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`IMMUNOGEN 2299, pg. 1
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`Papers
`
`Single-dose murine monoclonal antibody ricin
`A chain immunotoxin in the treatment of
`metastatic melanoma: a phase I trial
`
`Rene Gonzalez, MD,* Philip Salem, MD,T Paul A. Bunn, Jr., MD,*
`Alexander A. Zukiwski, MD,T Ray Lamb, MD,* Robert S. Benjamin, MD,T
`Lynn Spitler, MD,i Nancy Wedel, MD,§ and William A. Robinson, MD*
`*Division of Medical Oncology, The University of Colorado Cancer Center, Denver, Colorado,
`USA; 7"The University of Texas MD. Anderson Cancer Center, Houston, Texas, USA; iNorthern
`California Melanoma Center, Tiburon, California, USA; §Xoma Corporation,
`Berkeley, California, USA
`
`To determine the maximally tolerated dose of a ricin A chain-conjugated antimelanoma antibody
`(XomaZyme-Mel), 20 patients with metastatic melanoma were treated with escalating doses of the
`marine immunotoxin given as single intravenous infusion over 30 minutes. The starting dose was 0.6
`mglkg and was escalated infive groups to a maximum of].6 mg/kg. The maximally tolerated dose was
`1.25 mg/kg as three of six patients treated at 1.6 mg/kg developed unacceptable toxicity. The dose-
`limiting toxicity consisted ofprofoundfatigue, myalgias, and arthralgias. These occurred within 4 days
`and resolved in 7 to 10 days. Other non—dose—limiting toxicities encountered consisted of hypoalbu-
`minemia, weight gain, peripheral edema, mild hypotension, andfluJi/{e syndrome; the severity ofthese
`was also dose related. In addition, two allergic reactions occurred, one severe. There was one durable
`complete response of 12+ months" duration apd one brief mixed response lasting 3 months. We
`conclude that the maximum tolerated single dose of XomaZyme—Mel is 1.25 trig/kg. Phase I studies
`evaluating 1.25 mg/kg given in multiple doses at2- to 4—week intervals and phase II studies to determine
`the response rate ofa single 1.25 mg/kg dose are warranted,
`
`Keywords: Melanoma; monoclonal antibody; immunotoxin
`
`Introduction
`
`The incidence of malignant melanoma is increasing
`steadily. Among the white population in California and
`Australia, there are at least 15 cases per 100,000 indi-
`viduals, with doublc that rate in Hawaii' Approxi—
`mately 28,000 new cases were expected in the United
`States during 1990. At the present rate of increase it is
`estimated that by the year 2000, one of every 100 white
`individuals in the United States will develop malignant
`melanoma.2 Surgery has been successful in the early
`treatment of the primary tumor, but in its disseminated
`form melanoma has been poorly responsive to most
`conventional types oftherapy. With this in mind, there
`
`Supported in part by Public Health Services, Research grant no.
`MOl—RROUOS] from the Division of Research Resources, and by
`NIH grant no. 1P30CA46934»02 to the University of Colorado Can-
`cer Center for Clinical Investigation, Data Management, and Bio-
`statistics.
`Address reprint requests to Dr. Robinson, University of Colorado
`Cancer Center, Box B171, 4200 East 9th Avenue, Denver, CO
`80262, USA.
`Accepted for publication July 25, 1991.
`
`is an obvious need for newer modalities of treatment to
`be used separately or in combination with current
`strategies.
`The development of hybridoma methodology has
`greatly increased our ability to detect and characterize
`tumor—associated antigens. Monoclonal antibodies
`(MoAbs) have been used as therapeutic agents in a
`variety of malignancies,3‘12 including melanoma.”—18
`A number oi' melanoma-associated antigens have
`been described. The most common are high molec-
`ular weight cytoplasmic and membrane-bound anti—
`gens?”22 p97,” 3 and the melanoma-associated gan-
`gliosides GD2, >GM2,
`9-0-acetylatcd GD3,
`and
`GD3.13']4’24’25
`’ The MoAb L72, directed to the ganglioside GDZ,
`has been used for intralesional therapy of cutaneous
`nodules resulting in regression of a significant number
`of treated nodules.13 Systemically, murine MoAbs rec-
`ognizing high molecular weight antigens, the p97 mel—
`anoma-associated antigen, and the ganglioside GD3
`have been administered intravenously in escalating
`doses with no response};18 The antiganglioside GD3
`MoAb R24, an IgG3, has been associated with three
`partial and two mixed responses in 14 patients treated
`in this manner,16 possibly because of more efficient
`
`192
`
`© 1991 Butterworth—Heinemann
`
`Mol. Biother., 1991, vol. 3, December
`
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`mediation of complement and cell—mediated lysis of
`antibody-coated tumor cells. This highlights a possible
`limitation to the effectiveness of MoAbs: the finite ca-
`pacity of the immune effector system to eliminate an-
`tibody—coated tumor cells resultant from immunosup-
`pression due to prior treatments or inherent in the
`disease process itself.
`Because meaningful responses are unlikely to be
`achieved with naked MoAbs, conjugates with radio—
`isotopes or toxins have been developed. With regard
`to melanoma radioinnnunolllera y, Larsen el al26 ad-
`ministered therapeutic doses of " l-labeled Fab1 (50 to
`150 mCi) fragments of anti-p97 MoAb, with stabiliza-
`tion of disease in two patientsand a partial response in
`a third. In the area of immunotoxins, Spitler et [11.27
`conducted a phase I trial with murinc MoAbs coupled
`to the ricin A chain. Doses ranged from 0.01 mg/kg/d
`for 5 days to 1 mg/kg/d for 4 days. Encouraging clinical
`results were observed and toxicity was acceptable.
`Based on these data we implemented a phase I trial of
`XomaZyme—Mel in metastatic melanoma with the goal
`of determining the maximum tolerated dose (MTD)
`and of gaining additional information regarding effi-
`cacy.
`
`Methods
`
`Monoclonal antibody
`
`For the generation of the hybridoma, the hybridiza-
`tion, cloning, and recloning were performed according
`to the conventional procedure described by Kohler
`and Milstein28 with minor modifications.29 BALB/c
`mice were immunized with cultured human melanoma
`cells. The spleen cells were harvested and fused with
`the S—azaguanine—ristant murine myeloma line P3-X63—
`Ag8 in the presence of polyethylene glycol. The cells
`were cultured overnight, and resuspended in medium
`containing hypoxanthine, aminopterin, and thymidine.
`They were then cloned. Hybridomas secreting anti—
`bodies with the appropriate specificity were subcloned
`twice by limiting dilution using BALB/c splenocytes as
`feeder cells.
`The monoclonal antibody used in the preparation of
`the immunotoxin was produced from murine ascites
`and was purified by XOMA Corporation (Berkeley,
`CA, USA) using a staphylococcal protein A column
`with elution at pH 3.5. It is an IgGZa antibody and
`reacts with melanoma—associated antigens having mo-
`lecular weights of 220,000 and over 500,000. The hy-
`bridoma and the monoclonal antibody have been fully
`characterized in accordance with guidelines proposed
`by the Food and Drug Administration in “Points to
`Consider in the Production of Monoclonal Antibody
`Products for Human Use.” On frozen sections, the
`antibody shows minimal reactivity with normal tissues
`except for vascular endothelium, in which the reactiv—
`ity appears to be. cytoplasmic. The antibody also
`cross—reacts with nevus cells. The purified antibody
`contains neither virus nor parental hybridoma DNA or
`RNA.30 Both the hybridoma and the purified antibody
`
`Mol. Biother., 1991, vol. 3, December
`
`Ric/n A immunotoxin in melanoma: R. Gonzalez er al.
`
`are free of other murine viral contaminants as deter-
`mined by the mouse antibody production test.
`
`Ricin toxin A chain
`
`The ricin toxin A chain (RTA) was purified from castor
`beans by a series of column—based separations, includ-
`ing immunoaffinity chromatography.31 The RTA was
`greater than 95% pure, as judged by SDS-PAGE, and
`contained no detectable ricin or ricin toxin B chain by
`any assay including immunoprecipitation. The ICSO
`level of the purified RTA as measured by a reticulo-
`cyte lysate assay31 was less than 10 pM. This assay
`measures inhibition of protein synthesis in a cell—free
`system. In a mouse toxicity assay, RTA injected into
`BALB/c mice at 10 mg/kg produced no deaths.
`
`XomaZyme-Mel immunotoxin
`
`The immunotoxin, consisting of the murine monoclo-
`nal antimelanoma antibody conjugated to ricin A
`chain, is produced by XOMA Corporation. The con—
`jugation technique has been described in detail else—
`where.32 The immunotoxin is provided in a sterile, py-
`rogen—free formulation at a concentration of 1.0 mg/ml
`in 0.9% phosphate-buffered saline solution, pH 7.0.
`Preclinical testing demonstrated binding specificity of
`the immunotoxin similar to that of the unmodified an—
`tibody and cytotoxic antimelanoma activity both in
`vitro and in vivo.
`
`Patient population and treatment plan
`
`Patients entered on this study met the following crite-
`ria: age greater than 18 years, histologically docu-
`mented melanoma, measurable metastatic lesions be-
`yond regional lymph nodes, life expectancy of at least
`3 months, performance status greater than 80% (Kar-
`nofsky), leukocyte count higher than 4,000/dl, platelet
`count higher than 150,000/dl, serum albumin higher
`than 3.5 g/dl, hematocrit higher than 30% with no his-
`tory of blood transfusions for 3 weeks prior to treat-
`ment, creatinine less than two times normal, bilirubin
`less than two times normal, and written informed con—
`sent approved by the institutional review board. Pa-
`tients were excluded for the following reasons: brain
`metastases, chemotherapy or biologic agents within 4
`weeks of study entry, nitrosoureas within 6 weeks
`prior to study, anticoagulation therapy, pregnancy or
`lactation, history of prior therapy with murine antigens
`or known allergy to murine antigens, significant heart
`disease defined as uncentrolled arrhythmias, conges-
`tive heart failure, and uncontrolled angina or myocar-
`dial infarction within 6 months of study entry.
`The treatment plan called for a single intravenous
`infusion of the immunotoxin over 30 minutes. The
`starting dose was 0.6 mg/kg and was escalated in step—
`wise fashion by 25% until the MTD was determined.
`Prior to administration of the drug, a skin test was
`performed during which 0.1 ml containing 10 ug of
`immunotoxin (diluted with normal saline) was injected
`
`.‘-.l|
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`I.
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`Papers
`
`intradermally and the patient was observed for 30 min-
`utes. The skin test was considered negative if the re»
`sultant wheel was less than 5 mm; an intravenous chal-
`lenge dose of 0.2 mg to 0.4 mg was then administered.
`If no reaction occurred after 30 minutes, the full dose
`diluted in normal saline was administered as a slow
`intravenous infusion over 30 minutes under close med—
`ical supervision. The patients were observed for 24
`hours and were then assessed for toxicity using a stan-
`dard toxicity scale based on World Health Organiza-
`tion and criteria at days 4 to 5 and 7 to 8.
`The MTD was defined as that dose level which did
`not produce grade IV toxicity (excluding allergy). Tu-
`mor response was assessed at days 14, 28, and 60.
`A complete response was defined as the disappear—
`ance of all detectable disease For at least 28 days, par-
`tial response as: the average reduction ol'the product of
`the largest diameter and its perpendicular of each tu-
`mor mass by at least 50% for at least 28 days as mea—
`sured on clinical examination or radiographic studies,
`no response as average decrease of measurable dis—
`ease by less than 50% for at least 28 days, and pro—
`gressive disease as any measurable increase in tumor
`size or the appearance of new lesions. Duration of
`response was measured from the date of first docu—
`
`Table 1. Patient characteristics
`
`mentation of response to the date of disease progres-
`sion, death, or last patient contact. Survival was cal-
`culated from the date of starting the first cycle of
`therapy until the date ofdeath or last patient contact.
`”patients responded and subsequently relapsed they
`were eligible to receive a second course of treatment
`as long as they met the entry criteria.
`
`Results
`
`Twenty eligible patients were registered prior to treat-
`ment and received a total of 22 courses of treatment on
`this study. Patient characteristics are listed in Table 1.
`There were 13 men and seven women. The median age
`was '46 years (range, 24 to 69 years). All but three
`patients were previously treated, usually with immu—
`notherapy, chemotherapy, or combined modalities.
`All 20 patients are evaluable for toxicity. Acute side
`efi‘ecls are detailed in Table 2. The frequency and se-
`verity was generally dose related. Six patients were
`treated at the L6 trig/kg dose level. and three devel-
`oped dose—limiting toxicity manifested as grade lV fa-
`tigue (reduction of patients activity to <25%J. Also
`noted at this dose level were two episodes ol‘gradc llI
`toxicity: fatigue (reduction of activity to 25% to 50% of
`
`
`
`' Maximum
`weight
`Maximum
`Albumin
`increase
`Dose
`temperature
`nadir
`(% total
`level
`Performance
`Sites of
`Age
`Patient
`No.
`Sex
`(yr)
`metastases
`status
`(mg/kg)
`Prior therapy
`body weight)
`l% change)
`(“Cl
`
`1
`F
`41
`Lung
`100
`0.6
`lmuven
`11.6
`4.2
`36.8
`2
`M
`34
`$0
`100
`0.6
`lFN, lL-2/LAK
`13.9
`2.8
`36.4
`3
`F
`30
`LN
`100
`0.8
`IFN
`33.3
`6.7
`38.1
`4
`M
`58
`SO, LN, lung
`100
`0.8
`RT
`25.6
`ND
`37.4
`5
`F
`41
`$0
`100
`0.8
`BCG, ARA—C, CDDF,
`18.4
`5.8
`38.2
`lmuvert
`BCG, ARA-C, CDDP,
`Imuvert
`lFN
`None
`lFN, ECG
`RT, Vinblastine/CDDP,
`IFN
`None
`Piritrexim, lrnuvert
`Piritrexim, Imuvert
`None
`DTIC, |L-2, IFN, RT
`DTlC
`IFN, lmuvert,
`combination chemo
`lmuvert, Piritrexim,
`combination chemo,
`BCG
`
`5b
`
`6
`7
`8
`9
`
`10
`11
`11h
`12
`13
`14
`15
`
`16
`
`F
`
`F
`M
`F
`M
`
`M
`F
`F
`M
`M
`M
`M
`
`F
`
`41
`
`24
`69
`45
`36
`
`58
`46
`46
`57
`49
`37
`50
`
`36
`
`SO
`
`SC
`LN, lung
`$0
`Brain, SO,
`Bowel, lung
`SO, LN
`SO, lung
`SO
`SO, LN
`50, lung
`SO, LN, lung
`Lung
`
`SO, LN
`
`100
`
`100
`100
`100
`80
`
`100
`90
`90
`100
`100
`100
`100
`
`100
`
`0‘8
`
`1.0
`1.0
`1.0
`1.0
`
`1.25
`1.25
`1.25
`1.25
`1.25
`1.25
`1.6
`
`1.6
`
`15.8
`
`14.2
`266
`24.3
`30.9
`
`29.4
`23.4
`—
`35.2
`14.2
`15.3
`34.2
`
`21.4
`
`ND
`
`6.1
`3.9
`83
`ND
`
`3.4
`3.6
`—
`6.6
`2.2
`4.9
`6.7
`
`10.9
`
`38.7
`
`37.3
`37.6
`37.4
`37.5
`
`37.4
`39.1
`a
`37.8
`37.5
`38.5
`38.0
`
`37.5
`
`17
`18
`
`M
`M
`
`35
`69
`
`SO, LN, lung
`Lung, LN
`
`100
`100
`
`1.6
`1.6
`
`23.5
`24.4
`
`7.7
`4.1
`
`38.1
`37.7
`
`IFN, combination chemo
`|L»2/|FN/ACT—D, TN F,
`CDDP
`37.5
`5.7
`34.9
`lL-2/LAK, carboplatin, RT
`1.6
`100
`SO, lung, kidney
`60
`M
`19
`
`
`
`
`
`
`
`
`
`M 54 Lung 100 1.6 BCG, lL—2/lFN , 29.4 1.720 38.4W
`
`
`
`Abbreviations: SQ, squamous; LN, lymph node: IFN, interferon; |L»2/LAK, interleukin-2/Iymphocyte-activated killer cells; FlT, radiation therapy; BCG,
`bacille Calmettefiuérin; ARA-C, cytosine arabinoside; CDDP, cisplatin; DTIC, dacarbazine; combination chemo, dacarbazine, cispletin, BCNU, and ta-
`moxifen; ACT—D, actinornycin D; TNF, tumor necrosis factor.
`
`194
`
`Mol. Biother., 1991, vol. 3, December
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`Ric/n A immunotoxln in melanoma: Fl. Gonzalez er al.
`
`Table 2. Toxicity of XomaZyme—Mel at various dose levels
`
`Dose level (mg/kg)
`
`
`0.6
`0.8
`1.0
`1.25
`1.6
`Total
`
`Toxicity grade
`1
`2
`3
`4
`1
`2
`3
`4
`1
`2
`3
`4
`1
`2
`3
`4
`1
`2
`3
`4
`N
`
`Fatigue
`1 — — — 1 — 1
`——
`1
`2
`—— — — 1
`2 — — 1
`1
`3
`14
`
`1 — — — 2 i ; — 3
`1 — 12
`Arthralgias/myalgias
`2 — — — 1
`1 7 — 1
`1
`3
`—
`Weight gain
`! — —— — 1
`fl —
`2 — —
`7
`Hypoalbuminemia
`— 7 — —-
`3 — — — 3 ; — ——
`1
`1 — — 4
`1 — — 13
`Proteinuria
`— — A
`-— — — — — —— — i 1 — — ——
`4
`1 — e 6
`Fever
`— — — — 2 — — — —— —- — ——
`1
`1
`1
`——
`4 — — — 9
`Allergy
`—- — — —— — i e 1
`1 — — — — — — — — — — — 2
`Total
`'
`3 — — -—
`8
`1
`‘l
`1
`8
`3 — — 4
`5
`3
`——
`15
`6
`2
`3
`MW—
`
`70
`60
`35
`65
`30
`45
`10
`
`°/o
`
`195
`
`normal) and arthratgiaslmyalgias (requiring narcotics).
`The mean serum albumin felt from 4.“) i 0.42 gldl
`before treatment to a nadir ol' 3.| |
`:c 0.46 gftll. This
`was associated with a median weight gain of 5.3% i
`LEW/b of total body weight. usually with peripheral
`edema and signs of mild hypovolemia such as tachy-
`cardia attd a modest decrease in blood pressure. Se-
`rum creatininc did not change significantly from 0.69
`:t: 0.]9 ntgfdl pretreatment to ME 1' 0.39 mgldl post-
`trealmcnt. Clinically relevant proteinuria was not ob-
`served. These effects usually occurred within 4 days of
`drug administration and gradually resolved over the
`course of the next 7 to 10 days.
`Three patients also experienced t’evcr [P38.5°C} to
`a maximum of 39.1%? and other constitutional symp-
`toms such as anorexia but these were usually mild and
`sclfslintitcd. There was no evidence of hematologic
`toxicity or coagulopathy. Likewise.
`liver enzymes.
`urinalysis, cardiac enzymes, and serial electrocardio-
`grams remained stable.
`the
`Two patients suffered allergic reactions. At
`completion ol‘the infusion. one patient (no. 7, Table l)
`developed a rash, watery eyes. and swollen tongue,
`which responded to diphenhydratnine. Another pa-
`tient (no. 4. Table I} had a 9-mm wheat on skin testing
`and a negative intravenous challenge. After beginning
`the close of immunotnxin, the patient became [’lnshcd.
`nauscated, and light~headed Blood pressure dropped
`to 54ft). This quickly responded to interruption of the
`infusion. epinephrine, hydrncortisonc. and diphenhy-
`drainine.
`All 20 patients were evaluable for response. Fifteen
`progressed within 60 days and were removed from
`study. The remaining five patients had a response or
`stable disease lasting at least 60 days. Two ot‘ these
`(nos. 5 and I]. Table D had objective responses. Pa-
`tient no. 5 had a mixed response at day 60 and was
`retreated at the saute dose level at day 95. By day 35 of
`the second course. this patient had progressed and was
`removed from study. Patient no.
`it developed com-
`plete disappearance 'of lung and subcutaneous me-
`tastases gradually over the course of 1 year without
`further treatment. It was then felt that this patient had
`
`Mot. Biother., 1991, vol. 3, December
`
`relapsed at a solitary subcutaneous site and was re—
`treated at the same dose level. However, the patient
`continued to complain of pain; a fine needle aspirate of
`the suspected relapse was performed and resulted pos-
`itive for melanoma. This was resected 4 months after
`retreatment. There was no evidence of melanoma in
`the surgical specimen and the patient remains well and
`free of disease 24 months after initial treatment. The
`remaining three responding patients progressed at 3, 4,
`and 8 months.
`
`Discussion
`
`We have studied the administration of a single dose of
`murine monoclonal antibody conjugated with RTA in
`patients with metastatic melanoma. Patients were
`treated at five dose levels and data suggest that 1.25
`tngfkg represents the MTD. Higher doses cause severe
`fatigue and myalgiaslarthralgtas in the majority of pa-
`tients. both of which are reversible. The spectrum of
`toxicities encountered also includes flu—like syndrome
`and Itypoalbuminemia with weight gain. tachycardia.
`anti mild hypertension suggesting vascular leak. No
`bone marrow. ttcurologic, cardiac, hepatic. or renal
`toxicity was encountered. All of the side effects ap-
`peared to be dose related. Two additional patients de-
`veloped allergic reactions, one severe.
`Although the M’I‘D of 1.25 mglkg is somewhat sub-
`jective. we believe this is appropriate for the outpa-
`tient setting. Higher doses could be administered with
`the intent of admitting patients to intensive care units.
`Further studies to evaluate the effect of 1.25 mgfkg of
`XomuZyrne-Mel in multiple doses every 2 weeks are
`warranted.
`Most patients in the present study were heavily pre-
`treated, and only a single close of immunotoxin was
`used. Despite this there was an objective response. a
`mixed response. and three additional patients with sta-
`ble disease for (30 days or longer. The proposed mech-
`anism of action of this immunotoxin is the delivery of
`RTA into the ribosome with interruption of protein
`synthesis and cell death. improvement of the antintel~
`nnoma activity might be thSSilliC by increasing deliv—
`
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`
`cry of RTA to the cell using a different schedule of
`administration or an antibody that binds to different
`epitopes, although these approaches might be ham—
`pered by the development of antibodies to murine an-
`tigens or binding of the immunotoxin to circulating
`antigen. Improved efficacy might also be possible by
`developing ways to increase internalization and intra-
`cellular transport 01' RTA lo the ribosome. Finally, in
`the patient with the compielc response while the pro—
`posed mechanism may have been operative. the long
`interval between immunotoxin administration and the
`observed response suggests other factors, perhaps ac-
`tivation or other nonhumoral components of the im-
`mune system. This intriguing finding, although noted
`only in a single patient, requires further study.
`
`References
`
`1. Menck 1-1, Henderson BE: Cancer incidence in the pacific basin.
`Natl Cancer Inst Monogr 1985; 69:105—111.
`2. Kopf AW, Rigel DS, Friedman RJ: Thc rising incidence and
`mortality rate of malignant melanoma. J Dermatol Surg Oncol
`1982; 8:760—761.
`3. Miller RA, Maloney DG, Warnke R, at al: Treatment of B cell
`lymphoma with monoclonal anti-idiotype antibody. N Engl J
`Med 1982; 306:517—522.
`4. Meeker TC, Lowder .l, Maloney DG, e! a]: A clinical
`trial of
`anti-idiotype therapy for
`13
`cell malignancy. Blood 1985;
`65213494363.
`5. Ritz .l, Pesando JM, Slalan SE, 21 ul: Serotherapy of acute lym»
`phoblastic leukemia with monoclonal antibody. Blood 1981;
`589:141—152.
`
`6. Foon KA, Schroff RW, Mayer SA, el al; Monoclonal antibody
`therapy of chronic lymphocytic leukemia and cutaneous T-cell
`lymphoma: preliminary observations. In: Boss V, Langman R,
`Trowbridge IU, cl al. (eds): Monoclonal Antibodies and Can
`ccr. Orlando, 171., Academic, 1983; 39.
`7. Foon KA, Schrot't'RW, Burn PA, at al: Effects of monoclonal
`antibody serotherapy in patients with chronic lymphocytic len-
`kemia. Blood 1984; 64:1085—1093.
`8. Miller RA, Maloney DG, McKillop J, et (II: In vivo effects of
`murine hybridoma monoclonal antibody in patients with T»cell
`leukemia. Blood 1981; 58:78—86.
`9. Miller RA, Oseioff AR, Stratte PT, er a]: Monoclonal antibody
`therapeutic trials in seven patients with T—cell lymphoma. Blond
`1983; 62:988—995.
`_
`10. Dillman R0, Shuwlcr UL, Sobol RE, 21 ul: Murine monoclonal
`antibody therapy in two patients with chronic lymphocytic leu»
`kemia. Blood 1982; 59:1036—1045.
`11. Ball ED, Bernier GM, Cornwell CG 111. et al: Monoclonal an-
`tibodies to myeloid differentiation antigens:
`in vivo studies of
`three patients with acute myelogcnous leukemia. Blood 1983;
`6232034210.
`12. Sears HF, Atkenson B, Mattis J, et at: Phase I clinical trial of
`monoclonal antibody in treatment of gastrointestinal tumors.
`Lancet 1982; 1:762—765.
`13. his RF, Morton DL: Regression of cutaneous metastatic mela-
`noma by intralesional injection with human monoclonal anti-
`body to ganglioside GD2. Proc Natl Acaa’ Sci USA 1986;
`83:8694—8698.
`14. Ravindranath MH, Morton DL, lrie RF: An epitope common to
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`2E}.
`
`21
`
`22.
`
`23.
`
`ganglioside o-ncetyl GD3 and GD3 recognized by antibodies in
`malignant melanoma after active specific immunotherapy. Can—
`(27‘ Rex 1989; 49389173897.
`Goodman GE. Beaumier P, Hellstrom 1, er 0/: Pilot trial of
`murine monoclonal antibodies in patients with advanced mela—
`noma. J Clin Oncol 1985; 32340—352.
`Houghton AN, Mintzer D, Cordon-Cardo C, el al.‘ Mouse
`monoclonal IgG'l antibody detecting GD3 ganglioside: a phase I
`trial in patients with malignant melanoma. Proc Nail Acad Sci
`USA 1985; 82:1242—1246.
`In-
`Dippold WG, Knuth KRA, Meycrzumbuschenfcldc KH:
`flammatory tumor response to monoclonal antibody infusion.
`Eur J Cancer Clin Oncol 1985; 21:907—912.
`Oldham RK, Foon KA, Morgan AC, er al: Monoclonal antibody
`therapy of malignant melanoma: in Vivo localization in cutane-
`ous metastasis after intravenous administration. LCIin Oncol
`1984; 2:1235—1244.
`_
`Uincmuini P, Vegiin F, Cortliali
`ll'ei P, et a]: Level of a mem—
`brane-hound high-molecular-wcight melanoma—associated anti-
`gen and a cytoplasmic melt!norm-associated antigen in surgi»
`cally removed tissues and in set-u from patients with melanoma.
`('mit‘n‘ RH 1934: (14:1281—1287.
`Naitnli 13:11. liigotti A. Cavaliers: R. at (11': l’hcnolyping of lesions
`of melnnncyle origin with melanonm-associated antigens and to
`“LA-antigens. J Natl Cancer Inst 1984: ?3: 13—24.
`Nntali PG. Imai R. Wilson 133. w m': Structural properties and
`tissue distribution ol‘thc antigen recognized by the monoclonal
`antibody {153.4% to human melanoma cells. .i Not! (Tana-i- hm
`19111: {17591—6111.
`Garrigues H], Tilgen W, Hellstrom I, el al: Detection of a hu~
`Innn meInpuma—associated antigen. p97. in liistolngic section!- of
`primary human melanomns. in! J (.‘mrrt'r 1983, 29:511—5I5.
`Brown JP. Wooilhm'y RU, Hart CE. ('1' nl: Qumniuitivc analysis
`or Inelnnonin-nssuuiutctl antigen p97 in normal um! neoplnslic
`lissucx.
`i‘r'm‘ Null f‘trrm' Sci USA 1931: 78:539—543.
`. Cnruhin JM, Yu 11K. Macnln 1.1. or rel: Gangliomdcs ol' normui
`and neoplastic: Inelnnncyles. Hindu-m Hiripltju' Res Cmnmmr
`1913-1:
`IEUfiDUaSD-l.
`. ‘l'scuchitln '1'. Suntan RF. Morton ”1.. or oi: (iangliosides 01‘
`inmnm melanoma. J Nrfl.’ Crow-r hm 198?; 78:45-54.
`. Lnrsnn SM. (Turrilsqnillo 1A, Krohn KA. or at: Loenlimtion ol'
`IJI-l-hihelletl [aw-specific Fab fragments in human melanoma
`us at basis of rndiolllcrapy. .1 Clin ill't‘i’n'f 19113; 72:2101—211-1.
`. Spiller 1-1:.
`that Rio M. thntigun A. er ni: 'l'hcrnpy ol'palicnls
`with malignant melanoma using :1 monoclonal :itllilnelnnoma tin-
`tibody—I'icin A chuin imniunuluxin. (.‘rmr'erKc‘s 1937;427:171?-
`1723.
`Kohler G, Milstein C: Continuous cultures offused cells secret-
`ing antibody of predefined specificity. Nature 1975; 256:495—
`497.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`Qlinrumzt V. linai K, Molinarot'lA. er of: Manufacture ot'mono-
`clunnl antibodies to human meinnonia associated and hislocum—
`putibility antigens. In: Nukaniuru RM. Dilo WR. Tucker ES
`(oils).
`intiminonssays: Clinical Laboratory 'l'cchniqnes for the
`1980's. New York. Liss. 1980‘. 301—324.
`'
`Levy 1A. Lee HM. KuWahata RT, 21 al: Purification of mono-
`clonal antibodies from mouse ascitis eliminates contaminating
`infectious mouse type c viruses and nucleic acids. Clin Exp
`hnmmm.’ 191111: 56: | lit—120.
`Kernan NA, KnoWles RW, Burns M], el al.‘ Specific inhibition
`of in vitro lymphocyte transformation by an anti—pan T cell
`(gp67) ricin A chain immunotoxin. J Immunol 1984; 133:1377
`146.
`
`Scannon PJ, Spiller LE, LeeHM, er a]: Human melanoma spe-
`cific immunotoxins. United States Patient No. 4,590,071, May
`20, 1986.
`
`196
`
`Mol. Biother., 1991, vol. 3, December
`
`
`
`IMMUNOGEN 2299. pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`IMMUNOGEN 2299, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`