[CANCER RESEARCH 48, 4639-4645, August 15, 1988)

Three Novel Mouse Monoclonal Antibodies, OM-A, OM-B, and OM-C,Reactive with Mucinous Type Ovarian Tumors1

Katsumi Sakakibara, Ryuzo l'oda, Masahiro Olita, Nobuo Nakashima, Yutaka Tomoda, and Toshitada Takahashi2

Department of Obstetrics and Gynecology [K.S., Y. T.], Department of Clinical Laboratory [N. N.], Nagoya University School of Medicine, Showa-ku, Nagoya 466,Japan, and Laboratories of Chemotherapy [R. U.¡and Immunology [T. T.] and Department of Gynecology [M. O.J, Aichi Cancer Center, Chikusa-ku, Nagoya 464, Japan

ABSTRACT

Three mouse IgGl monoclonal antibodies (MoAbs) reactive predominantly with cytoplasmic antigens of mucinous type ovarian tumors wereproduced. OM-A MoAb was reactive with 11 of 14 mucinous type andtwo of three endometrioid type ovarian tumors, although only a minorpopulation of the tumor cells was positive in the latter type. This MoAbwas not reactive with serous type, clear cell type, or other types of ovariantumors, nor with various types of uterine carcinoma. Normal adult andfetal tissues of female genital organs were not positive with this MoAb.Among nongynecological carcinomas, three of six metastatic tumors tothe ovary from the gastrointestinal tract, one of five gastric carcinomas,and one of eight lung adenocarcinomas were positive. As for normal adultand fetal tissues of nongynecological origin, epithelium of the normalstomach, small bowel, and bronchus as well as epithelium of fetal smalland large bowel and secretory products were weakly positive. Thus, thisMoAb showed a selected specificity against mucinous and endometrioidtypes of ovarian tumors.

OM-B MoAb showed a broader specificity than OM-A, reacting withall mucinous type, two of three endometrioid type, and three of 16 seroustype ovarian tumors, but not with clear cell type tumors. Adenoma type,but not squamous type, cervical carcinomas and one-half of endometrialcarcinomas were positive. This antigen is present in cervical mucosa, butnot in ovary or endometrium. OM-C MoAb showed a specificity similarto, but broader than that of, OM-B; i.e.. 11 of 14 mucinous type, two ofthree endometrioid type, nine of 16 serous type, and one of nine clear celltype ovarian tumors were positive. It is reactive with adenoma typeuterine carcinoma and normal mucosa of the uterine cervix and withnormal surface epithelium of the oviduct. Among nongynecological tumors, OM-B antigen was present in metastatic tumors to the ovary aswell as in gastric and pancreatic carcinomas, while OM-C was in metastatic tumors to the ovary and gastric and colonie carcinomas.

Thus, the serological analysis showed that these three MoAbs showedselective specificities to mucinous and endometrioid types of ovariantumors. Preliminary characterization of these three OM antigens suggested that these are distinct from carcinoembryonic antigen or ABHblood group-related antigens.

INTRODUCTION

MoAbs3 have been produced against a variety of human

tumors including ovarian tumors, and several MoAbs havealready been applied for immunohistological diagnosis andserum diagnosis (1-5). Furthermore, even the treatment ofcarcinoma patients with MoAbs has been attempted (6, 7). Asfor ovarian tumors, OC-125 MoAb produced by Bast et al. (8)in 1981 is reactive with the antigen present predominantly onserous type ovarian tumors. CA-125 antigen, which is detected

Received 1/11/88; revised 5/9/88: accepted 5/19/88.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

' This work was supported in part by a Grant-in-Aid from the Ministry ofHealth and Welfare for the Comprehensive 10-Year Strategy for Cancer Control;a Grant-in-Aid for Cancer Research from the Ministry of Education, Science,and Culture. Japan: and a grant from the Cancer Research Institute, Inc., NewYork, NY.

2To whom requests for reprints should be addressed.' The abbreviations used are: MoAb, monoclonal antibody; CEA, carcinoem

bryonic antigen; ABC, avidin-biotin-peroxidase complex; IF, immunofluores-cence; M-MHA, mouse mixed hemadsorption; ELISA, enzyme-linked immuno-sorbent assay.

by OC-125 MoAb, has already been used for serum diagnosisof ovarian carcinoma patients, since it is often detected in thesera with non-mucinous type tumor, especially in those withserous type tumor (1, 9, 10). Several other MoAbs reactive withovarian tumors were also reported (2, 11-19), but only a fewshowed a selective specificity against mucinous type ovariantumors by immunohistological analysis (11, 13, 14). To date,no tumor marker restricted to mucinous type tumor is availableyet.

In this study, we attempted to produce MoAbs with IgGisotype reactive predominantly with mucinous type ovariantumors and obtained three IgGl MoAbs detecting novel cytoplasmic antigens of mucinous type tumors.

MATERIALS AND METHODS

Cell Lines. Cultured cell lines including ovarian carcinoma cell linesand representative lines expressing ABH-Lewis blood group antigens(20) were kindly provided by Dr. L. J. Old of Memorial-Sloan KetteringCancer Center, New York, NY.

MoAbs. Mouse MoAbs were produced according to the proceduredescribed by Kohler and Milstein (21), with a slight modification (22).The supernatant fluid was screened first by ELISA in order to obtainthe MoAb with IgG isotype. Thereafter, it was screened by immunohistological staining to select the MoAb reactive with the immunizingmucinous type tumor, but not (or very weakly) with serous type or clearcell type tumors, nor with dysgerminoma of the ovary.

A standard MoAb against CEA, CA208, was kindly provided by Dr.K. Imai, Sapporo Medical College, Sapporo, Japan (23), and OC-125was purchased from Centcore, Inc. (Malvern, PA). CA208 MoAb wasreported to show no reactivity to nonspecific cross-reacting antigen andNCA-2 (23).

ELISA. For determination of the isotype of the MoAbs, 96-wellplates (Nunc, Roskilde, Denmark) were first coated with goat anti-mouse IgG, heavy and light chain specific (Cappel, Malvern, PA), atthe concentration of 50 pg/m\, and then reacted with culture supernatant of hybridoma cells. The wells were incubated with horseradish-peroxidase-conjugated F(ab'>2 fragment goat anti-mouse IgG, Fc frag

ment specific (Cappel; diluted 1:1000), and developed with O-phenylene-diamine (1.5 mg/ml) and H2O2 (0.35 Ml/ml). After the reaction wasterminated with 5 mM NaNj, the extinctional wave length (492 nm) ofeach well was estimated.

For the reactivity of MoAbs against CEA, each well was first coatedwith purified CEA at the concentration of 10 Mg/ml, and then reactedwith MoAbs produced in this study as well as that against CEA.Thereafter, the procedure was the same as that described above. PurifiedCEA was kindly provided by Dr. K. Imai, Sapporo Medical College,Sapporo, Japan (23).

Immunohistological Staining. Tumor tissues and normal adult tissueswere obtained from postmortem and/or surgical specimens. Fetal tissues from 11 to 42 wk of gestation were obtained from therapeuticabortions. Tissues were embedded in O.C.T. compound (ICN, Lisle,IL) and quickly frozen in liquid nitrogen. Five- to N /mi thick frozensections were fixed with acetone for 10 min and then stained by theABC method using a Vectastain ABC kit (Vector, Burlingame, CA),followed by counterstaining with 0.125% methyl green for 10 min aspreviously described (24). The sections illustrated in the figures werevery lightly counterstained. Therefore, all nuclei are not visible. Thesefrozen sections were treated with 0.03% H2O2 in absolute methanol

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ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

after incubation with primary MoAb in order to block the endogenousperoxidase activity.

Sections were also prepared from formalin-fixed and paraffin-embedded tissues, stained with hematoxylin and eosin, and histologicallyexamined. Histológica! diagnosis was carried out based on WHOclassification (25). Some of the sections were stained with the ABCmethod as described above after cleaning of paraffin in xylene.

IF, M-MIIA. and Hemagglutination Assays. For the detection ofcytoplasmic antigen of cultured cells, an indirect IF assay was used,while M-MHA assay was performed to detect surface antigens aspreviously described (26). Hemagglutination assay was also carried outto detect blood group antigens as previously described (27).

Chemical and Enzyme Treatments. Periodate oxidation of the frozensections of antigen-positive tumors was accomplished with 10 or 100mM metaperiodate for l h at room temperature. Neuraminidase digestion (Behringwerke AC, Marburg, West Germany) of the frozen sections was carried out at the concentration of 0.1 unit/ml or 1 unit/mlat 37°Cfor 2 h. Heat stability of the antigens was also tested byincubation of the sections at 100'C for 15 min.

RESULTS

Establishment of Three Hybridoma Clones. Attempts weremade to obtain IgG MoAbs reactive predominantly with mu-cinous type ovarian tumors, and three hybridoma clones, OM-A, OM-B, and OM-C, were established. OM-A and OM-Cclones were derived from immunization with fresh tumor cellsof mucinous cystadenocarcinoma, while OM-B clone was produced by immunization with mucinous cystadenoma, low potential malignancy. The isotype of all these MoAbs was IgGl.

Reactivity of OM-A, OM-B, and OM-C MoAbs with CommonEpithelial Ovarian Tumors. Forty-three common epithelialovarian tumors including 14 mucinous type tumors were stainedwith these 3 MoAbs by the ABC method (Table 1; Figs. 1 to3). Among these, OM-A MoAb showed a most selective specificity to mucinous type ovarian tumors, while OM-B and OM-C MoAbs showed a similar specificity to each other, the formerbeing narrower than the latter. OM-A MoAb reacted with 11of 14 mucinous type tumors, but not with 16 serous type or 9clear cell type tumors. Two of three endometrioid type ovariantumors were also positive, but only less than 10% of the tumorcells was positive. OM-B MoAb reacted strongly with all mucinous type tumors and with 3 of 16 serous type tumors and 2of 3 endometrioid type carcinomas, although the percentage ofpositive cells was generally lower than 50% in the latter twotypes. OM-C MoAb was strongly positive with 11 of 14 mucinous type tumors and also with 9 of 16 serous type tumors and2 of 3 endometrioid type carcinomas, although the stainingintensity and the percentage of positive cells were lower in thelatter two types. Anti-CEA and OC-125 MoAbs were positivewith mucinous, serous, and clear cell types of ovarian epithelialtumors, but the distribution pattern of CEA and OC-125 positive cases was clearly different from that of OM-A, OM-B, andOM-C.

Reactivity of Three MoAbs with Gynecological Tumors andNormal and Fetal Tissues of Female Genital Organs. OM-AMoAb did not react with ovarian tumors of germ cell or sexcord stromal origin, nor with cervical and endometrial carcinomas of the uterus (Table 2). It reacted with 3 of 6 metastatictumors to the ovary from the stomach, although two amongthem were very weakly positive. Among the normal tissues ofthe female genital organs tested, none was positive with OM-AMoAb. OM-B MoAb reacted with 2 mature teratomas of 8germ cell tumors. This MoAb reacted with cervical adenocar-cinomas of the uterus (but not squamous cell carcinoma), andalso with 3 of 6 endometrial adenocarcinomas. Furthermore, it

Table 1 Jmmunohistological staining of common epithelial ovarian tumors withOM-A, OM-B, and OM-C MoAbs and two control MoAbs, CEA and OC-12S

Reactivity with MoAbs by the ABC method*

No.12345,678910111213141516171819,202122-242526272829303132,33343536,373839404142Histopathology"MucinousMMMLPMLPMLPMLPMLPMLPMBBBBSerousMMMMMMMMMMMLPMLPMClear

cellMMMMMMMEndometrioidMMMOM-A3++'3++—3++2+2+2+1+—3++3+2+-————————————-————————1+1

+OM-B3++3++2++3++3++3++3++3++3++3++3++3++3++2++1++1++————————————————-2++3+-OM-C2++3++2++3-t-f3++3++3++3++——3++3++-1+1+_1++1+1+1+—————-2+—————-1++2+-CEA3++3++3++1++2+3++3++3++3++—3++3++3+_1+2++3++1++1++_1++1+——2+—3+2++2++1++———2++2+1+OC-

125_3++3++—2++3+——3++—_2+—3++3++3+_3++3+3++3++2+3+2++3++3++2++1++——3++2+1++3++_2+

43Unclassified

M" Histológica! diagnosis was carried out based on WHO classification (Ref.

25). M, malignancy; LPM, low potential malignancy; B, benign tumor.* Frozen sections of tumor specimens were stained at the concentration of 5

Mg/ml of each MoAb, and the results were evaluated based on the histologicaldistribution and the staining intensity.

0Histological distribution (percentage of positive cells): 1, scare (

ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

Fig. 1. Immunohistological staining ofovarian mucinous cystadenocarcinoma withOM-A, OM-B, and OM-C MoAbs. Serial frozen sections prepared from the tumor tissue(Case No. 1 of Table 1) were stained by theABC method with OM-A (A), OM-B (B), andOM-C MoAbs (C), together with anti-CEAMoAb. OM-A (A) MoAb shows homogeneouscytoplasmic staining of the carcinoma cells,while OM-B (B) and OM-C (C) MoAbs stainpredominantly the apical part of the tumorcells, similarly to anti-CEA MoAb (D), x 50.

. .. .. . * ». r .

... ? Jf" V

_

Wi &••»-à :

Fig. 2. Immunohistological staining ofovarian mucinous cystadenoma with OM-A,OM-B, and OM-C MoAbs. Serial frozen sections prepared from the tumor tissue (CaseNo. 11 of Table 1) were stained by the ABCmethod with OM-A (A), OM-B (B), and OM-C (C) MoAbs, together with OC-125 MoAb(/>)•Adenoma cells are strongly stained withOM-A (A) and OM-B (A) MoAbs, whereasOM-C MoAb does not show positive staining(C), similarly to OC-125 MoAb (D), x 123.

gastric carcinomas. In addition, only a few other carcinomas (5of 41) were positive.

Reactivity of Three MoAbs with Normal Adult and FetalTissues of Nongynecological Origin. As shown in Table 4, OM-A MoAb reacted with bronchial epithelium and partially andweakly with surface epithelium of the normal stomach andsmall bowel and acinous cells of the pancreas. This MoAb alsoreacted with epithelium of small and large bowel and secretoryproducts in fetuses. OM-B MoAb reacted with epithelium ofthe stomach, gall bladder, and bronchus as well as with ductalepithelium of the pancreas. With regard to fetal tissues, itreacted with bronchial epithelium, stomach surface epithelium,goblet cells in small and large bowel, and secretory products.OM-C MoAb reacted with surface epithelium of the normalgastrointestinal tract and bronchus. In addition, it was weaklypositive with the medullary region of thymic epithelium. Infetuses, similar tissues were also positive with OM-C MoAb.

Preliminary Characterization of OM-A, OM-B, and OM-CAntigens. More than 30 cultured cell lines, including 7 ovariancancer lines, were tested with these OM MoAbs and anti-CEAand OC-125 by M-MHA and fixed cell IF assay to detect the

expression of the antigens on the membrane and in the cytoplasm, respectively. None of OM-A, OM-B, and OM-C MoAbsshowed a positive reaction by M-MHA with any of the celllines, including several standard lines expressing known ABH-Lewis blood group antigens (A, B, H-2, Le", Leb, Le", and LeY)

(20). By fixed cell IF, OM-A MoAb was virtually negative,while OM-B and OM-C MoAbs were reactive with a few lines,including one ovarian cancer line. In contrast, anti-CEA andOC-125 MoAbs showed positive reactions with 3 and 4 of 7ovarian cancer lines by M-MHA, respectively. These OMMoAbs were not reactive with normal or fetal human RBC ofvarious blood groups.

Since anti-CEA was positive with most mucinous type ovar-

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ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

A B

Fig. 3. Immunohistological staining ofovarian serous cystadenocarcinoma with OM-A, OM-B and OM-C MoAbs. Serial frozensections prepared from the tumor tissue (CaseNo. 25 of Table I) were stained by the ABCmethod with OM-A (A), OM-B (A), and OM-C (C), together with OC-125 MoAb (D). OC-125 MoAb shows a positive reaction with ad-enocarcinoma cells (D), whereas neither OM-A (X), OM-B (B), or OM-C (C) MoAb ispositive, x 50.

K*

Table 2 Reactivity of OM-A, OM-B, and OM-C MoAbs tested againstgynecological tumors and normal tissues of the female genital tract by the ABC

method

No. of positivetissuesTissuesTumor

tissuesOvaryCommon

epithelium"MucinousSerousClear

cellEndometrioidUnclassifiedGerm

ceirGranulosacellMetastati(/UterusCervical

carcinomaAdenoSquamousEndometrial

carcinomaLeiomyomaNormal

tissuesOvaryOviductCervical

mucosaEndometriumPlacentaFetal

tissues'"OvaryOviductNo.

tested431416931816633664435232OM-A10

(3)*10

(1)000

(2)000\'(1f000000000000OM-B17

(2)141

(2)0202"0y

ay3303000

(1)'3*0000OM-C13

(10)110

(9)11

(D02'02*0)*2

(D2(1)00

(1)000

(4)>3*0

(1)'002"

"Summary of Table 1.* Numbers in parentheses, number of tissue specimens with positive cells less

than 10% (see Footnote c to Table 1).' Two endoderma! sinus tumors, one dysgerminoma, one immature teratoma,

three mature teratomas. and one squamous cell carcinoma (dermoid cyst withmalignant transformation).

'' Bronchial-like epithelium and nonspecific mucinous gland of mature tera

toma.' Endoderma! sinus tumor and nonspecific mucinous gland of mature teratoma.

Five from stomach and one from rectum.* From stomach.

From rectum.' A minor population of secretory cells.' Reserved cells.* Mucosa! epithelium and mucus.'A minor population of endometrial cells.* Tissues from three fetuses (30, 32, and 42 wk of gestation)." Apical border of surface epithelium.

ian tumors by immunohistological study as shown in Table 1,the reactivity of the OM MoAbs against purified CEA wastested by ELISA. The results showed clearly that none wasreactive.

Formalin-fixed, deparaffinized sections were prepared fromseveral representative tissues, such as ovarian mucinous tumorand normal stomach, and were stained by ABC method. Whenthe reactivity of these MoAbs was compared with frozen tissuesections, the staining intensity with OM-B and OM-C MoAbsshowed a slightly weaker reactivity. No clear difference in thestaining intensity with OM-A MoAb was observed, althoughnonspecific staining of stroma tissues was occasionally observed.

Chemical treatment and enzyme digestion of the antigens infrozen tissues were also carried out. The staining intensity ofOM-A MoAb became very weak after periodate oxidation,while that of OM-B and OM-C MoAbs was slightly weakerthan the control. Regarding neuraminidase digestion, all theantigens were resistant. Heat stability of the antigens was alsotested, and it was found that OM-C was sensitive, but bothOM-A and OM-B were rather resistant. These results altogethersuggested that OM-A and OM-B determinants are carbohydrates, while OM-C determinant is, rather, a protein.

DISCUSSION

The present study demonstrated that three MoAbs, OM-A,OM-B, and OM-C, detect antigenic determinants present predominantly in mucinous type ovarian tumors. Among theMoAbs reported so far, three MoAbs, 1D3, MOv-1, and 4C7,showed good specificities to mucinous type ovarian tumors (11,13, 14). 1D3 MoAb reported by Bhattacharya et al. (Il, 28)reacts with mucinous type ovarian carcinoma, but not withmucinous adenoma of the ovary, nor with nonmucinous ovariancarcinomas. This antibody shows a similar specificity to OM-C MoAb, reacting with gastric and colonie carcinoma andnormal colon as well. As far as the specificity to gynecologicaltumors, OM-A MoAb has a slightly broader specificity than1D3 MoAb, because it shows a weak, but positive reaction withendometrioid type ovarian tumors as well. Although a few

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ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

B

Fig. 4. Immunohistological staining ofnormal ovary with OM-A. OM-B, and OM-CMoAbs. Serial frozen sections prepared fromthe normal ovary were stained by the ABCmethod with OM-A (A), OM-B (B), and OM-C (C) MoAbs, together with OC-125 MoAb(D). OC-125 MoAb is reactive with germinalepithelium of the normal ovary (D), as previously reported by Nouwen et al. (Ref. 3). butOM-A (A). OM-B (B). and OM-C (C) MoAbsare negative. (See Table 2.) X 123. >

\

Fig. 5. Immunohistological staining ofnormal cervical mucosa with OM-A, OM-B,and OM-C MoAbs. Serial frozen sections prepared from the normal uterine cervix werestained by the ABC method with OM-A (A),OM-B (B), and OM-C (C) MoAbs, togetherwith OC-125 MoAb (D). Cells consisting ofcervical mucosa are stained with OM-B (B)and OM-C (C) MoAbs, similarly to OC-125MoAb (D), but OM-A MoAb is negative (A).(See Table 2.) x 123.

\

i

.'

exceptional cases have been noticed, OM-A MoAb does notreact with gastric or colonie carcinomas in contrast to thepositive reactivity of l D3 or OM-C MoAb. This OM-A MoAbis, however, positive with one-half of the met astatic carcinomasof stomach origin to ovary, suggesting that the metastaticcarcinomas to ovary have a tendency to be more reactive withthis MoAb than the primary gastric carcinomas, although thenumber of the cases studied so far is relatively small. MOv-1MoAb reported by Tagliabue et al. (13) seems to show a similarspecificity to OM-A MoAb, although the number of mucinoustype tumors tested is very small. This antibody does not reactwith serous or endometroid tumors, showing a better specificitythan OM-A MoAb. MOv-1 MoAb is reactive with normalcolon, while OM-A is positive with fetal colon and normalstomach and small bowel; normal colon is not reactive. Tsuji etal. (14) reported 4C7 MoAb, which is reactive with mucinousand endometrioid types of ovarian tumors, similarly to our

MoAbs, and with the clear cell type of ovarian tumor as well.This MoAb is particularly interesting in that it does not reactwith any normal or fetal tissues tested, suggesting that theantigen detected is tumor specific.

As discussed above, the serological specificities of the threeMoAbs described by other investigators and our MoAbs aredifferent from each other. The nature of the antigen moleculesdetected, however, may be similar to each other; i.e., it ispossible that the determinants detected are present on mucintype glycoproteins which are very rich in this type of ovariantumor. Mucin as antigens has been studied by several investigators. Bara et al. (29) have reported a common antigen betweenovarian mucinous cystic fluid and mucin of the gastrointestinaltract. Recently, they produced 5 MoAbs reactive with oncofetalmucin Ml antigen by immunization with ovarian mucinousfluid (30). Although the reactivity against ovarian mucinoustumors was not examined yet, all these MoAbs are positive

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ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

Table 3 Reactivity ofOM-A, OM-B, and OM-C MoAbs tested againstnongynecological tumors by the ABC method

TumorCarcinomaEsophagusStomachColonPancreasKidneyLungSmallLargeAdenoSquamousBreastSarcoma*MelanomaCarcinoidNeural

tumor'LymphomaT-cellB-cellNo.

tested2552287875432722No.OM-A00(1)°000000(1)00000000of

positivetissuesOM-B03(2)0KD000000000000OM-C04500(1)001(1)0(1)1000000

* Numbers in parentheses, numbers of cases with positive cells less than 10%

(see Footnote c to Table 1).* Two leiomyosarcomas. one osteosarcoma. and one liposarcoma.' Two astrocytomas. one glioblastoma, one medulloblastoma, one neurinoma,

one meningioma. and one neuroblastoma.

Table 4 Reactivity of OM-A. OM-B, and OM-C MoAbs tested against fetal andadult normal tissues by the ABC method

TissueEsophagusStomachSmall

bowelLargebowelPancreasGall

bladderLiverKidneyBreastThyroidLungThymusSpleenBrainSkinNo.

ofadulttissuestested2113921122122112OM-AOM-BOM-CFetus"

Adult Fetus" Adult Fetus"Adult_

_____+»+«• +

ANTIBODIES TO MUCINOUS TYPE OVARIAN TUMOR

gland antigen defined by the OM-I monoclonal antibody is expressed at highdensity on the surface of ovarian carcinoma cells. Eur. J. Cancer Clin. Oncol.,21:1019-1035, 1985.

17. Poels, L. G., Peters, D., Van Megan, Y., Vooijs, G. P., Verheyen, R. N. M.,Willemen, A., Van Niekerk, C. C, Jap, P. H. K., Mungyer, G., and Kene-mans, P. Monoclonal antibody against human ovarian tumor-associatedantigens. J. Nati. Cancer Inst., 76: 781-791, 1986.

18. Miotti, S., Canevari, S., Menard, S., Mezzanzanica, D., Porro, G., Pupa. S.M., Regazzoni, M., Tagliabue, !•'...and Colnaghi, M. I. Characterization of

human ovarian carcinoma-associated antigens defined by novel monoclonalantibodies with tumor-restricted specificity. Int. J. Cancer, 39: 297-303,1987.

19. Ward, B. G., and Cruickshank, D. J. Circulating tumor-associated antigendetected by the monoclonal antibody HMFG2 in human epithelial ovariancancer. Int. J. Cancer. 39: 30-33, 1987.

20. Sakamoto, J., Furukawa, K..,Cordon-Cardo, C., Yin, B. W. T., Retting, W.J., Oettgen, H. F., Old, L. J., and Lloyd, K. O. Expression of Lewis', Lewis6,

X, and Y blood group antigens in human colonie tumors and normal tissueand in human tumor-derived cell lines. Cancer Res., 46: 1553-1561, 1986.

21. Kohler, G., and Milstein, C. Continuous cultures of fused cells secretingantibody of predefined specificity. Nature (Lond.), 256:495-497, 1975.

22. Ueda, R., Tanimoto, M., Takahashi, T., Ogata, S., Nishida, K., Namikawa,R., Nishizuka, Y., and Ota, K. Serological analysis of cell surface antigensof null cell acute lymphocytic leukemia by mouse monoclonal antibodies.Proc. Nati. Acad. Sci. USA, 79:4386-4390, 1982.

23. Kitagawa. II.. Ohkouchi, !•'..Fukuda, A., Imai, K., and Yachi, A. Character

ization of carcinoembryonic antigen-specific monoclonal antibodies and specific carcinoembryonic antigen assay in sera of patients. Jpn. J. Cancer Res.(Gann), 77:922-930, 1986.

24. Namikawa, R., Mizuno, T., Matsuoka, H., Fukami, H., Ueda, R., Itoh, G.,

Matsuyama, M., and Takahashi, T. Ontogenic development of T- and B-cells and non-lymphoid cells in the white pulp of human spleen. Immunology,57:61-69, 1986.

25. Serov, S. F., Scully, R. E., and Sobin, L. H. Histológica! typing of ovariantumors. In: International Histológica! Classification of Tumors, No. 9.Geneva: WHO, 1973.

26. Carey, T. E., Takahashi, T., Resnick, L. A., Oettgen, H. F., and Old, L. J.Cell surface antigens of human malignant melanoma: mixed hemadsorptionassays for humoral immunity to cultured autologous melanoma cells. Proc.Nati. Acad. Sci. USA, 73: 3278-3282, 1976.

27. Sakamoto, J., Yin, B. W. T., and Lloyd, K. O. Analysis of the expression ofH, Lewis, X, Y, and precursor blood group determinants in saliva and redcells using a panel of mouse monoclonal antibodies. Mol. Immunol., 21:1093-1098, 1984.

28. Gangopadhyay, A., Bhattacharya, M., Chatterjee, S. K., Barlow, J. J., andTsukada, Y. Immunoperoxidase localization of a high-molecular-weight niuein recognized by monoclonal antibody ID3. Cancer Res., 45: 1744-1752,1985.

29. Bara, J., Malarewicz, A., Loisillier, F., and Burtin, P. Antigens common tohuman ovarian mucinous cyst fluid and gastric mucosa. Br. J. Cancer, 36:49-56, 1977.

30. Bara, J., Gautier, R., Daher, N., Zaghouani, H., and Decaens, C. Monoclonalantibodies against oncofetal mucin M1 antigens associated with precancerouscolonie mucosae. Cancer Res., 46: 3983-3989, 1986.

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32. Pant, K. D., Fenoglio-Preiser, C. M., Berry, C. O. A., Zamora, P. O., Ram,M. D., Fulks, R. M., and Rhodes, B. A. COTA (colon-ovarian tumor antigen).An immunohistochemical study. Am. J. Clin. Pathol., 86: 1-9, 1986.

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1988;48:4639-4645. Cancer Res Katsumi Sakakibara, Ryuzo Ueda, Masahiro Ohta, et al. OM-C, Reactive with Mucinous Type Ovarian TumorsThree Novel Mouse Monoclonal Antibodies, OM-A, OM-B, and

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