupling chemistry, novel radiometals which have nuclear decay properties amenable for radiotherapy are being evaluated. Yttrium-90, copper-67, rhenium-188, phosphorus-32, bismuth-212, and astatine-211 have moderate to high LET energy particulate emissions (beta or alpha) which theoretically have the potential for the in vivo radiotherapy of tumors. These radionuclides are still undergoing investigation in animals since there are recurring problems with their coupling chemistry and many are radiotoxic. Other potential radionuclides which may be useful for radiotherapy are low-energy Auger electron emitters such as iodine-125 or bromine-77 [25-27]. Such Auger electron emitters have been studied following their
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incorporation into DNA or as its bromine-77 analog. The uptake of these thymidine analogs into mammalian cells in culture results in efficient cell killing as densely ionizing radiations of high LET such as alpha particles. If monoclonal antibodies are internalized (modulation) once they bind to their cell-surface antigen as Woo and Li have demonstrated, the radiobiological effectiveness of Auger electron emitters may provide better irradiation of the cell since the volume with less radiation to nontumor cells and subsequently less whole body exposure. Theoretical estimates indicate that the localized energy deposition of Auger electrons is about 335 eV and occurs within a 10-Ångström sphere of the decay site [28]. One of the major obstacles to radioimmunotherapy approaches is that the absolute tumor uptake as observed from imaging studies is extremely low. Therefore, rational attempts to increase the vascular permeability as well as to increase blood flow into the tumor may allow for greater uptake of the monoclonal antibody. In addition, to increase the likelihood of direct antigen-antibody interaction at the tumor site, it may be necessary to administer larger amounts of antibody to increase its circulating concentration in the tumor for greater uptake. The chemistry of attachment of the radioisotope to the monoclonal antibody is now in a high state of accomplishment as put forth by Woo et al. [29]. Using various bifunctional chelates, the attachment has aided considerably in the understanding of the bidistribution of the antibodies. Using chelate molecules such as DTPA or EDTA has considerably expanded the work relative to these antibodies. Borlinghaus et al. [26] have indicated a quantitative relationship between loading factors (the number of molecules of a drug coupled to a monoclonal antibody) and antigenicity. McGann et al. [30] defined the limitations of radioimmunotherapy related to targeting efl'iciency, radionuclide availability, and normal tissue toxicity. These limitations restrict the range of radiation dosages from 5 rad/h to a maximum of 15 rad/h. This continuous low dose rate (CLDR) subjects radioimmunotherapy efficacy to the differential radioresponsiveness produced by opportunities for repair of cellular damage, alterations in the proliferative status of cells, and reoxygenation of cells at a distance from the vascular network. Dillehay and Williams [31] identified the response of human tumor cells in vitro irradiated with dose patterns that simulate those observed for radiolabeled immunoglobulin therapy in vivo. They concluded that the inhibition of cell proliferation is of major importance in considering the
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effects of decreasing dose-rate patterns and cell sensitivity to growth inhibition and the criticality of this important parameter in the response of tumor cell populations. Within this context, normal tissue toxicities must be considered. As with other cancer therapies, radiolabeled immunoglobulin therapy is limited by normal tissue tolerance, hematopoietic toxicity. Their conclusion pointed out that improved radiolabeled immunoglobulin therapy might be improved through the combined use with chemotherapy and/or external beam radiation therapy. Abrams [32] discussed the potential for imaging of a given antibody limited to gamma-emitting radionuclides such as technetium-99m and iodine-123. This group has demonstrated excellent targeting using technetium-99m stably linked to monoclonal antibody fragments that recognize melanoma, lung cancer and colon cancer. Simultaneous studies with rhenium-186 (a beta emitter) and technetium-99m have shown an identical targeting and metabolic fate. Dose escalation studies are underway. Other therapeutic applications were discussed using antibodies labeled with drugs and toxins. The targeting concept allows for more acceptable toxicity. This work has been with trichothicenes, a class of mycotoxins. Major tumor regression has been achieved. Human trials are underway with antibodies labeled with pseudomonas exotoxin. Jain [34] pointed out that the effectiveness of cancer treatment using monoclonal antibodies or other macromolecules bound to radionuclides has been limited by their ability to reach the target in vivo in adequate quantities. Heterogeneity of tumor-associated antigen expression alone has failed to explain the nonuniform uptake of antibodies. The physiologic barriers responsible for the poor localization have been identified to be heterogeneous blood supply, elevated interstitial pressure and large transport distances in the interstitium. From Jaín's [34] presentation, fulfillment of the expectations of this type of treatment demand that strategies be developed to overcome the identified physiologic barriers. Leichner et al. [33] discussed the dosimetry and treatment planning in radioimmunotherapy. They pointed out that quantitative image analysis and radiation-absorbed dose calculations must be performed for every patient undergoing radiolabeled immunoglobulin therapy. The dosimetry must be as accurate as possible and must be provided in a timely fashion for the development of treatment strategies as well as the assessment of tumor response to therapy. This improved dosimetry is based upon image analysis, isodose curves that can be superimposed on patients' computed
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tomography scans and IRI scans, as well as the related anatomical structures in these scans. These applications will lead to improved dosimetry providing important information about tumor response to radioimmunoglobulin therapy. Kemshead [35] presented experiences using monoclonal antibodies for targeting with radioisotopes. They suggest that labeling with radioisotopes is the feasible proposition and other work presented at this meeting has confirmed that. His efforts have been directed toward using antibodies as targeting agents concentrating on the central nervous system compartment. Patients with malignant meningitis arising from a variety of tumors have been treated with radiolabeled antibodies. Responses in excess of 12 months have been recorded particularly in patients with radiosensitive tumors. Press et al. [36] reported on high-dose radioimmunotherapy of refractory non-Hodgkin's lymphomas with autologous marrow rescue. The biodist bution toxicity and efficacy of iodine-131-labeled anti-CD37 monoclonal antibody ΜΒ-1 and anti-CD20 monoclonal antibody IF5 have been assessed. Ten patients with advanced low and intermediate grade nonHodgkin's lymphomas failing conventional therapy were treated. No significant toxicity was noted and all 4 evaluable patients achieved complete tumor remissions lasting from 4 to 7 months. Press et al. [36] concluded that the tolerable toxicity and encouraging efficacy warranted further dose escalation in this phase I trial. DeNardo [37] reported 18 patients with stage IV B-cell malignancies (lymphoma and leukemia) treated with fractionated doses of iodine-131labeled Lym-1 (an IgG2a monoclonal antibody). Of the patients, 10 had objective evidence of complete or partial remission. Toxicity was modest. Senter [38] discussed the antitumor monoclonal antibodies L6, 1F5, and P1-17 covalently linked to alkaline phosphatase. These conjugates bind to the surface of antigen-positive tumor cells and have the capability of converting the phosphorylated derivatives of etopside, mitamycin, and ad amycin, which were relatively noncytotoxic into drugs with high cytotoxic activity. Α strong antitumor response was observed in tumor-bearing mice that were treated with L6-AP followed by prodrug treatment 24-48 h later. This response was superior to that of the drugs or prodrugs given alone. Spitler [39] discussed the utilization of monoclonal antimelanoma antibodies conjugated with anti-T cell antibodies demonstrating that satu-
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ration of the tumor cells by antibody could be achieved following in vivo administration in patients. No clinical responses were observed in the limited number of patients studied. Stickney [40] described the complexities of organization of a monoclonal antibody clinical unit. This required several education and communication objectives such as training of nuclear medicine personnel in standard preparation and calibration techniques, patient communication before, during and after the diagnostic and/or therapeutic procedures, referring physicians in general community presentations and communications to promote the program. With a dedicated support staff, effective resources in terms of facilities and clinical programs can be carried out in a rapid expeditious manner. Wessels and Yorke [41 ] described the dosimetry of heterogenous uptake of radíolabeled antibody for radioimmunoglobulin therapy. Woo et al. [29] in their presentation described the basic foundations for labeling of the various monoclonal antibodies for clinical management, and, with the group at Hahnemann University, demonstrated the application of iodine-125-labeled anti-epidermal growth factor receptor-425 in the treatment of malignant tumors of the brain as well as the use of iodine125-labeled 17-1Α monoclonal antibodies in the treatment of various malignant tumor sites. Macey [42] presented a program using a nuclear medicine computer system providing dose calculations derived from in vivo pharmacokinetics originating from sequential quantitative gamma camera images using radiolabeled monoclonal antibodies. Dosimetric data can be used in treatment planning in lymphoma patients receiving iodine-131 Μ ΑΒ Lym 1. Steplewskí [43] reviewed more than 500 patients with advanced gastrointestinal tumors infused with murine-produced monoclonal antibodies (CO 17-1A, an IgG21 murine protein with restricted binding specificity for gastrointestinal tumors). Of 100 patients with cancers of the pancreas who were treated, 22 had evidence of biologic response with few side effects. All patients developed human antímouse antibody (ΗΑΜΑ) without significant toxicities. The ΗΑΜΑ response consisted of Igl and IgA during the first 7-14 days and IgG, especially IgG 1, from day 10. The antímouse response consisted of both anti-isotope and anti-idiotype responses. Antiídiotype (Ab2) response leads to the development of Αb3, which may be a part of the patient's own antitumor response, resulting in late tumor regression in monoclonal-antibody-treated patients.
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Delardo [44] presented potentially useful data for patients with metastatic breast cancer using copper-67 and yttrium-90 with tailored antibodies as treatment. Markoe et al. [45] at Hahnemann University reported two series of patients with gastrointestinal cancers treated with the monoclonal antibody CO 17-1A. In 53 patients treated with iodine-125-labeled CO 17-1A, there was 1 partial response and 8 patients achieving stability of disease, but no complete responses. There were no significant toxicities in this dose escalation study. In the other study, leukophoresis admixed with CO 17-1A was incubated and resdministered to the patient in multiple sessions. Three complete responses, one partial response and 1 patient with stable disease were noted. The complete responders remained free of disease 4-30 months after treatment. Brady et al. [46] at Hahnemann University have treated 15 patients with recurrent malignant glioma of the brain using intra-arterially administered iodine-125-labeled anti-epidermal growth factor receptor-425. One patient had a complete response, surgically documented, 2 partial responses (more than 50 % reduction in tumor volume), and in 2 patients disease was stable. The median survival from primary treatment (surgery/ radiation therapy) was 3 months and after antibody therapy greater than 5 months. Although the full potential of monoclonal antibody application has not yet been realized, technological advances and major work continues with greater intensity at a number of academic and industrial research institutions. Continuous production of monoclonal antibodies will yield a variety of highly specific antibodies and novel approaches for improving target specificity and chemical modifications resulting in greater knowledge of tumor immunogenicity. However, problematic areas and antibody modifications still need further work and clarification. As new diagnostic and therapeutic approaches continue to develop, monoclonal antibodies will still play a major role as targeted carriers providing that adequate funding from industry and government can be readily obtained. More critical clinical evaluations are needed and government streamlining and support can facilitate this process. Presently, the future of monoclonal antibodies' use in diagnosis and therapy appears to have more realistic goals. At best monoclonal antibodies can still be considered the mythical magic bullet; at worst, much work on their development for diagnostic therapeutic use still remains to be done.
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1 Kohler G, Milstein G: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495-497. 2 Ballou Β, Levin G, Hakala TR, et al: Tumor location detected with radioactively labeled monoclonal antibody and external scintigraphy. Science 1979;206:844847. 3 Beaumier PL, Krohn KA, Carrasquillo JA, et al: Melanoma localization in nude mice with monoclonal Fab against p97. J Nucl Med 1985;26:1172-1179. 4 Chatal JF, Saccavini JC, Fumoleau P, et al: Immunoscintigraphy of colon carcinoma. J Nucl Med 1984;25:307-314. 5 Halpern SE, Stern PH, Hagan PL, et al: Radiolabeling of monoclonal antitumor antibodies comparison of 1-125 and In-111 CEA with Ga-67 in a nude mousehuman colon tumor model. Clin Nucl Med 1981;6:453. 6 Larson SΜ, Brown JP, Wright PW, et al: Imaging of melanoma with I-131 labeled monoclonal antibodies. J ludl Med 1983;24:123-129. 7 Mach JP, Carrel S, Forni M, et al: Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma. N Engl J Med 1980; 303:5-10. 8 Mach JP, Chatal JF, Lumbroso JD, et al: Tumor localization in patients by radiolabeled monoclonal antibodies against colon carcinoma. Cancer Res 1983;43:55935600. 9 Meares CF, Goodwin DA: Linking radiometals to proteins with bifunctional chelating agents. J Protein Chem 1984;3:215-228. 10 Stern P, Hagan P, Halpern S, et al: The effect of the radiolabel on the kinetics of the monoclonal anti-CEA in a nude mouse-colon tumor model; in: Hybridomas in Cancer Diagnosis and Treatment. New York, Raven Press, 1982, pp 245-253. 11 Belitsky P, Ghose T, Aquino J, et al: Radionuclide imaging of metastases from renal cell carcinoma of 1311-labeled antitumor antibody. Radiology 1978;126:515-517. 12 Dykes PW, Hine KR, Bradwell AR, et al: Localization of tumor deposits by external scanning after injection of radiolabeled anticarcinoembryonic antigen. Br Med J 1980;280:220-222. 13 Hnatowich DJ, Griffin TW, Kosiuczyk C, et al: Pharmacokinetics of an indium-111 labeled monoclonal antibody in cancer patients. J ludl Med 1985;26:849-858. 14 Bernstein A, Hurwitz E, Marin R, et al: Higher antitumor efficacy of daunomycin when linked to dextran. In vivo and in vitro studies. J Nail Cancer Inst 1978;60: 379-383. 15 Rostock RA, Klein JL, Leichner PK, et al: Selective tumor localization in experimental hepatoma by radiolabeled antifemtin antibody. Int J Radiat mcii Biol Phys 1983;9:1345-1350. 16 Koprowskí H, Steplewski Z, Herlyn D: Study of antibodies against human melanoma produced by somatic cell hybrids. Proc Natl Acad Sci USA 1978;75:34053409. 17 Goldenberg DM, Deland F, Kim E, et al: Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N Engl J Med 1978;298:1384-1388. 18 Goldenberg DM: New developments in cancer imaging with radioactive antibodies. Abstr West Coast Cancer Symp, 1989.
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19 Order SΕ, Ettinger JL, Alderson P, et al: Phase I—II study of radiolabeled antibody integrated in the treatment of primary hepatic malignancies. Int J Radiat mcii Bio! Phys 19806:703-710. 20 Klein JL, Ling MN, Leichner PK, et al: A model system that predicts effective half-life for radiolabeled antibody therapy. Int J Radiat Oncol Biol Phys 1985;11: 1489-1494. 21 Leichner PK, Klein JL, Garrison JB, et al: Dosimetry of 131 I-labeled antiferritin in hepatoma. A model for radioimmunoglobulin dosimetry. Int J Radiat Oncol Bio! Phys 1981;7:323-333. 22 Leichner PK Klein JL, Siegelman SS, et al: Dosimetry of 131 í-labeled antiferritin in hepatoma. Specific activities in the tumor and liver. Cancer Treat Rep 1983;67: 647-658. 23 Order SΕ, Klein JL, Ettinger D, et al: Use of isotopic immunoglobulin in therapy. Cancer Res 1980;40:300 !-3007. 24 Keenan AM, Harbert JC, Larson SM: Monoclonal antibodies in nuclear medicine. J Nucl Med 1985;26:531-537. 25 Barendson GW: Mechanism of action of different ionizing radiations on the proliferative capacity of mammalian cells; in Cole A (ed): Theoretical and Experimental Biophysics, vol 1. New York, Dekker, 1967, pp 167-231. 26 Borlinghaus KP, Fitzpatrick DR, Heindel ND, et al: Radiosensitizer conjugation to CA 19-9 monoclonal antibody. Cancer Res, in press. 27 Kassks AI, Adelstein SJ, Haydock C, et al: Lethality of Auger electrons from the decay of bromine-77 in the DNA of mammalian cells. Radiat Res 1982;90:362373. 28 Urine PP, Lee LL, Raman S: Nuclear data sheets for A=77. Nucl Data Sheets 1973; 9:229-271. 29 Woo DA, DeRui L, Mattis J, et al: Auger electron damage induced by radioiodinated I-125 monoclonal antibodies. Abstr West Coast Cancer Foundation Symp, 1989. 30 McGann JK, Langmuir VK, Sutherland RI: Modulators of tumor responsiveness to radioimmunotherapy. Abstr West Coast Cancer Foundation Symp, 1989. 31 Dillehay LE, Williams JR: Radíobiology of dose-rate patterns achievable in radiummunoglobu!in therapy. Abstr West Coast Cancer Foundation Symp, 1989. 32 Abrams PG: Specific targeting of cancer with monoclonal antibodies. Diagnostic and therapeutic applications. Abstr West Coast Cancer Foundation Symp, 1989. 33 Leichner PK, Hawkins WG, Yang N-C, et al: Dosimetry and treatment planning in radioimmunotherapy. Abstr West Coast Cancer Foundation Symp, 1989. 34 Jain RK Tumor physiology and antibody delivery. Abstr West Coast Cancer Foundation Symposium, 1989. 35 Kemshead JT, Coakham HB, Lashford LS: Intrathecal administration of radiolabelled monoclonal antibodies for the treatment of malignant meningitis. Abstr West Coast Cancer Foundation Symp, 1989. 36 Press OW, Eary J, Badger C, et al: High dose radioimmunotherapy (RIT) of refractory non-Hodgkin's lymphomas (NHL) with autologous marrow rescue. Abstr West Coast Cancer Foundation Symp, 1989. 37 DeNardo GL: Chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Abstr West Coast Cancer Foundation Symp, 1989.
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Luther W. Brady, MD, Department of Radiation Oncology and Nuclear Medicine, Hahnemann University, Philadelphia, PA 19102 (USA)
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38 Senter PD: Anti-tumor effects of antibody-enzyme conjugates in combination with prodrugs. Abstr West Coast Cancer Foundation Symp, 1989. 39 Spitler LE: Monoclonal antibodies in the treatment of malignant melanomas. Abstr West Coast Cancer Foundation Symp, 1989. 40 Stickney DR: Organization of a monoclonal antibody (MAb) clinical unit. Abstr West Coast Cancer Foundation Symp, 1989. 41 Wessels BW, Yorke ED: Dosimetry of heterogeneous uptake of radiolabeled antibody for RIT. Abstr West Coast Cancer Foundation Symp, 1989. 42 Macey DJ: A treatment planning program for radioimmunotherapy. Abstr West Coast Cancer Foundation Symp, 1989. 43 Steplewskí Z: Patients immune response during treatment with mucine monoclonal antibodies. Abstr West Coast Cancer Foundation Symp, 1989. 44 DeNardo SJ: Today and tommorow: radiochemistry and radioimmunotherapy of breast cancer. Abstr West Coast Cancer Foundation Symp, 1989. 45 Markoe AM, Brady LW, Amendola BE, et al: The treatment of gastrintestinal cancer using monoclonal antibodies. Abstr West Coast Cancer Foundation Symp, 1989. 46 Brady LW, Markoe AM, Woo DV, et al: Treatment of glioblastomas with iodine-125 radiolabeled monoclonalantibody against epidermal growth factor receptor. Abstr West Coast Cancer Foundation Symp, 1989.
The Present and Future Role of Monoclonal Antibodies in the Management of Cancer Summary Luther W. Brady 1, Arnold M. Markoe, David V. Woo Department of Radiation Oncology and Nuclear Medicine, Hahnemann University, Philadelphia, Pa., USA
With the development of the hyb doma technique by Kohler and Milstein [ 1 ] in 1975, multiple areas of research have been pursued attracting a wide variety of disciplines. Realization of the full potential of labeled antibodies for increasing the selectivity of cancer cell identification and destruction requires continued persistent efforts by researchers in tumor cell biology, immunology, pharmacology, radiopharmaceutical and protein chemistry as well as in clinical medicine. Although there has been much work with monoclonal antibodies, presently there is no one monoclonal antibody that has entered routine clinical use in the treatment of any given cancer. The theoretical versus the practical applications of monoclonal antibodies have not always agreed with each other. For this reason, the practical advantages and limitations of monoclonal antibodies need to be further explored to clarify whether greater effort and resources are necessary for any given use of monoclonal antibodies in cancer treatment. Because radioisotopes offer certain advantages in labeling monoclonal antibodies, many diagnostic and therapeutic studies have been performed with a variety of radiolabels and monoclonal antibodies. Perhaps the Hylda Cohn/American Cancer Society Professor 0f Clinical Oncology and ChairDownloaded by: Université de Paris 193.51.85.197 - 2/5/2020 11:16:26 PM
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easiest approach to evaluating the biodistribution and kinetics of monoclonal antibodies in vivo is through the use of the nuclear gamma camera [2-10]. In humans, this method has yielded important information concerning the specificity of the radiolabeled antibody for the target tumor compared to other tissues [4, 5, 8, 11-15]. However, in many of these studies, just what is considered to be specific uptake and what is nonspecific is still not well defined. From the standpoint of diagnostic application, the basic major indications for tumor imaging are directed toward detection of the presence of the tumor, the localization of the sites of the disease and in the follow-up of the patient's course in terms of assessment of the effects of the administered therapy, prediction of early treatment failure as well as new sites of disease and to reinforce a sense of patient well-being in those individuals where there is no clinical evidence of recurrence. Using monoclonal antibodies developed by Koprowski et al. [ 16] to react specifically with colorectal tumor antigens and labeled with iodine131, Mach et al. [8] reported a cancer detection rate of 41 % using conventional images which slightly improve to 51 % using single photon emission, computed tomography (SPECT). Because background radioactivity was relatively high and partially obscured the image of the tumor particularly with iodine-131 emissions, digital enhancement techniques have slightly improved the detection rate of the lesions. This procedure has been fairly common to deal with the low target to nontarget uptake as observed with radiolabeled antibodies [7, 17]. In addition, the detection rate could be further improved as cited by Mach et al. [8] to 61 % by using a modified form of the monoclonal antibody, namely an F(ab')2 fragment. Furthermore, if it were possible to note precisely that the target tumor antigen existed in preselected patients, the detection rate might significantly improve as Larson et al. [6] reported with an 88 % detection rate for antimelanoma IgG specific for the P-97 antigen. In contrast to these studies, studies by Goldenberg et al. [ 17] reported a 91 % detection rate for polyclonal anti-CEA antibodies in patients with colorectal cancer. In other studies, Chatal et al. [4] evaluated two iodine-131-labeled monoclonal antibodies called 17-1A and 19-9 F(ab')2 fragments by scintigraphy of patients with colon cancer. They observed for 17-1 A that 59% of the known colorectal cancer sites were detected while for 19-9, 66% were detected. Both are monoclonal antibodies specific for colorectal tumors; however, their target antigens are different. Also, the 17-1A anti-
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gen is not shed by the tumor while the 19-9 antigen is shed into the bloodstream. When combinations of these two antibodies are co-administered, the detection rate was increased to 77 % of patients with colon cancer. More recently, improved chemical modification of tumor-specific monoclonal antibodies have allowed radionuclide metal atoms to be stably attached resulting in better image detection and less overall radiation dose. In studies by Hnatowich et al. [13], a total of 14 patients were imaged with indium-111-labeled 19-9 F(ab')2 and whole body clearance kinetics were determined. Nine of these patients had identifiable sites of metastatic disease from colorectal cancers (8 patients), pancreatic (2 patients), ovarian (3 patients), and small cell lung cancer (1 patient). The detection rate in this study was 67 % of the patients who were externally imaged 48-72 h after injection, results similar to those obtained by Chatal et al. [4]. The successful detection of malignant melanoma in patients using an indium-111-labeled 96.5 monoclonal antibody reported by Halpern et al. [5] indicated detection rates of 61 % without digital subtraction techniques. In addition, prolonging serum half-time by increasing the mass dose of the antibody appeared to improve tumor detection. The detection rates observed in the various studies highlight some of the problems in the application of monoclonal antibodies as diagnostic imaging agents. The overall accuracy appears to average somewhere between 40 and 70 % depending upon the specific monoclonal antibody, the radiolabel, and the type of imaging. The criteria used for selection of patients should be more precisely identified, the known cross-reactívítíes of the specific monoclonal antibodies used for diagnostic purposes should be known, whether the patient has specific antigen present should be identified, and the appropriate imaging technique defined. These are only a few of the questions that need to be addressed before monoclonal antibodies can be used as diagnostic imaging agents. Goldenberg [ 18] in his presentation identified the various tumor serum markers that might be used for diagnostic purposes. With the development of a broad, new array of tumor-associated antibodies through hybridoma technology, new innovative areas for tumor targeting have been open for exploration. Even though the initial studies were done with iodine-131, better imaging agents are now available with radionuclides of lower energy such as iodine-123, indium-111, and technetium-99m. With
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the significant progress made in the development of technetium-99mlabeling methods and the use of short-lived isotopes such as iodine-123 and technetium-99 rapid targeting agents such as bivalent or monovalent antibody fragments have been pursued. Using both F(ab')2 and F(ab') fragments of a CEA monoclonal antibody accurate imaging of CEA-producing tumors has been achieved using both iodine-123 and technetium99 with both planar and SPECT imaging. With this technology known cancer sites can be identified with an accuracy of at least 85%, including the demonstration of new lesions. Goldenberg [18] has pointed out that technetium-99 conjugated by new direct methods appears to be the preferred agent allowing for rapid clinical application. The major advantages offered by the ability to generate gram quantities of very pure and monospecific antibodies to a particular tumor-associated antigen as well as avoidance of cross-reactivity, dealing with the variability and antigen expression and the potential problem of circulating serum antigens, clinical work with radiolabeled antitumor antibodies has made remarkable progress in the last several years. As tumor imaging techniques are refined using radionuclides, the oncologist will push for earlier detection of even smaller tumor cell masses. The advent of new technology will allow the achievement of scintographic techniques to meet these morphological constraints of cancer medicine. Conceivably, monoclonal antibodies, if measured in quantitative terms proportional to a tumor mass, may reflect their degree of cellular differentiation or antiplasticity. Thus, the advent of diagnostic application of labeled monoclonal antibodies offers an exciting method to examine the behavior of tumors as well as to record their presence. Ehrlich and co-workers recognized the therapeutic potential of antitumor antibodies as carriers of toxic substances that could be selectively targeted to tumor cells. Although the concept of specific antibodies reacting with specific antigens on the surface of the tumor cell but not normal cells is easily appreciated, its realization is not without problems. Antibodies to tumor-associated antigens have proved to be valuable research tools and have moved rapidly from the laboratory into the clinic. The application of antibodies as a major therapeutic modality is still in the early developmental stages. There is much hope for monoclonal antibodies to be carriers of cytotoxic drugs and radioisotopes. Yet, the same problems associated with imaging such as tumor uptake and specificity still exist with approaches to radioimmunotherapy. In addition, the radiation dose to normal tissues
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and tumor becomes a major factor in evaluating the efficacy of treatment in cancer patients. A variety of radioisotopes are suitable for delivering a significant radiobiological dose to kill cells. Radioactive iodine-131 which is used for diagnostic imaging can also be used for therapy because of its numerous beta emissions. Its advantages include easy radiolabeling, high radiation dose per unit of activity, and the ability of most monoclonal antibodies to still bind to their target antigen after incorporation of the label. Numerous clinical studies reported by Order and co-workers [19-23] using iodine-131 to labeled tumor-associated polyclonal antibodies (antifemtin) resulted in fairly good success in the treatment of primary liver cancers. Monoclonal antibodies (antiferritin) have been developed and are presently being evaluated by the same group. The method of attachment of the radioiodine is generally applicable to all proteins containing accessible tyrosine residues and has seen major use as the first isotope to label monoclonal antibodies. However, there are major problems associated with the use of iodine-131 as a potential radionuclide for treatment. Although radiotagging iodine-131 to antibodies provides a reasonably stable attached label without significant loss of antibody activity, in vivo administration of iodinated antibodies into animals or humans has resulted in significant loss of radiolabel through dehalogenation. As much as 75 % of the radioactivity can be found in the urine at 24 h after injection [5, 24]. Moreover, the free iodide ion may be sequestered by the thyroid and excreted by the kidney resulting in an appreciable radiation dose to nontarget organs. It now appears that dehalogenation of the radioactive iodine occurs primarily in normal tissues as well as in the tumor. However, dehalogenation is not a problem for circulating antibodies since both indium-111- and iodine-131-labeled monoclonal antibodies have been found to show similar blood clearance curves. With better coupling chemistry, novel radiometals which have nuclear decay properties amenable for radiotherapy are being evaluated. Yttrium-90, copper-67, rhenium-188, phosphorus-32, bismuth-212, and astatine-211 have moderate to high LET energy particulate emissions (beta or alpha) which theoretically have the potential for the in vivo radiotherapy of tumors. These radionuclides are still undergoing investigation in animals since there are recurring problems with their coupling chemistry and many are radiotoxic. Other potential radionuclides which may be useful for radiotherapy are low-energy Auger electron emitters such as iodine-125 or bromine-77 [25-27]. Such Auger electron emitters have been studied following their
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incorporation into DNA or as its bromine-77 analog. The uptake of these thymidine analogs into mammalian cells in culture results in efficient cell killing as densely ionizing radiations of high LET such as alpha particles. If monoclonal antibodies are internalized (modulation) once they bind to their cell-surface antigen as Woo and Li have demonstrated, the radiobiological effectiveness of Auger electron emitters may provide better irradiation of the cell since the volume with less radiation to nontumor cells and subsequently less whole body exposure. Theoretical estimates indicate that the localized energy deposition of Auger electrons is about 335 eV and occurs within a 10-Ångström sphere of the decay site [28]. One of the major obstacles to radioimmunotherapy approaches is that the absolute tumor uptake as observed from imaging studies is extremely low. Therefore, rational attempts to increase the vascular permeability as well as to increase blood flow into the tumor may allow for greater uptake of the monoclonal antibody. In addition, to increase the likelihood of direct antigen-antibody interaction at the tumor site, it may be necessary to administer larger amounts of antibody to increase its circulating concentration in the tumor for greater uptake. The chemistry of attachment of the radioisotope to the monoclonal antibody is now in a high state of accomplishment as put forth by Woo et al. [29]. Using various bifunctional chelates, the attachment has aided considerably in the understanding of the bidistribution of the antibodies. Using chelate molecules such as DTPA or EDTA has considerably expanded the work relative to these antibodies. Borlinghaus et al. [26] have indicated a quantitative relationship between loading factors (the number of molecules of a drug coupled to a monoclonal antibody) and antigenicity. McGann et al. [30] defined the limitations of radioimmunotherapy related to targeting efl'iciency, radionuclide availability, and normal tissue toxicity. These limitations restrict the range of radiation dosages from 5 rad/h to a maximum of 15 rad/h. This continuous low dose rate (CLDR) subjects radioimmunotherapy efficacy to the differential radioresponsiveness produced by opportunities for repair of cellular damage, alterations in the proliferative status of cells, and reoxygenation of cells at a distance from the vascular network. Dillehay and Williams [31] identified the response of human tumor cells in vitro irradiated with dose patterns that simulate those observed for radiolabeled immunoglobulin therapy in vivo. They concluded that the inhibition of cell proliferation is of major importance in considering the
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effects of decreasing dose-rate patterns and cell sensitivity to growth inhibition and the criticality of this important parameter in the response of tumor cell populations. Within this context, normal tissue toxicities must be considered. As with other cancer therapies, radiolabeled immunoglobulin therapy is limited by normal tissue tolerance, hematopoietic toxicity. Their conclusion pointed out that improved radiolabeled immunoglobulin therapy might be improved through the combined use with chemotherapy and/or external beam radiation therapy. Abrams [32] discussed the potential for imaging of a given antibody limited to gamma-emitting radionuclides such as technetium-99m and iodine-123. This group has demonstrated excellent targeting using technetium-99m stably linked to monoclonal antibody fragments that recognize melanoma, lung cancer and colon cancer. Simultaneous studies with rhenium-186 (a beta emitter) and technetium-99m have shown an identical targeting and metabolic fate. Dose escalation studies are underway. Other therapeutic applications were discussed using antibodies labeled with drugs and toxins. The targeting concept allows for more acceptable toxicity. This work has been with trichothicenes, a class of mycotoxins. Major tumor regression has been achieved. Human trials are underway with antibodies labeled with pseudomonas exotoxin. Jain [34] pointed out that the effectiveness of cancer treatment using monoclonal antibodies or other macromolecules bound to radionuclides has been limited by their ability to reach the target in vivo in adequate quantities. Heterogeneity of tumor-associated antigen expression alone has failed to explain the nonuniform uptake of antibodies. The physiologic barriers responsible for the poor localization have been identified to be heterogeneous blood supply, elevated interstitial pressure and large transport distances in the interstitium. From Jaín's [34] presentation, fulfillment of the expectations of this type of treatment demand that strategies be developed to overcome the identified physiologic barriers. Leichner et al. [33] discussed the dosimetry and treatment planning in radioimmunotherapy. They pointed out that quantitative image analysis and radiation-absorbed dose calculations must be performed for every patient undergoing radiolabeled immunoglobulin therapy. The dosimetry must be as accurate as possible and must be provided in a timely fashion for the development of treatment strategies as well as the assessment of tumor response to therapy. This improved dosimetry is based upon image analysis, isodose curves that can be superimposed on patients' computed
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tomography scans and IRI scans, as well as the related anatomical structures in these scans. These applications will lead to improved dosimetry providing important information about tumor response to radioimmunoglobulin therapy. Kemshead [35] presented experiences using monoclonal antibodies for targeting with radioisotopes. They suggest that labeling with radioisotopes is the feasible proposition and other work presented at this meeting has confirmed that. His efforts have been directed toward using antibodies as targeting agents concentrating on the central nervous system compartment. Patients with malignant meningitis arising from a variety of tumors have been treated with radiolabeled antibodies. Responses in excess of 12 months have been recorded particularly in patients with radiosensitive tumors. Press et al. [36] reported on high-dose radioimmunotherapy of refractory non-Hodgkin's lymphomas with autologous marrow rescue. The biodist bution toxicity and efficacy of iodine-131-labeled anti-CD37 monoclonal antibody ΜΒ-1 and anti-CD20 monoclonal antibody IF5 have been assessed. Ten patients with advanced low and intermediate grade nonHodgkin's lymphomas failing conventional therapy were treated. No significant toxicity was noted and all 4 evaluable patients achieved complete tumor remissions lasting from 4 to 7 months. Press et al. [36] concluded that the tolerable toxicity and encouraging efficacy warranted further dose escalation in this phase I trial. DeNardo [37] reported 18 patients with stage IV B-cell malignancies (lymphoma and leukemia) treated with fractionated doses of iodine-131labeled Lym-1 (an IgG2a monoclonal antibody). Of the patients, 10 had objective evidence of complete or partial remission. Toxicity was modest. Senter [38] discussed the antitumor monoclonal antibodies L6, 1F5, and P1-17 covalently linked to alkaline phosphatase. These conjugates bind to the surface of antigen-positive tumor cells and have the capability of converting the phosphorylated derivatives of etopside, mitamycin, and ad amycin, which were relatively noncytotoxic into drugs with high cytotoxic activity. Α strong antitumor response was observed in tumor-bearing mice that were treated with L6-AP followed by prodrug treatment 24-48 h later. This response was superior to that of the drugs or prodrugs given alone. Spitler [39] discussed the utilization of monoclonal antimelanoma antibodies conjugated with anti-T cell antibodies demonstrating that satu-
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ration of the tumor cells by antibody could be achieved following in vivo administration in patients. No clinical responses were observed in the limited number of patients studied. Stickney [40] described the complexities of organization of a monoclonal antibody clinical unit. This required several education and communication objectives such as training of nuclear medicine personnel in standard preparation and calibration techniques, patient communication before, during and after the diagnostic and/or therapeutic procedures, referring physicians in general community presentations and communications to promote the program. With a dedicated support staff, effective resources in terms of facilities and clinical programs can be carried out in a rapid expeditious manner. Wessels and Yorke [41 ] described the dosimetry of heterogenous uptake of radíolabeled antibody for radioimmunoglobulin therapy. Woo et al. [29] in their presentation described the basic foundations for labeling of the various monoclonal antibodies for clinical management, and, with the group at Hahnemann University, demonstrated the application of iodine-125-labeled anti-epidermal growth factor receptor-425 in the treatment of malignant tumors of the brain as well as the use of iodine125-labeled 17-1Α monoclonal antibodies in the treatment of various malignant tumor sites. Macey [42] presented a program using a nuclear medicine computer system providing dose calculations derived from in vivo pharmacokinetics originating from sequential quantitative gamma camera images using radiolabeled monoclonal antibodies. Dosimetric data can be used in treatment planning in lymphoma patients receiving iodine-131 Μ ΑΒ Lym 1. Steplewskí [43] reviewed more than 500 patients with advanced gastrointestinal tumors infused with murine-produced monoclonal antibodies (CO 17-1A, an IgG21 murine protein with restricted binding specificity for gastrointestinal tumors). Of 100 patients with cancers of the pancreas who were treated, 22 had evidence of biologic response with few side effects. All patients developed human antímouse antibody (ΗΑΜΑ) without significant toxicities. The ΗΑΜΑ response consisted of Igl and IgA during the first 7-14 days and IgG, especially IgG 1, from day 10. The antímouse response consisted of both anti-isotope and anti-idiotype responses. Antiídiotype (Ab2) response leads to the development of Αb3, which may be a part of the patient's own antitumor response, resulting in late tumor regression in monoclonal-antibody-treated patients.
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Delardo [44] presented potentially useful data for patients with metastatic breast cancer using copper-67 and yttrium-90 with tailored antibodies as treatment. Markoe et al. [45] at Hahnemann University reported two series of patients with gastrointestinal cancers treated with the monoclonal antibody CO 17-1A. In 53 patients treated with iodine-125-labeled CO 17-1A, there was 1 partial response and 8 patients achieving stability of disease, but no complete responses. There were no significant toxicities in this dose escalation study. In the other study, leukophoresis admixed with CO 17-1A was incubated and resdministered to the patient in multiple sessions. Three complete responses, one partial response and 1 patient with stable disease were noted. The complete responders remained free of disease 4-30 months after treatment. Brady et al. [46] at Hahnemann University have treated 15 patients with recurrent malignant glioma of the brain using intra-arterially administered iodine-125-labeled anti-epidermal growth factor receptor-425. One patient had a complete response, surgically documented, 2 partial responses (more than 50 % reduction in tumor volume), and in 2 patients disease was stable. The median survival from primary treatment (surgery/ radiation therapy) was 3 months and after antibody therapy greater than 5 months. Although the full potential of monoclonal antibody application has not yet been realized, technological advances and major work continues with greater intensity at a number of academic and industrial research institutions. Continuous production of monoclonal antibodies will yield a variety of highly specific antibodies and novel approaches for improving target specificity and chemical modifications resulting in greater knowledge of tumor immunogenicity. However, problematic areas and antibody modifications still need further work and clarification. As new diagnostic and therapeutic approaches continue to develop, monoclonal antibodies will still play a major role as targeted carriers providing that adequate funding from industry and government can be readily obtained. More critical clinical evaluations are needed and government streamlining and support can facilitate this process. Presently, the future of monoclonal antibodies' use in diagnosis and therapy appears to have more realistic goals. At best monoclonal antibodies can still be considered the mythical magic bullet; at worst, much work on their development for diagnostic therapeutic use still remains to be done.
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1 Kohler G, Milstein G: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495-497. 2 Ballou Β, Levin G, Hakala TR, et al: Tumor location detected with radioactively labeled monoclonal antibody and external scintigraphy. Science 1979;206:844847. 3 Beaumier PL, Krohn KA, Carrasquillo JA, et al: Melanoma localization in nude mice with monoclonal Fab against p97. J Nucl Med 1985;26:1172-1179. 4 Chatal JF, Saccavini JC, Fumoleau P, et al: Immunoscintigraphy of colon carcinoma. J Nucl Med 1984;25:307-314. 5 Halpern SE, Stern PH, Hagan PL, et al: Radiolabeling of monoclonal antitumor antibodies comparison of 1-125 and In-111 CEA with Ga-67 in a nude mousehuman colon tumor model. Clin Nucl Med 1981;6:453. 6 Larson SΜ, Brown JP, Wright PW, et al: Imaging of melanoma with I-131 labeled monoclonal antibodies. J ludl Med 1983;24:123-129. 7 Mach JP, Carrel S, Forni M, et al: Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma. N Engl J Med 1980; 303:5-10. 8 Mach JP, Chatal JF, Lumbroso JD, et al: Tumor localization in patients by radiolabeled monoclonal antibodies against colon carcinoma. Cancer Res 1983;43:55935600. 9 Meares CF, Goodwin DA: Linking radiometals to proteins with bifunctional chelating agents. J Protein Chem 1984;3:215-228. 10 Stern P, Hagan P, Halpern S, et al: The effect of the radiolabel on the kinetics of the monoclonal anti-CEA in a nude mouse-colon tumor model; in: Hybridomas in Cancer Diagnosis and Treatment. New York, Raven Press, 1982, pp 245-253. 11 Belitsky P, Ghose T, Aquino J, et al: Radionuclide imaging of metastases from renal cell carcinoma of 1311-labeled antitumor antibody. Radiology 1978;126:515-517. 12 Dykes PW, Hine KR, Bradwell AR, et al: Localization of tumor deposits by external scanning after injection of radiolabeled anticarcinoembryonic antigen. Br Med J 1980;280:220-222. 13 Hnatowich DJ, Griffin TW, Kosiuczyk C, et al: Pharmacokinetics of an indium-111 labeled monoclonal antibody in cancer patients. J ludl Med 1985;26:849-858. 14 Bernstein A, Hurwitz E, Marin R, et al: Higher antitumor efficacy of daunomycin when linked to dextran. In vivo and in vitro studies. J Nail Cancer Inst 1978;60: 379-383. 15 Rostock RA, Klein JL, Leichner PK, et al: Selective tumor localization in experimental hepatoma by radiolabeled antifemtin antibody. Int J Radiat mcii Biol Phys 1983;9:1345-1350. 16 Koprowskí H, Steplewski Z, Herlyn D: Study of antibodies against human melanoma produced by somatic cell hybrids. Proc Natl Acad Sci USA 1978;75:34053409. 17 Goldenberg DM, Deland F, Kim E, et al: Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N Engl J Med 1978;298:1384-1388. 18 Goldenberg DM: New developments in cancer imaging with radioactive antibodies. Abstr West Coast Cancer Symp, 1989.
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Luther W. Brady, MD, Department of Radiation Oncology and Nuclear Medicine, Hahnemann University, Philadelphia, PA 19102 (USA)
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38 Senter PD: Anti-tumor effects of antibody-enzyme conjugates in combination with prodrugs. Abstr West Coast Cancer Foundation Symp, 1989. 39 Spitler LE: Monoclonal antibodies in the treatment of malignant melanomas. Abstr West Coast Cancer Foundation Symp, 1989. 40 Stickney DR: Organization of a monoclonal antibody (MAb) clinical unit. Abstr West Coast Cancer Foundation Symp, 1989. 41 Wessels BW, Yorke ED: Dosimetry of heterogeneous uptake of radiolabeled antibody for RIT. Abstr West Coast Cancer Foundation Symp, 1989. 42 Macey DJ: A treatment planning program for radioimmunotherapy. Abstr West Coast Cancer Foundation Symp, 1989. 43 Steplewskí Z: Patients immune response during treatment with mucine monoclonal antibodies. Abstr West Coast Cancer Foundation Symp, 1989. 44 DeNardo SJ: Today and tommorow: radiochemistry and radioimmunotherapy of breast cancer. Abstr West Coast Cancer Foundation Symp, 1989. 45 Markoe AM, Brady LW, Amendola BE, et al: The treatment of gastrintestinal cancer using monoclonal antibodies. Abstr West Coast Cancer Foundation Symp, 1989. 46 Brady LW, Markoe AM, Woo DV, et al: Treatment of glioblastomas with iodine-125 radiolabeled monoclonalantibody against epidermal growth factor receptor. Abstr West Coast Cancer Foundation Symp, 1989.
