Initial Clinical Evaluation of Iodine -125-Labeled Chimeric 17-lA for Metastatic Colon Cancer

Ruby F. Meredith, M.B. Khazaeli, Walter E. Plott, Sharon A. Spencer, Richard H. Wheeler, Luther W. Brady, David V. Woo and Albert F. LoBuglio

Departments of Oncolo,@j@and Medicine, University ofAlabama, Birmingham, Alabama; Departments of Radiation and Oncology, Hahnemann University, Philadelphia, Pennsylvania; Centocor Inc., Malvem, Pennsylvania

tumor cells while sparing the bone marrow is the use of low The internalizingproperties of murineantibody 17-lA in human energy Auger emitters such as 125!conjugated to colon cancer cells make it attractive as a carnerfor radionuclides antibodies that internalize into the target cells. Early ap with short range emissions such as 1251.Munne 17-lA lgG2a proaches to this radionuclide have included ‘@I antibody, which reacts against human gastrointestinalcancers, bound to DNA precursors, intercalating compounds, as has been chimerized by joining its variable region with human well as translocated agents such as hormones and antibod lgGl k constant region.A pilot clinicaltrialof increasingdoses of ies (1—9).Our study utilizes an antibody, 17-lA (10—12), 125I-chimeric17-lA in patientswith metastaticcolorectalcancer hasbeenconducted.Methods Patientsweretreatedingroups which has characteristics of internalization, translocation to of 2—4;2 patients at HahnemannUniversityand 26 at the Uni the nucleus (Rakowicz-Szulcynska EM, personal communi versity of Alabama at Birmingham.Groups 1-5 recen@edsingle cation, 1994) and selective chromosomal toxicity when la administrations with 1251doses of 20, 40, 60, 80 or 100 mCi. beled with ‘@-@I(13). Subsequent groups receivedtherapeutic doses of 150, 200 or Efficient cell killing has been noted with ‘@Inucleotide 250 mCi,withthedosesubdrvkiedintoinfusingof50 or100mCi incorporation into DNA as well as with intranuclean local at 4-day intervals.M treatmentSwere dekveredinan outpatient ization of other ‘MI-labeledcompounds. Less toxicity has setting using radiation precautions. Labelingat 10 mCVmgan been noted with cytoplasmic localization and negligible tibody was performed on the day of treatment Results Phar toxicity with 125!at the cell membrane as would be the case macokinetics of circulating antibody was studied for initial pa with nontanget cells such as the bone marrow (4,6,8,14). tients, showing aT1,@of 17—27hr and f3T@ of 100—190hr. Whole-body T1,,@of radioactivitywas determined by measunng These results derive from the small gamma component of urinaryexcretion or gamma emissions.Treatmentwas well tol ‘@Iemissions (7%, 35 keV) and from the range of the erated without significant acute or late side effects. No signifi Auger and (0.06—17@tm)be cant bone marrow suppression or other dose-limiting toxicities ing too small to effectively reach the chromatin without were noted over this dose range. No objective responseswere intranuclear translocation (4,15,16). noted. Conclusion: These results show that high-dose outpa With 125!internal conversion for 93% of decays, a shower tient radioimmunotherapywith an 125lI@@J internalizinganti of as many as 21 electrons with low energies and short body can be achievedwithout significantpatienttoxicity or ranges results in a high density of ionizations near the site radiation hazard. of decay (17). This brings about 3—4DNA strand breaks Key Words colon cancer iodine-125-chimeric17-lA per decay (3). Although the ‘@Imust be near the DNA J Nuci Med 1995;362229—2233 helix, its range is sufficient to result in both ipsilateral and contnalatenal DNA strand breaks, thus resulting in frag mentation of the DNA structure. The relative biologic ef fectiveness of 125Jis 7—8compared to x-nays (17) due to variety of radionuclides have been used for radioim irreversible DNA damage and the typical initial shoulder munotherapy. The dose-limiting toxicity for most nadionu following x- of mammalian cells in the low dose clides, used with antibody conjugates, is bone marrow sup range is eliminated (18). The highly efficient killing with pression. Hematopoietic toxicity results from a substantial intranuclean localization but sparing of nontarget cells due to the medium-long range beta and makes ‘@I-conjugatesvery attractive for cancer therapy. gamma emissions characteristic of most radionuclides cur Although previous clinical experience using ‘@I-labeled rently used. An alternate approach to killing individual antibodies in cancer patients has been reported (19,20), this study represents the first systematically dose escalating study. ReceivedMay 25, 1994;revisionaccepted Nov. 11, 1994. In our current clinical trial, the chimenicversion of 17-lA Forcorrespondenceorrepdntscontact RubyF.Meredith,MD,PhD,Unh,ersity of i@Jabamaat Birmingham, LB WaII@e Tumor lnstitute-117, 1824 Sbdti Ave. antibody was used. The chimenic antibody, designated as South, Birmingham, AL35294-3300. c-li-lA, contains the variable region of the munne 17-lA

lodine-125-chimenc17-lA PhaseI •Meredithat al. 2229 joined to constant regions comprised of human IgG1 heavy human-anti-chimeric antibody (HACA) response. HACA assays chain and kappa -chain sequences (21 ). Previous stud were performed as previously described (23). ies had confirmed that ‘251-c-17-1Abehaved in a manner Patients were monitored at 6-wk intervals for evidence of re identical to that of 125I-munine 17-lA in its extent of inter sponse to therapy. Tumor measurements were recorded in centi nalization, cytotoxicity and growth inhibition of human co meters as the longest perpendicular diameters. Complete remis sion was defined as disappearance of all clinical evidence and Ion cancer xenografts in nude mice and the two antibody symptoms of active tumor for a minimum of 4 wk. Partial remis forms were equally effective in producing antibody depen sion was defined as 50% decrease in the sum of the products of dent cell-mediated cytotoxicity (22). It was anticipated that perpendicular diameters of all objectively measurable lesions and the longer half-life and decreased immunogenicity of the significant improvement in all evaluable (nonmeasurable) tumor chimenic antibody (23) would enhance the therapeutic po sites. No simultaneous increase in the size of any lesion or the tential of ‘@I-c-17-1Anadioimmunothenapy. appearance of new lesions could occur and the remission had to be maintained for 4 wk. Stable disease was considered a response less than partial remission and not having evidence of progression MATERIALS AND METhODS for a minimumof 6 wk. There could be no appearance of new Patient Selection and Trial Design lesions and no worsening of symptoms. Progression was defined as Study patients had pathologically proven colorectal cancer that an increase of 50% in the size of any measured lesions or the was metastatic but not to the central nervous system. The patients appearance of new lesion(s). were not judged to be curable with surgical resection. Patients had Antibody Preparation a performance status of 80 on the Karnofsky scale and had no G1Kc-17-1Awassuppliedby Centocor,Inc.,as a sterile,non history of other prior or concurrent malignancy. At the time of therapy, all patients had a WBC 2500/mm3,platelet count pyrogenic solution containing 2 mg of monoclonal IgGi per ml in a solution which contains 0.03 M sodium phosphate, 0.15 M so iOO,000/mm3,BUN <30 mg%, creatinine <2 mg%, bilirubin <4.5 mg% and normal calcium, glucose and electrolytes.No dium chloride, pH 7.0. Each vial contained 2 mg of antibody. The producthad been screenedfor the presenceof muninevirusesand known prior exposure to murine immunoglobulin was permitted and no patient receivedconcurrentmedicationsknownto affect had passed release tests including the general animal safety test, rabbit pyrogen test and fmal product sterility tests, all of which immune function. No patients were pregnant and none had re conform to 21 CFR requirements. ceived chemotherapy within 6 wk of treatment or radiation in 4 wk Radiolabeling was carried out aseptically using the lodogen preceding treatment. Pretherapy, all patients had a physical exam technique, lodogen —(1,3,4,6-tetrachloro-3a,6a-di-phenylglycolu ination, EKG, urinalysis, chest x-ray, laboratory studies, including nil)fromPierce(Rockford,IL).Specificactivitywas10mCi/mg,as a thyroid profile and radiographic studies of disease sites. All previously described (24). Iodine-1251, NaI solution was obtained patients gave informed consent. Patients received Lugol's solution from Dupont NEN (Billerica, MA) (100 mCilml). The radiola 1 day prior, on the day of treatment and 1 day post-therapy. The beled antibody was separated from the unbound iodine by gel study was designed as a dose-escalating trial with at least 2 wk of filtration chromatography. The radiolabeled product passed qual observation for adverse experience before treatment of patients at ity control tests, including and Limulus amebocyte the next dose level. Patients were treated in groups of 2—4with assay before patient administration. single-dose levels of 20, 40, 60, 80 and 100mCi. Subsequent groups received split-dose therapy of 150 mCi (100 mCi, Day 1; 50 mCi, Day4), 200mCi (100mCi,Day 1; 100mCi,Day4) and 250mCi RESULTS (100 mCi, Day 1; 100 mCi, Day 4; 50 mCi, Day 8). All treatments were carried out without need for hospi Permission was obtained through the Division of Radiation talization. Patients and their social contacts were agreeable Safety and the State of Alabama Radiation Regulatory officials to to home radiation precautions. Twenty patients received a administer as much as 100 mCi on an outpatient basis using single infusion and eight patients were treated with a split radiation precautions and with exposure of <5 mR/hr at 1 meter dose schedule as shown in Table 1. from the patient. Patients and their families were counseled and given written guidelines for home radiation precautions. No severe hematologic on other toxicity was recorded The antibody preparation was aseptically injected as an intra during the 6-wk evaluation period after therapy. Only three venous bolus over 3 mm by a freely running intravenous set-up. patients had platelet counts that nadired < 100,000/mm3. After infusion, vital signs were monitored immediately, at 30 mm, Two patients who received 60 mCi ‘@I-c-17-1Ahad platelet 60 mm and 24 hr. count nadins of 94,000 and 66,000/mm3 while one patient Group 1 patients had blood samples obtained 1, 2, 4, 7, 10, 14 who received 150 mCi ‘@I-c-17-1Ahad a platelet nadir of and 30 days postinjection, which were assayed for ‘@Iactivity and 97,000/mm3 during the 6-wk follow-up. Baseline pretreat antigen binding capability using a whole cell assay. Group 1 pa ment platelet counts for the patients were 153,000, 174,000 tients also had their total urine output collected daily for 72 hr and 121,000/mm3,respectively, although it is notable that postinjection. The urine volumes were measured and aliquots were the first of these patients had a platelet count of 97,000 2 wk counted in a scintillation counter. The counts obtained were con before treatment. Two patients at the 200 mCi ‘@Ilevel had verted to percent injected dose to determine the whole-body clear ance of radioactivity. Determination of whole-body clearance of a white blood cell count below the normal range (3800/ radioactivity from patients receiving 80 mCi doses was accom mm3) during the 6-wk follow-up. plished by serial whole-body gamma counting with a Nal detector No objective tumor responses were observed at the dose probe at a distance of 13.5 feet. Blood samples were obtained schedules used in this group of patients with advanced, weekly following therapy for CBC determination and evidence of metastatic disease that was generally refractory to systemic

2230 The Journal of NuclearMedicine•Vol.36 •No. 12 •December 1995 TABLE I DISCUSSION Dose Schedule of lodine-125-c-17-lA The potential therapeutic advantages of 1@Ibound to (mCTotalDose agents that allow close approximation to the DNA has been Group of no.No.8142020244040346060448080541001006310050150731001002008210010050250patients125l@17-lA(mCi)Day1Day 4Day studied in several preclinical settings, including ‘251-17-1A treatment of human colon cancer cells in culture or as xenografts in nude mice (2—9,13,25).With the exception of one report (26), these studies showed tumor inhibition and the results prompted the initiation of the clinical trial re ported here. The maximum tolerated dose was not reached with escalation to our highest dose of 250 mCi 125Jtotal dose, given in three portions over 8 days. Since no significant hematologic toxicitywas noted at the highest dose level, the infrequent Grade 1 toxicity level blood counts for three patients at lower dose levels are chemotherapy. As shown in Table 2, 10 patients were stable suspected of being coincidental rather than a true reflection at the 6-wk evaluation, 3 patients were considered to have of @I-relatedtoxicity. Bone marrow cells do not react with disease progression on the basis of increased size of index c-17-1A and internalize it, thus the radiation exposure to lesions, 9 patients developed new areas of disease and 6 the marrow should only be from the low level gamma patients had general disease progression and decreased emissions and not the more abundant Auger electrons. performance status. Although the dose to bone from the 7% 35 keV gamma Pharmacokinetics was undertaken using serial serum emissions will be greaten than to nontarget soft tissues due samples of patients in the lowest dose group (20 mCi to the dominance of the photoelectric effect (27), this only 1@I-c-17-lA). The data best fit a two-compartment model affects a 10-micron transition zone at the bone-soft tissue with individual patient values shown in Table 3. interface and would still relatively spare most of the mar The whole body half-life of radioactivity in Group 1 row cavity. Other 1251-labeledantibody trials have not re patients receiving 20 mCi ‘25I-c-17-1Awas 82—112hr based ported significant toxicities (19,20) after administrations of on determinations from urinary loss of radioactivity during s50 mCi at intervals of 1 wk. the first 3 days after treatment. For patients receiving 80 In this study of patients with bulky advanced metastatic mCi ‘251-c-17-1Awhole-body half-life for loss of nadioac colon cancer, no objective tumor regressions were observed tivity ranged from 32 to 177 hr based on serial gamma while 10 patients were stable and 18 progressed. Without probe counts. measurable tumor regressions, it is difficult to determine if As shown in Table 4, Patient 11 demonstrated an anti some patients may have had therapeutic benefit from the c-17-1A assay value 2.5 times the pretreatment level dun 125I-c-17-1Atreatment. Four patients whose disease was ing the initial 6-wk evaluation period. In this patient, an stable 6 wk after a single treatment and who did not im elevation to 29 ng/ml was observed 7 days post-therapy and mediately receive other forms of therapy remained stable at had dropped to 9 ng/ml by 14 days. No other samples up to last follow-up of 9, 12, 12 and 16 wk. Long-term tumor Day 94 exceeded the pretreatment level of 3 ng/ml. One stability has been reported for three patients with advanced other patient (Patient 18) had 10 ng/ml anti-c-17-1A anti neuroblastoma who were treated with a single administra body detected 47 days after therapy whereas the 6 weekly tion of @I-metaiodobenzylguanidine (MIBG) (28,29). samples preceding this elevation were @3ng/ml. Although One of these neunoblastoma patients who survived >1 yr study design excluded patients who had previously been had stable measurable tumor mass during that follow-up exposed to murine antibodies, Patient 16 may have previ interval, whereas the tumor was rapidly growing before ously received a small amount of c-17-1A. This patient therapy. Subsequently, at > 1 yr after treatment, tumor remained negative for an anti-c-17-1A antibody response. growth was again detected (29).

TABLE 2 Comparison of DiseaseStatus after Therapy with DoseAdministered of patientswithresponseat each 125l-c-17-1A20 doselevelof mCiStable22DiseaseresponseNumber mGi40 mCi60 mCi80 mCi 100mCi150 mCi200 mCi250 222Progression lesions111Newof known 1Clinicalsitesof diseasenoted3221 without12111measuredprogression @sions

lodine-l25-chimenc17-lA PhaseI •Meredithat al. 2231 TABLE 3 Plasma PharrnacokineticsFollowinga Single Infusionof Iodine-l25-c-l 7-lA under residence thecurve timein rate kg)1271902651261301.032251504441281120.8831710021294971.04MeanPatientno.aT1,@ (hr)(h@Area (hr @g/m@Mean plasma(hr)VDss (mVkg)Clearance(mVhr

±1s.e.23 ±3147 ±26307 ±70116 ±11113 ±100.98 ±0.05

The lack of objective responses may be due to poor munine 17-lA counterpart (32—34)and other chimenic an penetration of antibody through large human tumor masses tibodies (e.g., ch-B72.3) (35—37). and/or inadequate nuclear translocation. The fact that ad The pharmacokinetic parameters measured in Group 1 juvant use of multiple administrations of large doses (100— patients of this study (20 mCi ‘@I-c-17-1A)were similar to 500 mg) of unlabeled 17-lA has shown a significant im phanmacokinetics studies of ‘31I-c-17-1Ain similar patients. provement in survival and freedom from distant metastasis The whole body half-life of radioactivity measurements as adjuvant for patients with risk of microscopic disease among patients of the current study was more variable than suggests that therapeutic benefit is greaten with small dis that of patients receiving a tracer dose of 1311-c-17-1A(32). ease deposits (30). One would expect greater efficacy with This difference likely represents the limitations of measun radiolabeled 17-lA, taking advantage of both early cell ing the low energy gamma component where scatter and toxicity from the internalized nabiolabeled antibody and attenuation, perhaps even from clothing, varies despite re immunologic mechanisms that might be effective long after producible patient positioning. radioactivity decay. A low objective response rate (2/53) for measurable metastatic disease has been reported with mul CONCLUSION tiple infusions of ‘@I-labeled17-lA (20). In that study, This dose escalating trial shows that high-dose outpatient however, it is difficult to determine the effects of the ‘@I radioimmunothenapy with a @I-labeledinternalizing anti 17-lA alone since patients also received external beam body can be achieved without significant patient toxicity or radiation in addition to the nadioimmunotherapy. radiation hazard to health care personnel. The human immune response studies are consistent with our previous experience showing c-17-1A to be of low immunogenicity in humans (23,37). Chimenic 17-lA ap ACKNOWLEDGMENTS pears to have little immunogenic potential compared to its The authors express appreciation to Sharon Garrison for prep aration of the manuscript, M.A. Markiewicz for pharmaceutical services, Tern Kirchler for nursing skills and to Gayle Elliott and TABLE 4 Mark Luehmann for technical assistance. This study was con Anti-c-l 7-lA AntibOdyLevelsbefore and after Treatment* ducted at the Department of Radiation Oncology at the University of Alabama at BirminghamComprehensiveCancer Center and PatientDayofno. PretreatmentPost-treatment abnormalvalue was supported by Centocor, Inc., Malvern, PA.

632-3722-3822-392210221132-29122213141422-31536-81633-71722-31822-101923-82022-3REFERENCES 1. Krisch RE, Ley RD. Induction of lethality and DNA breakage by the decay of iodine-125 in bacteriophage T4. mt I Radiat Biol 1974;25:21—30. 2. Burki Hi, Koch C, Wolff S. Molecular suicide studies of ‘@Iand 3H disintegration in the DNA of Chinese hamster cells. Curr Top Radial Res Q 7 1977;12:408—425. 3. Sundell-Bergman5,JohansonKJ.RepairableandunrepairableDNAstrand breaks induced by decay of 3H and @1incorporated into DNA of mamma han cells. Radiat Environ Biophys 1980;18:239—248. 4. BloomerWD,McLaughlinWH,WeichselbaumRR,HansonRN,Adelstein Si, Seitz DE. The role of subcellular localization in assessing the cytotoxicity of iodine-125-labeled iododeoxyuridine, iodotamoxifen and iodoantipyrine.J RadioanalChem 1981;65:209—221. 5. Hofer KG, Hughes WL. Radiotoxicity of intranucleartritium, @1and ‘@‘i. RadiatRes1971;47:94—109. 6. Bradley EW, Chan PC, Adelstein Si. The radiotoxicity of iodine-125 in mammaliancells. I. Effects on the survivalcurve of radioiodine incorporated @Valuesareexpressedasng/mlsera.A positiveassaywasdefinedas into DNA. Radiat Res 1975;64:555—563. a post-therapyvaluewh@hwasat leasttwicethepretherapyvalueand 7. Chan PC, Lisco E, Lisco H, Adelstein Si. The radiotoxicity of iodine-125 in mammalian cells. II. A comparative study on cell survival and cytogenetic exceeded12 ng/ml,whichis 2 s.d.abovethe mean(5.4±3.3)of 44 responses to ‘@1UdR,‘31IUdRand 3HtdR. Radiat Res 1976;67:332—343. coloncancerpatientspriorto exposureto murineantibody(24). 8. Kassis Al, Sastiy KSR, Adelstein Si. Kinetics of uptake, retention and

2232 The Journal of •Vol. 36 •No. 12 •December 1995 radiotoxicity of ‘@IUdRin mammalian cells: implications oflocalized energy 24. MarkwellMAX. FoxCF.Surface-specificiodinationof membraneproteins deposition by Auger processes. Radiat Res 1987;109:78—89. of viruses and eucaryotic cells using 1,3,4,6-tetrachloro-3a,6a-diphenylgly 9. Kassis At, Fayad F, Kinsey BM, Sastiy KSR, Taube RA, Adelstein Si. coluril. Biochemist,y 1978;17:4807—4817. Radiotoxicity of 125!in mammalian cells. Radiat Ret 1987;111:305—318. 25. Joshi SS, Sivinski CL, Bliss KD, Colcher D, Tempero MA. Therapeutic 10. Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma efficacy of internalizing @-‘I-labeledmonoclonal antibody 17-lA against specific antigen: detection by means of monoclonal antibodies. hoc Nat! humancoloncarcinoma[Abstract].hoc AmAssnCancerRes1994;35:648. Acad Sci USA 1979;76:1438—1442. 26. Aronsson EF, Gretarsdottir J, Jacobsson L, Ct al. Therapy with ‘@‘I-labeled 11. Koprowski H, Steplewski Z, Mitchell K, Herlyn M, Herlyn D, Fuhrer JP. internalized and non-internalized monoclonal antibodies in nude mice with Colorectal carcinoma antigens detected by hybridomaantibodies. Somat Cell human colon carcinoma xenografts. Nuc! Med Biol 1993;20:133-144. Genet 1979;5:957—972. 27. Yorke ED, Huang YCD, Schell MC, Wong R, LAngCC. Clinical implications 12. Herlyn D, Powe J, Alavi A, et al. Radioimmunodetection of human tumor ofl-125 ofbone and bone-soft tissue interfaces. IntlRadiat Onco! xenografts by monoclonal antibodies. CancerRes 1983;43:2731—2735. Bio! Phys 1991;21:1613—1619. 13. Woo DV, Li D, Mattis JA, Steplewski Z. Selective chromosomal damage and 28. Sisson JC, Hutchinson Ri, Shapiro B, Ct al. Iodine-125-MIBG to treat cytotoxicity of WI-labeled 17-lA in human cancer neuroblastoma: preliminary report. I Nuc! Med 1990;31:1479—1485. cells. Cancer Res 1989;49:2952—2958. 29. Sisson JC, Shapiro B, Hutchinson Ri, et al. Treatment of neuroblastoma 14. Rao DV, Narra VR, Howell RW, Sastry KSR. Biological consequence of with‘@I-MIBG.I Nuc!Bit,!Med1995:inpress. nuclear versus cytoplasmic decays of @I:cysteamine as a radioprotector 30. RiethmullerG,Schneider-GadickeE,SchlimokG,etal.Randomisedtrialof against Auger cascades in vivo. Radiat Res 1990;124:188—193. monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal 15. Martin RF, Haseltine WA. Range of radiochemical damage to DNA with carcinoma. Lancet 1994;343:1177—1183. decay of iodine-125. Science 1981;213:896—898. 31. Meredith RF, LoBuglio AF, Plott WE, et at. Pharmacokinetics, immune 16. Berger J. MIRD Manual No. 7. 1 Nuci Med 19715(suppl):12. response, and biodistribution of iodine-131-labeled chimeric mouse/human 17. Adelstein Si, Kassis Al, Baranowska-Kortylewicz I, Van Den Abbeele AD, IgGl,k17-lA monoclonalantibody.I NuciMed1991;32:1162—1168. Mariani G, Ito S. Potential for tumor therapy with iodine-125-labeled im 32. Haga Y, Sivinski CL, Kay HD, et at. Biologic responses to multiple high munoglobulins. Nuci Med Biol l991;18:43-44. doses of munne monoclonal antibody (17-lA) in pancreatic cancer patients. 18. Bloomer WD, McLaughlin WH, Adelstein Si. Therapeutic implications of iodine-125 cytotoxicity. mt i Radiat Onco! Biol Phys 1982;8:1903—1908. Antibod Jmmunoconj Radiopharm 1992;5:179-190. 19. Brady LW, Woo DV, Markoe A, et al. Treatment of malignant gliomas with 33.SteplewskiZ, FoxK, GlickJ, KoprowskiH. Humanantimouseantibody ‘@1-labeledmonoclonal antibody epidermal growth factor receptor. Ann response in patients treated with multiple infusions of monoclonal antibody body Immunoconj Radiopharm 1990;3:169—179. C017-IA. In: Vaeth JM, Meyer JL, eds. The present and Jiaure rok of 20. Markoe AM, Brady LW, Woo D, et a!. Treatment of gastrointestinal cancer nwnoclona! antibodies in the management of cancer, vol. 24. Basel: Karger; using monoclonal antibodies. In: Vaeth JM, Meyer JL, eds. The present and 1990:69—72. future role of monoclonal antibodies in the management of cancer, vol. 24. 34. Khazaeli MB, Sateh MN, Wheeler RH, et at. Phase I trial of multiple large Based:Karger; 1990:214—224. doses of murine monoclonat antibody C017-1A. H. Pharmacokinetics and 21. Sun LK, Curtis PE, Rakowicz-Szulczynska E, et al. Chimeric antibody with immune response. I Nat! Cancer Inst 1988;80:937—942. human constant regions and mouse variable regions directed against a 35. Khazaeli MB, Saleh MN, Liu TP, et. at. Pharmacokinetics and immune carcinoma-associated 17-IA antigen. &oc NatlAcad Sci USA 1987;84:214— response of ‘311-chimericmouse/human B72.3 (human y4) monoclonal an 218. tibody in humans. Cancer Res 1991;51:5461—5466. 22. Shaw DR, Khazaeli MB, Sun LK, et al. Characterization of a mouse/human 36. Meredith RF, Khazaeli MB, Plott WE, et at. Comparison of two mouse/ chimeric monoclonal antibody (17-lA) to a colon cancer tumor-associated human chimeric antibodies in patients with metastatic colon cancer.Antibod antigen. I Immunol 1987;138:4534—4538. Jmmunoconj Radiophann 1992;5:75—80. 23. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric mono 37. Begent RHJ, Ledermann JA, Bagshawe KD, et at. Chimeric B72.3 antibody clonal antibody in man: kinetics and immune response. !‘@vcNat! Acad Sci for repeated radioimmunotherapyof colorectal carcinoma. Antibod Immu USA 1989;86:4220—4224. noconj Radiopharm 1990;3:86.

Iodine-l25-chimeric17-lA PhaseI •Meredithat al. 2233