Disposition of a murine monoclonal
`antibody vinca conjugate
`(KS1 / 4-DAVLB) in patients
`with adenocarcinomas
`
`The pharmacokinetics of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) was
`investigated in 13 patients with adenocarcinomas who received single intravenous doses ranging from 40
`to 250 mg/m2 and in three patients who were administered 1.5 mg/kg every 48 to 72 hours for up to
`15 doses. Five patients in the single-dose study also received 100 RCi of [2H]-KS1/4-DAVLB. Overall
`mean values for the pharmacokinetic variables were as follows: elimination half-life, 31.5 hours;
`distribution volume, 4.43 L; and clearance, 0.09 L/hr. KS1/4-DAVLB demonstrated linear elimination
`kinetics in both the single- and multiple-dose studies. Significant concentrations of KS1/4-DAVLB were
`noted in a pleural effusion. Ten percent of the radioactive dose was recovered in the urine and 20% in
`the feces over a 5-day period. Small molecular weight vinca species were detected in the feces but not in
`the serum. (CLIN PHARMACOL THER 1990;47:36-41.)
`
`Dennis Schneck, MD, PhD, Fred Butler, MD, William Dugan, MD,
`Donna Littrell, RN, Bruce Petersen, PhD, Ron Bowsher, PhD,
`Allyn DeLong, PhD, and Susan Dorrbecker, PhD Indianapolis, Ind.
`
`Several studies have examined the potential thera-
`peutic value of unmodified monoclonal antibodies
`tumor therapy by use of in vivo
`(MOABs) as
`models of human
`tumor growth and
`in human
`clinical trials.' Additional reports have used conju-
`gates of MOABs with radionuclides, plant and micro-
`bial toxins, and oncolytic agents such as methotrexate,
`adriamycin, and the vinca alkaloids." These efforts
`have sought to test the concept of using the MOAB as
`a site-directed targeting agent for tumors in humans.
`The IgG2a murine monoclonal antibody KS1 /4 rec-
`ognizes a 40,000 Da cell surface glycoprotein found in
`high density in the tumor cell membrane of a human
`lung, colon, rectal, pancreatic, and ovarian adenocar-
`cinomas.'2 The KS1 / 4 antigen is also expressed on
`
`From Lilly Laboratories for Clinical Research, Eli Lilly Co., the
`Departments of Medicine and Pharmacology, Indiana University
`School of Medicine, and Methodist Hospital.
`Presented (in preliminary form) at the Ninetieth Annual Meeting of
`the American Society for Clinical Pharmacology and Therapeutics,
`Nashville, Tenn., March 8-10, 1989.
`Received for publication June 26, 1989; accepted Sept. 18, 1989.
`Reprint requests: Dennis Schneck, MD, PhD, Lilly Laboratories for
`Clinical Research, Wishard Memorial Hospital, 1001 West Tenth
`St., Indianapolis, IN 46202.
`13/1/16842
`36
`
`Structure of KS1 / 4-DAVLB. Four to six desacetylvinblastine
`molecules are covalently bonded by means of hemisucinate
`linkers to epsilon amino groups of lysine residues.
`
`the cell surface of a variety of normal tissues, including
`the epithelium of the gastrointestinal tract, kidney tu-
`bular cells, bile and pancreatic ductal epithelium, bron-
`chial and alveolar epithelium, ovary epithelium, and
`sweat ducts.
`The conjugate KS1/4-DAVLB, containing 4 to 6
`molecules of desacetylvinblastine (DAVLB) bound co-
`valently to KS1 /4 by means of hemisuccinate linkers
`(see Structure), retains a high degree of reactivity with
`the tumor-associated antigen. Preclinical pharmacology
`
`IMMUNOGEN 2310, pg. 1
`Phigenix v. Immunogen
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`
`VOLUME 47
`NUMBER 1
`
`Disposition of murine monoclonal antibody 37
`
`Table I. KS1/4-DAVLB dose schedule for
`patients enrolled in the single-dose study
`
`KSI I4-DAVLB Dose
`
`Patient
`No.
`
`(mg/m2)
`
`(mg)
`
`(mg vinca)
`
`Infusion time
`(hr)
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`
`40
`40
`80
`80
`140
`140
`140
`140
`140
`250
`250
`250
`250
`
`56
`60
`168
`44
`137
`175
`196
`252
`293
`350
`500
`525
`550
`
`1.4
`1.5
`4.3
`3.6
`3.5
`4.5
`5.0
`6.4
`7.4
`8.9
`12.7
`13.3
`13.9
`
`2.0
`2.0
`2.0
`2.0
`4.5
`1.5
`2.0
`2.0
`2.0
`2.0
`4.2
`6.2
`7.6
`
`experiments demonstrating the antitumor properties of
`KS1/4-DAVLB have been reported.' This study de-
`scribes the pharmacokinetic characteristics of KS1 / 4-
`DAVLB in patients who were administered single and
`multiple intravenous infusions of the drug.
`
`PATIENTS AND METHODS
`Single-dose study. Six women and seven men with
`adenocarcinoma of the lung (Stage III), colon, or rec-
`tum (stage D) participated in this study. Patients were
`40 to 76 years old and weighed from 104 to 230 pounds.
`Life expectancy of at least 2 months and a Karnofsky
`performance value of at least 60% were required for
`enrollment. Adequate marrow function (Hb > 10
`gm/di; white blood cell count >4000/mm3; plate-
`let count > 100,000/mm3),
`liver function (biliru-
`bin < 2.5 mg /dl), and kidney function (creatinine <
`2.5 mg/di) were also required. The patients were in-
`formed of the nature and objectives of the studies and
`gave written consent. The studies were approved by
`the Indiana University Institutional Review Committee
`and by the Methodist Hospital Institutional Review
`Board (Indianapolis, Ind.).
`Each dose of KS1/4-DAVLB was infused over a 1.5-
`to 2-hour time period. The infusion vehicle was nor-
`mal saline solution that contained human albumin
`(5 gm/100 m1). Patients fasted from midnight until
`completion of the infusion. The dosing schedule for
`this study is shown in Table I.
`At the end of the 2-hour infusion of KS1/4-DAVLB,
`a trace dose of tritium-labeled KS1 / 4-DAVLB (100
`3.2 mg, label in the vinca molecule) was given
`
`CGF (500 mg. 4.2 hr inf.)
`o IRMA data
`a FCM data
`A 3H data (3.195 mg dose)
`
`6
`
`24
`
`418
`
`72
`96
`Time (hours)
`
`120
`
`Fig. 1. Concentration-versus-time data for patient 3 after in-
`travenous infusion of KS! /4-DAVLB.
`
`PDR (293 mg. 2 hr inf.)
`0 IRMA data
`0 FCM data
`A 3H data
`
`II i
`
`0
`
`12
`
`24 36
`
`1-111111
`
`96 108 120
`
`48 60 72 84
`Time (hours)
`
`Fig. 2. Concentration-versus-time data for patient 9 after in-
`travenous infusion of KS1/4-DAVLB.
`
`as a bolus to patients 10 and 11. For patients 5, 6, and
`9, the tritium-labeled KS1/4-DAVLB was added to the
`main dose and administered over the entire infusion.
`Serial blood samples were obtained from each patient
`for up to 7 days after the KS1/4-DAVLB infusion. The
`serum concentration of KS1/4-DAVLB was measured
`by means of immunoradiometric (IRMA) and flow cy-
`tometric assays (FCM). In the IRMA assay, goat anti-
`mouse immunoglobin covalently bonded to acrylic mi-
`crospheres, is incubated with human serum containing
`KS1/4-DAVLB. This complex is mixed with 121-
`labeled goat anti-mouse immunoglobin and the radio-
`activity binding to the microspheres measured. This
`assay does not require that a functional antigen binding
`site be present on the mouse immunoglobulin. Details
`of the IRMA assay have been published.' The FCM
`assay consisted of a modification of the method de-
`scribed by Marder et al.' Dilutions of serum samples
`
`IMMUNOGEN 2310, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`3 8 Schneck et al.
`
`CLIN PHARMACOL THER
`JANUARY 1990
`
`6000
`
`5000
`
`8
`6 4000
`
`< 3000
`
`< 2000-
`
`1000-
`
`0-
`
`0
`
`o IRMA Assay
`o ECM Assay
`Overall regression
`
`Y= 12.4 X
`r2= 0.860
`
`Total
`
`-----
`Fecesi
`
`Urine
`
`go 160 Igo 260 20 300 350 400 450
`KS1/4-DAVLB Dose (mg/70 kg)
`
`24
`
`48
`
`72
`
`120
`
`T (hr)
`
`Fig. 3. KS1/4-DAVLB AUC versus weight-normalized dose
`after single intravenous infusions.
`
`Fig. 4. Recovery of urinary and fecal radioactivity after ad-
`ministration of 100 1.1.Ci tritium-labeled KS1/4-DAVLB.
`
`Table II. Mean values of pharmacokinetic variables for KS1/4-DAVLB after a single intravenous infusion
`Elimination
`42*
`(hr)
`
`Assay
`
`Systemic
`clearance
`(Llhr)
`
`Volume of
`distribution
`(L)
`
`IRMA (n = 13)
`FCM Assay (n = 13)
`(n = 5)t
`
`33.5 ± 12.0
`29.8 ± 9.02
`33.6 ± 6.47
`
`0.085 ± 0.027
`0.097 ± 0.034
`0.104
`0.036
`
`4.60
`2.77
`4.26 ± 1.19
`5.34 ± 2.44
`
`Data are mean values ± SD.
`IRMA, Immunoradiometric assays; FCM, flow cytometric.
`*Harmonic mean.
`Walues were determined from the serum radioactivity content.
`
`from patients infused with KS1 / 4-DAVLB, normal se-
`rum controls, and standard KS1 /4 dilutions were added
`to paraformaldehyde fixed P3-UCLA cells (human ad-
`enocarcinoma cell line, 8 x 10e5 /tube). These cells
`highly express the KS 1/4 membrane antigen. Thus,
`KS1/4-DAVLB must be immunoreactive with the an-
`tigen for this assay to measure the presence of this
`immunoconjugate in human serum. The mixture was
`incubated at 4° C for 30 minutes, centrifuged, washed,
`and the cell pellet resuspended in 0.1 ml of fluorescein-
`conjugated sheep anti-mouse IgG antisera. This mixture
`was incubated at 4° C for 30 minutes in the dark, cen-
`trifuged, and the cells washed. Aliquots of the cells
`were analyzed for fluorescence intensity by use of an
`EPICS C flow cytometer (Coulter, Hialeah, Ha.). The
`mean channel of fluorescence was determined for each
`sample and the standard curve and the unknown con-
`centrations were determined by use of a computer pro-
`gram (RIASYS, Eli Lilly & Company) (Indianapolis,
`Ind.).
`Urine and fecal samples from each patient who was
`administered radioactive KS1 / 4-DAVLB were collected
`for up to 5 days after dosing. Aliquots of blood serum
`and urine were pipetted directly into Scintisol liquid
`
`(Isolab, Inc., Akron, Ohio) and the radioactivity was
`determined in a Beckman LS 3801 liquid scintillation
`system (Beckman Instruments, Fullerton, Calif.). Ali-
`gouts of 1/1 aqueous fecal homogenate were combusted
`with a Packard Tri Carb Model B 306 sample oxidizer
`(Packard Instrument Company, Inc., Downers Grove,
`Ill.). Determination of radioactivity in the combusted
`samples was similar to that described above for serum
`and urine. Radioactivity was converted to microgram
`equivalents of KS1/4-DAVLB per volume of biologic
`sample on the basis of the calculated specific activity
`of the administered drug.
`Serum KS1/4-DAVLB concentration data were an-
`alyzed by model-dependent pharmacokinetic methods.
`A one- or two-compartment open pharmacokinetic
`model was fitted to the individual concentration versus
`time data by use of an iterative nonlinear regression
`program, NONLIN84.16 The estimated values of the
`coefficients were corrected for the length of the intra-
`venous infusion, and corrected values for the coeffi-
`cients and the fitted values of the exponents were used
`to calculate values of pharmacokinetic variables."
`Multiple-dose study. Three male patients, ranging in
`age from 54 to 62 years and in weight from 151 to 179
`
`IMMUNOGEN 2310, pg. 3
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`

`
`VOLUME 47
`NUMBER 1
`
`Disposition of murine monoclonal antibody 39
`
`pounds, were administered multiple doses of KS1/ 4-
`DAVLB. The KS1/4-DAVLB dosing schedule for these
`patients was 1.5 mg/kg administered every 48 to 72
`hours for nine to 15 doses. Blood samples were obtained
`before and after completion of each infusion for mea-
`surement of the serum concentrations of KS1/4-
`DAVLB.
`
`RESULTS
`concentrations
`serum
`study. The
`Single-dose
`of KS1/4-DAVLB obtained by the IRMA and FCM
`assays were highly correlated with an r value of 0.93
`and a slope of 1.1.
`1 and 2 show semilogarithmic plots of
`Figs.
`concentration-versus-time data for two patients. Patient
`11 (Fig. 1A) received 31-I-KS1/4-DAVLB as an intra-
`venous bolus after completion of the main infusion.
`The KS1/4-DAVLB serum concentration estimated
`from radioactivity content was therefore calculated on
`the basis of labeled dose administered (3.2 mg). The
`serum KS! /4-DAVLB concentrations measured by
`IRMA and FCM methods were similar for the entire
`time profile. The slope of the 3H concentration-versus-
`time curve is also similar to that observed with the
`other two methods. Patient 9 (Fig. 2) received 3H-
`labeled KS1/4-DAVLB mixed with the total unlabeled
`dose. Therefore, the KS1/4-DAVLB serum concentra-
`tions estimated from radioactivity content were calcu-
`lated on the basis of total dose administered (293 mg).
`The serum KS1/4-DAVLB concentrations were com-
`parable among the three methods of analysis.
`Mean pharmacokinetic variables calculated from se-
`rum concentration data obtained by use of the three
`analytic methods are shown in Table II. No significant
`differences were detected among mean values of these
`variables for the three methods. Overall mean values
`for the IRMA and FCM assays were as follows: elim-
`ination half-life (42), 31.5 hours; systemic clearance,
`0.09 L/hr; and volume of distribution, 4.43 L. For those
`patients whose data were described by use of a two-
`compartment model (6 of 13 patients), the range of
`distribution t,,. values was 1.4 to 5.7 hours (all assay
`methods).
`Fig. 3 shows a plot of the KS1/4-DAVLB AUC ver-
`sus weight-normalized KS1/4-DAVLB dose. The AUC
`versus dose relationship was linear (r2 = 0.860), sug-
`gesting that KS1/4-DAVLB elimination kinetics were
`linear in the range of doses administered.
`Mean total urinary and fecal recovery of a radiola-
`beled dose of KS1/4-DAVLB was only 30% over the
`5-day collection period (Fig. 4). Two thirds of the re-
`covered dose was found in the feces and one third was
`found in the urine. Preliminary experiments that used
`size exclusion chromatography indicated that the mo-
`
`IRMA - serum
`IRMA - pleural fluid
`FCM - serum
`FCM - pleural fluid
`
`40-
`
`0.1-
`
`50
`
`100
`
`250
`150
`200
`Time (hours)
`
`300
`
`350
`
`400
`
`Fig. S. Pleural fluid KS1 / 4-DAVLB concentration.
`
`IV dose (mg)
`
`0.1
`-5
`
`0
`
`5
`
`10
`15
`Time (days)
`
`20
`
`25
`
`30
`
`Fig. 6. Serum concentrations of KS1 / 4-DAVLB during a
`multiple dose schedule. *Peak blood samples not available
`for analysis.
`
`lecular weight of the radioactive material in the feces
`was consistent with free desacetylvinblastine or metab-
`olite(s). Less than 1% of the radioactivity in the serum
`could be accounted for by a free vinca species.
`Patient 3 had a malignant pleural effusion from which
`serial samples were obtained for measurement of
`KS1/4-DAVLB concentration. The pleural fluid con-
`centrations of KS1/4-DAVLB relative to serum values
`are shown in Fig. 5. Peak pleural fluid concentration
`was approximately 2 lig /ml, occurring about 45 hours
`after drug administration. This concentration was main-
`tained for up to 150 hours after drug infusion.
`Multiple dose study. Nine 114-mg doses of KS1 /4-
`DAVLB were administered to a patient participating in
`the multiple-dose study. The peak and trough concen-
`trations of KS1/4-DAVLB for this patient are shown in
`Fig. 6. Steady state was achieved by the third infusion,
`and subsequent values did not change during repeated
`infusions of KS1/4-DAVLB. Similar observations were
`noted for the other two patients who received multiple
`
`IMMUNOGEN 2310, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`40 Schneck et al.
`
`CLIN PHARMACOL THER
`JANUARY 1990
`
`doses. For these three patients, the steady-state peak
`/ ml and the
`concentrations ranged from 55 to 65
`trough concentrations ranged from 10 to 20 lig/ ml.
`
`DISCUSSION
`KS1/4-DAVLB pharmacokinetic parameters in pa-
`tients are similar to values found for another murine
`IgG2a immunoglobulin, 17-1A, when it was infused
`into patients with metastatic gastrointestinal cancer, ex-
`cept the 17-1A t1/2 of about 18 hours appears to be
`shorter than the t2 found for KS1/4-DAVLB.18 The
`addition of vinca molecules to the immunoglobulin mol-
`ecule may reduce the rate of metabolism of the con-
`jugate relative to unconjugated protein. The mechanism
`by which murine immunoconjugates are eliminated in
`human beings is not known; however, it is possible that
`cells of the reticuloendothelial systemparticularly
`those in the liverare responsible for the initial deg-
`radation of these molecules. The fecal recovery of ra-
`dioactivity as low molecular weight vinca species in-
`dicates that the vinca is removed from the immuno-
`globulin. The vinca may then be further metabolized,
`followed by biliary excretion of parent drug and me-
`tabolites.
`The decay of serum radioactivity after the adminis-
`tration of [41]-vinca labeled KS1/4-DAVLB was sim-
`ilar to the concentration decay of KS1/4-DAVLB mea-
`sured by immunologic assays. The lack of recovery of
`small molecular weight compounds in the serum indi-
`cates that any free vinca formed does not appear in the
`circulation to any significant degree.
`Only a total of about 30% of the radioactive dose
`was recovered over a 5-day period. The lack of quan-
`titative recovery of radioactivity could indicate persis-
`tent binding of the conjugate to normal tissues that
`express the antigen or to tumor tissue. However, only
`about 30% of an intravenous [3H] dose of free vin-
`blastine is recovered over a 6-day period.' The recov-
`ery pattern of radioactivity in humans is similar to that
`observed in the rhesus monkey,' fisher rat,' and tumor-
`bearing nude mouse' after administration of single
`doses of KS1/4-DAVLB. In the rhesus monkey, ap-
`proximately 50% of a radioactive dose is recovered after
`7 days (80% of that is recovered in the feces). Similar
`results were obtained in the rat and mouse. The distri-
`bution volume also approximated the blood volume in
`these species. The tv, was longer in the nude mouse
`(= 90 hours), and rat (= 60 hours). These results are
`not surprising because one would anticipate a slower
`rate of clearance after administration of a mouse im-
`munoglobulin to rodent species.
`Multiple doses of KS1/4-DAVLB did not result in
`
`enhanced or diminished clearance of the compound be-
`cause peak and trough values remained constant during
`multiple dosing (Fig. 6). This result is similar to that
`reported earlier for 17-1A." None of the three patients
`studied after multiple dosing developed a significant
`antimouse antibody response during the time period that
`drug was administered. The effect of a human antibody
`response (HAMA) on the clearance of KS1/4-DAVLB
`is not known at this time.
`Significant concentrations of KS1/4-DAVLB were
`found in a malignant pleural effusion. This observation
`indicates that KS1/4-DAVLB can penetrate into third
`space tumor compartments.
`In summary, KS1/4-DAVLB has a rather long
`(31.5 hours), a low systemic clearance (0.1 L/hr), and
`an apparent volume of distribution approximating blood
`volume (4 to 5 L).
`
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`VOLUME 47
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