munuconjugates, and
`adiopharmaceuticals
`
`
`
`IMMUNOGEN 2311, pg. 1
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2311, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`ANTIBODY, IMMUN OCONJU GATES, AND
`RADIO PHARMACEUTICALS
`Volume 2, Number 2, I 989
`Mary Ann Licbcn , Inc., Publishers
`
`Phase I Studies with a Murine Monoclonal
`Antibody Vinca Conjugate (KS 1/4-DA VLB) 1n
`Patients with Adenocarcinoma
`
`•3 FRED BUTLER,3 WILLIAM DUGAN ,3
`DENNIS SCHNECK, 1
`DONNA LITTREL,3 SUSAN DORRB ECKER, 1 BRUCE PETERSON, '
`RON BOWSHER, 1 ALLYN DELONG , 1 and JOHN ZIMMERMANN '
`
`2
`
`•
`
`1 Lilly Research Laboratories , Eli Lilly and Company, Indianapolis, IN
`' Depanmellfs of Medicine and Pharmacology, Indiana Un iven ily School of Medicine, lndianapoli.l", IN
`1Mellwdist Ho.1pital, Indianapolis, IN
`
`ABSTRACT
`
`The mur i ne mono c l ona l a nt i body vinca co njuga t e (KS1/4 - DAVLB) was i nfu sed as
`a si ngl e IV dose t o 13 pat ie nts wi th colon o r lung tumo rs . The dose ra nged f rom
`40 t o 250 mg/M 2 .
`F i ve pa t ie nt s a l s o r eceive d KS1/4 -[ 3H] DAVLB. Nine pa ti ent s
`we r e a dmini s t e r e d mu l tipl e IV doses of KS1/4-DAVLB. Dose l i mi t i ng t oxici ty i n
`both the s ingl e a nd mult i ple dos e s tudi es was acute onse t of abd omi na l pa in,
`naus ea , emes i s a nd di a rrhe a. The MTD in the singl e do se s tudy was 250 mg/M 2 and
`a total cumulat i v e do se of a pprox ima t e ly 400 mg for mo s t of
`t he pati ent s in the
`multipl e do se s tudy. Examina t i on of duod ena l biop s i es in af fe c t ed pa tie nt s
`r eve a l e d ul c era ti on of epithe lium wi th lo ss of villous s tru cture a nd int ense
`acute i n f l amma t ory ce ll infilt ra t e . The degree of i nflammation was dose -depe nd e nt.
`KSl/4-DAVLB bound e xtens ive ly to duod enal ep i thel i um. Compl ement ac tiva ti on on
`t he s urfa ce of duode na l epithe lium may be r es pons ibl e for the ac ute i nfl amma tory
`r e action. Significa nt lo c al izat i on of KSl/4-DAVLB t o tumor ce ll s was ob se rved in
`the multipl e do se study. KS1/4- DAVLB pha rmaco kine ti c parame t ers we r e as f oll ows:
`t~ of 33 h r. , di s t r ibution vo lume 4 . 91 and a c l ea r a nce of 1 . 2 ml/hr/kg. Ten
`pe r ce nt of the r a di oac tive dos e was r e cove r e d in the ur i ne and 20% in the fe ces .
`
`INTRODUCTION
`
`Severa l s tudi es have exa mine d the pot e nt ial the r ape uti c v a lue of mono c lona l
`ant i body (moab) c onjugates with r a dionuc l i de s, pl a nt and mi c r obial t oxins , a nd
`on co lyti c agent s s uch as me thotrexa t e , adri amy c in and the vin c a alka l oid s (1, 2,
`3 , 4) . The s e e ff o rts have s ou ght t o t es t the concept of ut il i zi ng th e moab a s a
`si t e -direc t e d t a r ge ting a gent to human tumo r s .
`The murine (I gG2a ) monoc l ona l antib ody KS1/4 r ecognizes a t umo r assoc i a t e d
`ce ll s u r face a nti gen which i s a 40,000 M. W. glycoprotei n f oun d i n high de nsity
`on the tumo r ce ll membrane of huma n lung, col on, r ec t al , panc r eatic , a nd ovari an
`a de no ca r c inomas ( 5 ) . Th e conj uga t e KSl/4 - DAVLB cont a ining 4- 6 mol ecul es o f
`desace tylvinbl as t i ne cova l e ntly a tta che d to KSl /4 vi a hemi s u cc inate l i nke r s
`r e tains a hi gh deg r ee of r e a c tivity with the tumo r associa t ed a nti ge n.
`Prec l i nica l p ha rma cology expe r i me nt s re l a t e d t o the a nti - tumo r p roperties of
`
`93
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`IMMUNOGEN 2311, pg. 2
`Phigenix v. Immunogen
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`

`KS1/4-DAVLB have previously bee n reported (6). Pre lim inary results of Phase I
`s tudi es ut i lizing KS1/4 -DAVLB in pati e nt s with adenocar c inoma s are reported in
`this communi ca tion.
`
`Pati ents
`
`HETHODS
`
`Thirteen patients with a de no ca r cinoma of the lung (stage III) co l on or
`rectum (stage D) r a ngi ng in age fro m 40 to 76 years a nd in weight fro m 104 to
`230 pounds parti cipated in this s tudy. Life expecta ncy of at least two month s ,
`and a Karnofsky performan ce value o f at l east 60% were r eq u ired for e nrollment.
`Ad equa t e marrow function (Hb >10 g/dl, WBC >4,000/mm 3 ), liver function (bi lirubin
`<2 .5 mg/ dl), and kidney function (creatinine <2.5 mg/dl ) were also req u ired.
`Nine pa ti e nt s ranging in age from 28 to 70 years and ranging i n weight from 114
`to 254 pound s a nd with metastatic lung , co lon, or ovaria n a de nocarci noma
`parti cipat ed in the multipl e do se s tudy.
`KS1/4 - DAVLB was admini stered by the intravenous route over a time period not
`l ess than two hours . The infusion vehicle was normal sa lin e co n taining human
`albumin (5 g/100 ml). A 1 mg test do se o f KS1/4 - DAVLB was administered to each
`pati e nt prior to the mai n infusion. Adverse reactions t o t he test dose were not
`observe d in any pat ient. Th e dose schedu l e for t he patients administered a
`single infusion of KS1/4 - DAVLB is s hown i n Table 1.
`
`TABLE l.
`
`KS1/4 - DAVLB Dose Sc hed ul e
`
`KS1/4 -DAVLB Dose
`
`(mg/M 2 )
`
`(mg)
`
`40
`
`80
`
`140
`
`250
`
`56 ,
`
`60
`
`168, 144
`
`137 , 175
`
`19 6, 252
`
`293
`
`35 0, 50 0
`
`525 , 550
`
`Vinca Do se
`(mg)
`
`l. 4 I
`
`1.5
`
`4 . 3 ,
`
`3 .6
`
`3.5 1 4.5
`
`5.0, 6. 4
`
`7.4
`
`8.9, 12.7
`
`13. 3 , 13.9
`
`Pa ti e nt
`Number
`
`1 I
`
`31
`
`2
`
`4
`
`5, 6
`
`7•', I 8•',
`
`g.·,
`
`1 o·~c, 11 ,.,
`
`12, 13
`
`Patients 6 and 11 had adenocarcinoma of the lung , the remainder had
`co lorec tal ca n ce r.
`
`*These pati en t s re ce ived 100 ~Ci of [ 3H] - l ab el l ed KS1/4-DAVLB .
`
`94
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`IMMUNOGEN 2311, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`The sta~ti n g dos e fo~ eac h patie n t in the mu ltip l e dose s tudy was 63 mg/M2
`administe~ed eve~y two or t h ree da ys for up to nine doses.
`
`Pharma co kinetic Studies
`
`Serial b l ood samples were obtained from eac h patient who participated in
`t h e single do se study followi ng KSl/4 - DAVLB administratio n. The concentration
`of KSl/4-DAVLB in t h e serum prepared f r om t h ese sampl es was meas ured by mea n s of
`i mmunoradiometric (7) (IRMA) a nd flow cytome tric (8) (FCM) assays. The i niti al
`binding r eactio n in the IRMA assay con sists of the i n c ub a t ion of serum with b eads
`coated wit h goat anti- mouse IgG an t ibody. The beads a r e washed a nd then further
`incubated wit h 1 25 1 -l a belled goat a nt i -mou se I gG a nt i b ody. The radioactivity
`adhe~i ng to the beads was q uantified i n a ga mma counte~. The mur i n e IgG
`conce n t r atio n i n patie n t serum samp les was estimated fro m a standard curve of
`KSl/4 in se rum. Th e
`i n itia l binding reaction i n the FCM assay co n sis t s of s erum
`sa mples i n cubated with P3-UCLA tumor cells wh ich e xpress the KSl/4 a nt ige n. The
`mixt u re is t h e n ce nt rif uged, wa s he d a nd the cell pellet ~esusp end ed a nd incubated
`with fluorescein co njugated s heep anti - mo use I gG antibodies. Aliquots of ce ll s
`we r e ana l yzed for fl uorescence inte n sity using an Epic ' s C flow cytometer.
`KSl/4 - DAVLB serum co n centrations were es tima t ed from a sta ndard c urve developed
`from KS l/4 sta nd ards added to serum .
`Aliquot s of serum a nd u ri ne fro m patient s ad ministered radioactive
`KSl/4-DAVLB were pi pet t ed i nto Sci nt isol® a nd the ~adioactivity was determined
`i n a Beckman LS 3801 liquid scin t illatio n system. Aliquots of a n aqu eo u s f eca l
`h omo ge nate were combu sted with a Packard Tri Garb Model B306 oxidizer . The
`~adioa c tive co nt e n t
`i n the combu sted sampl es was
`t he n meas u red in a manner
`sim i l a~ to that de scribed for t he serum and urine sa mpl es . Urine and fecal
`output s were measured daily fo~ up to five days af t er infusion of ~adiolabelled
`KSl/4 -DAVLB .
`
`Assess ment of I mmune Respo n ses (HAMA ) to KSl/4 - DAVLB Infusio ns
`
`Blood was drawn at various time periods after infusions of KSl/4 - DAVLB to
`ob t ai n ser um for meas u rement of con ce nt rations of human a nt i -KS l/4-DAVLB
`antibodies .
`The antib ody r esponse to KSl/4-DAVLB was meas ured utilizing a n ELISA assay
`u s ing microtiter plate s wit h wells coated with the murin e immunoglobulin KSl/4.
`Antibodies prese nt i n t h e serum react with KSl/4 coated on the s u rface of the
`wells . Binding of huma n a ntibo dies to KSl/4 is detected by mea ns of peroxidase
`co njugated goat anti-human i mmun oglobulin s. The op ti cal density of the well
`s upernatents is measured following i n c ul ation with a perioxidase s ub strate
`system. The standard curve i s con stru cted u sing seria l d ilutions of a monkey
`serum known
`t o co nt ai n a nt i-KSl/4 antibo d ies .
`
`Binding of KSl/4 - DAVLB
`
`t o Duod e n a l Epithe lium a nd to Tumor Tissue
`
`F res hly frozen du o d e nal biopsy sa mpl es were thawed a nd s t ained us i ng direct
`or i nd irect sta nd ard avidin -b ioti n - compl ex (ABC) me thods. Alternatively simil ar
`t issue sec tion s were a l so stai ned u si ng a s t andard 4 stage PAP method.
`
`Binding of Complement to Du odenal Epitheli um
`
`Du ode nal biopsy specime n s were incuba t ed with f luorescei n lab e lled
`antibodies whi c h interact wit h ei ther the Clq or C3b comp on e nt s of compl e me nt.
`The sec t ion s we r e then ex amined u tilizi n g a fluorescence mi croscope.
`
`95
`
`IMMUNOGEN 2311, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Safety Studies
`
`Serial blood a nd urin e sampl es were obt ai ned from each patient following
`KSl/4-DAVLB infusio n fo r meas urement of CBC, biochemical profiles , and
`urinaly s i s. Specia l s tud ies were performe d when i ndi cated . These s tud ies
`in c lud ed x- ray exa minat io ns of the upp e r gastroi nt estinal tract , pa ne nd oscopy and
`bi opsy of the upp er gast rointesti nal tr act, and colo noscopy .
`
`Anti - Tumor Activity
`
`When po ss ibl e , direct meas ureme nt s of accessi ble tumor t iss ue were made .
`Repeat x-rays and CT sca ns o f tumor areas were performed. Serum CEA
`conce ntra t io ns were re pea t ed in a seria l mann er .
`
`RE SULTS
`
`Eight of thirteen patients admini s ter e d si ngle doses of KS l /4-DAVLB
`deve l oped symptom s of gas troint esti nal tr act t oxici t y. Sev en of n i ne pat i e nt s
`admi nistered multipl e do ses of KS l/4-DAVLB also exp erie nce d the sa me type of
`toxic e ffe c t. These patient s acutely developed na usea, v omi ti ng , epigast ri c
`pain, and diarrh ea. The symptom s were not e d du r ing or s hort ly aft er compl etion
`of th e infus i on. Th e maximum tolerated dose was 25 0 mg/M 2 in the si ngl e do se
`and ap proximately a total cumulative do se of 400 mg in the multipl e dose s tudy .
`Several pati ent s had duodena l endoscopy at 24 t o 52 ho ur s after t he start of the
`infusion and bi opsies t a ken. The duodenal mucosa was observed t o b e edemato u s ,
`co nges t ed , and friable. Mi croscop i ca lly loss of vi ll ou s str uctur e, epit he li a l
`ce ll dege nera t io n , intense infiltration wi th polymorphonuclear and mononuc l ea r
`ce ll s , edema and vascular co ngest ion were noted. Th e lesion was r evers ibl e a nd
`permament damage to the duod e num did not occ ur in any patie nt.
`Two pa ti e nt s in the si ngl e do se study had e ndo scopy a nd duod e na l biop sies
`a t the onset of symptoms (approximately two hou rs after the s t art of the
`lnfusion). Gro ss and mi croscopic exa minat ion was norma l a t this t i me .
`Immunop eroxi dase studi es demonstrated signif ica nt binding of KSl/4 - DAVLB t o the
`In addition, Clq a nd CJ b deposi ti on on th e e pith e l i um was
`ep1thel 1al ce ll s .
`observed. Re pea t endos co py of the duod e num a t 24 hour s in these patie n t s revealed
`an edematous inflamed mu cosa wi th acute i nfl amma t ory c hanges on microscopic
`examination .
`Inte nse bindin g of KSl/4 - DAVLB t o the ep i th eli um a nd Clq a nd C3b
`depo si tion was also not e d a t this time.
`
`120
`
`100
`
`Ci .s
`Q) 80
`"'
`0
`0
`Ill 60
`...J > <(
`0
`~ 40
`(;;
`~
`
`20
`
`0
`
`<X>
`
`"'
`
`<X>
`
`"'
`
`"'
`
`<0
`
`;::
`
`10 111 213 1415
`
`Days
`
`FIGURE 1. KSI/4 - DAVLB Dos e Schedule for a Patient Administered Multipl e Do ses
`
`96
`
`IMMUNOGEN 2311, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`The dose sc hedul e for a participant i n th e multipl e do se s tudy i s s h own in
`Figure 1.
`Sympto ms d e v e lop ed at th e e nd of t he seco nd infu sio n of KS1/4 - DAVLB
`(day 3, 78 mg ) but they compl ete ly resolved by s i x hour s after th e infu s ion.
`Th is patter n p ersiste d for eac h of th e s ub seq u e nt infusions. However,
`pro gressiv e ly l ess KSl/4 - DAVLB was tolerated with eac h inf usio n and th e study
`wa s s topp e d after only 10 mg of the s ixth infu sio n.
`Ibi s patient developed a leuko c yto sis (polymorpho n u c lear) a nd re c urr e n t
`f e ver as s hown in Figure 2 .
`
`.--------------------------------------,106
`
`0
`
`Jy~ LL.
`
`100 r::i E
`
`Q)
`1-
`
`71
`v
`
`10
`v
`
`94
`
`67
`v
`
`8
`
`Day
`
`FIGURE 2. WBC a nd Te mp e ratur e Res pons es of th e Pati e nt Who Receive d KSl/4 - DAVLB
`as Shown in FIGURE 1.
`
`Serum a myl ase and ser um lipase re s pon ses i n thi s pati e n t are s hown in
`Fig u re 3 .
`
`78mg
`
`78
`v
`
`78
`v
`
`67
`v
`
`71
`v
`
`10
`v
`
`o Serum amy lase
`• Seru m li pase
`
`1100
`1000
`900
`800
`700
`-J 600
`:3
`500
`400
`300
`200
`100
`
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`Day
`
`16
`
`FIGURE 3 . Serum Amylas e and Lipase Responses of the Patien t Who Received
`KSl/4 - DAVLB as Shown in FIGURE 1.
`
`The se rum total protein , al bumi n and ca l ci um c hanges are s hown in
`Fi g ur e 4.
`
`97
`
`IMMUNOGEN 2311, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`8.,_-----------------------------------r 2o
`
`Ol .s
`10 E
`~
`::J ·o
`n;
`()
`
`Albumm
`
`~ 0
`
`10
`v
`
`FIGURE 4 .
`
`Serum Total Protein Albumin and Calcium Responses of the Patient
`Who Received KSl/4-DAVLB as Shown in FIGill~E 1.
`
`The r es ult s obtained with this patient was typical of most patients in the
`multiple dose study. However, one of the patients in the multiple dose study
`was able to tol erate nine i nfusions of KS1/4 - DAVLB (total dose 1026 mg) w1thout
`developing the gastrointestinal toxicity. Biopsy of duodenum after the last
`infusion revealed no evidence of inf l ammat io n despite i n tense binding of
`KS1/4-DAVLB to the epitheli um . Minima l C1q and CJb deposition was observed .
`This patient was on parenteral morphine throughout the st ud y for relief of tumor
`pain .
`This pati e nt had a biopsy of a large metastatic hepatic l esion (1° tumor
`lung) performed 48 hour s after the last dose. A 100 ~Ci dose of [ J H]- lab e ll ed
`drug was also administered with the co ld KS1/4 - DAVLB. Th e tumor tissue had
`41 ~ g equivalents KS1/4-DAVLB per g as compared to 11 ~g equivale nts per ml of
`pla s ma.
`Immunoperoxidase stud ies also demonstrated significa nt localization of
`KS1/4 - DAVLB to tumor cells. Biopsy of a n abdominal tumor ( 1° tumor colon
`adenocarcinoma) in a patient who had received a total dose of 3 70 mg also
`demonstrated signifi ca nt tumor localization.
`The mean pharma cokinetic cha racte risti cs of the thirteen patients who
`par ti cipated in the single do se study were as follows: elimination ha lf-life
`3~ hours, distribution volume 4.9 lit ers , systemi c c l earance 0.1 1/hour .
`S1gn1f1cant difference between these values were not observed when the IHMA, FCH
`3
`H] data was analyzed separ~tely .
`or [
`In the pat ie nt s admini stered radioactive
`drug, approximately ten and twenty percent of the admini stered radioactivity was
`r ecovered in the urine and feces over a five day period (9).
`HAMA r esponses to single 250 mg/M2 infusion s of KS1/4 - DAVLB is s hown in
`Fig~re 5. Ten of thirtee n patients in the single dose st udy developed an
`ant1body response to KSl/4-DAVLB infusion . Hesponses were first not ed
`approx1mately five to ten days after infusion and peak responses were observed
`three to four weeks after infusion. The amount of KSI/4-DAVLB infused did not
`correla t e with either peak titers or day of peak response. Six of the nine
`patients in the multiple dose study developed HAMA responses. Preliminary
`experiment s indicate that both anti - constant and anti - variable region antibodies
`to KSI/4 - DAVLB are made.
`
`DISCUSSION
`
`Epithelial cells of the gastrointestinal tract express the KS1/4 antigen.
`He s ult s fro m this study demonstrat e that KS1/4 - DAVLB is bindin g to the duod e nal
`epithelial as early as two hour s after the start of the infusion and the degree
`of bind i ng increases over the next 24 hour s . Of i nterest was the observation
`
`98
`
`IMMUNOGEN 2311, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Anti KSt/4-Antibocy level s
`CGF Dose= 250 mg/Meter Sq.
`
`3000
`
`Anti KS114·Antlbody levels
`NlP Dose= 250 mg/M eter Sq.
`
`An ti KS 11 4·Antibody l evels
`lBM Dose= 250 mg/ Meter Sq.
`
`Anti KS1 14·Antlbody levels
`OlS Dose= 250 mg/Meter Sq.
`
`Day - 1 Day 5 Day 12 Day 18 Day 26 Day 32
`
`3000
`
`2750
`
`2500
`
`2250
`
`2000
`
`i
`1750
`~ 1500
`;§ 1250
`
`1000
`
`750
`
`500
`
`250
`
`Day - 1 Day 5
`
`Day 8 Day 16 Day 20 Day 30
`
`FIGURE 5 .
`
`HAMA Res p o n ses t o Sin g l e 25 0 mg/M 2 Do ses o f KSl/4-DAVLB.
`
`t i me whe n th e
`th a t Clq a nd C3b dep os iti o n was no t e d o n du o d e n a l e pithe lium a t a
`mi croscop ic c hanges o f i nfl a ~nat i on h a d not y e t b een es t a bl is h e d . These r es ul ts
`s ug ges t
`that ac ut e c ompl e me nt a c tivation s ub se que nt to KSl/4 - DAVLB b i nding to the
`KS l /4 a nti ge n ma y b e r es pon s ibl e f o r or b e a ma j o r co ntributor t o th e
`p a thoge n es i s o f this l es ion. The inte n s ity o f this r eac t ion wa s do se r e l a t e d a nd
`comp l e t e ly r eve r si b le . The d e v elopme nt o f gas t ro intes tin a l
`t ox i c ity a l so limit e d
`th e numb e r o f d oses th a t c ould b e a dm i ni s t ere d to the p a t ie nt s wh o par ti cip a t e d
`l e uk ocyto s i s and febril e r es p o n se ob se rv e d in
`i n th e multipl e d ose s tudy. The
`t h e p at i e nt f rom the multipl e dos e study i s r e a d i ly e xplain e d by th e duod e niti s .
`The r ise i n serum a myl ase and lip ase l e vels s ugge s t s ass o c i a ted p a n c r ea tit is .
`Alt e rn a t ive ly, the r ise in th e se rum co n ce nt r ati on s of th ese enz ymes might
`r ef l ec t a b s o r pti o n ac r oss a dama ge d duo d e n a l mu cosa. Howeve r, n o t a ll of the
`pat ient s wh o d e v elop e d toxi c s ymptom s d e v e loped ri ses i n th e se rum l eve l s o f
`i n
`these e n z ymes . Th e dr o p i n the se rum t otal prot e in a nd a lbumin c oncentra tion s
`thi s p a t ie nt was a c on s t a nt findin g in all p a ti e nt s who d e v e lop e d t oxi c e ff ec t s
`in both th e si ngl e a nd multipl e d os e s tudi es . The s e c h a nges probably re f l ec t
`lo ss of these pl as ma p ro t e ins into th e
`lwne n o f the da mage d duodenum. The
`s t omac h mucosa h a d a n o r mal a ppe a ran ce i n a ll pati e nt s end osc op e d .
`Some p a ti e nt s
`h a d c ol o n scopy p er f orme d a nd n o eviden ce o f c oliti s was ob se rv e d . Mic ro sc opi c
`exa mi n a t io n o f
`th e se t iss u es wa s a l so norma l . The r eason fo r th e
`l oca li ze d
`duod e n i t is i s unknown a t thi s time . Of in te r es t was the ob se rv a tion t h a t a
`p a t ie nt o n p are nte r a l mo rph i n e d i d n o t d e v e l op th e
`t oxic effec t s o f KS l/4-DAVLB .
`Mi n i ma l or n o ac t i vat ion of th e compl e ment c a sca d e on duod e n a l e p i th e lium was
`note d i n thi s p a ti e nt . What ro le
`i f a ny, o f morphine in prot ec t i n g thi s
`p a t ient ' s du odenum fr om th e
`time .
`t oxic , e ff ec t of KSl/4-DAVLB is unknown a t thi s
`Si gn i fi ca nt tumo r
`l oc al i zat ion of KSl/4 -DAVLB wa s ob se rved d es pite the
`d os ing r es t ric ti o n
`i n th e multipl e d ose s tudy.
`t o th e a pp earan ce o f huma n
`The a dverse effec t s co uld n o t b e ascr ibe d
`an timu ri n e a nt i b o di es.
`In mos t cases the a ntib ody r es p o n se was not d e t ec t ed
`unt i l a ft e r conju ga t e a dmin is tr a t i on was s t oppe d du e to the d e v e lopme nt of
`gas troi ntes t i n a l
`to xici ty.
`
`99
`
`IMMUNOGEN 2311, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`In the single dose s tudy app rox i mately one-half the pat i e nt s serum
`co nce ntration-time profi l e curves were best fit by a single comp artment model and
`the other half by a two compartme nt model. The distribution ha lf-l ife varied
`from 1.4 to 5 . 7 hour s for tho se data best fit usi ng a two-compartment model. The
`decay of serum radioactivity following administration of [ 3 H] labelled
`KS1/4-DAVLB was identi cal t o the concentratio n decay of KS1/4 - DAVLB measured by
`immunologi c assays. This observation indicates that the circulating KS1/4-DAVLB
`co njugate remains intact.
`Anti -tumor activity was not observed in any of the patients st udi ed. The
`development of gastrointestinal toxicity l i mit ed the amo unt of KS1/4-DAVLB that
`could be administe red to pati e nt s. Results from preclinical studies wit h
`KS1/4-DAVLB s uggested that s ub stantial ly higher doses than those achi eved in the
`human s tudie s would be required to observe anti-tumor activity.
`
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`Schneck, D. W., Petersen
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`Address reprint requests to:
`Dennis w. Schneck , M.D ., Ph .D.
`Lilly Laboratory Clinical Research
`Wishard Hospital
`1001 West lOth Street
`Indianapolis , IN 46202
`
`Submitted April 4, 1989
`Accepted June 21 , 1989
`
`100
`
`IMMUNOGEN 2311, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
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