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H F Sears

Publications and source records attributed to H F Sears.

At least 19 recordsLinked to original sources
PubMed1993

Expression of colorectal carcinoma-associated antigens in colonic polyps.

Immunohistologic techniques were used to study the expression of colorectal carcinoma-associated antigens in colonic polyps and to compare this with expression in the normal colonic epithelium. Forty-nine polyps were studied using monoclonal antibodies to 16 different blood group and differentiation antigens and carcinoembryonic antigen epitopes. With the Lewis(a) antigen and the two epitopes of CEA recognized by 3D6 and COL-4 expression in polyp tissue was the same as that in the normal colon. Five types of alteration of antigen expression in polyps were seen. The blood group antigens A, B, and Lewis(b), which are expressed only on the right side of the normal adult colon, were detected in both neoplastic and nonneoplastic polyps from the distal colon. The Lewis(x) antigen and the antigen epitopes detected by the antibodies COL-12, CA19-9, ME491, and GA73.3 showed an increased frequency of expression in all types of polyps in comparison with the normal colonic epithelium, while H-type 2, ND4, and the antigen epitope detected by CO29.11 showed a slightly decreased frequency of expression in polyp tissue. The X-like antigen which was expressed in only 7% of normal colon specimens showed increased frequency of expression in polyp tissue with significantly greater expression in neoplastic than hyperplastic lesions (P = 0.003). The TAG-72 antigen was detected only in adenomas with severe dysplasia (P = 0.01), correlating well with premalignant histology. These findings have helped us clarify the variation of antigen expression in colonic polyps and allowed us to define which antigens are worthy of further investigation as markers of possible malignant transformation.

ABO Blood-Group System↗
PubMed1991

Initial clinical evaluation of two murine IgG2a monoclonal antibodies for immunotherapy of gastrointestinal carcinoma.

Eleven patients with advanced gastrointestinal (GI) carcinoma were entered in Phase I initial clinical trials with IgG2a antiGI carcinoma monoclonal antibodies (MAbs) GA733 (five patients) or CO19-9 (six patients). Infusion of MAb GA733 in doses greater than 30 mg was accompanied by mild and short-lasting GI toxicity. Infused MAb GA733 was bound to each patient's tumor tissue in vivo. MAb circulated in the blood for 10-25 days. All patients developed anti-mouse antibodies between 15 and 60 days post infusion. Furthermore, all but one patient raised anti-idiotypic antibodies against MAb GA733. Following administration of 10-600 mg of MAb CO19-9, no immediate or delayed toxicity symptoms were noted. Binding of infused MAb CO19-9 to tumor cells in vivo could not be detected in any of the six patients studied. The MAb circulated in the bloodstream between 5 and 12 days. Human anti-mouse antibody was detected in sera of three patients. None of the eleven patients treated with either MAb had anti-tumor responses in this Phase I clinical trial. The strong binding reactivity of MAb GA733 to tumors in vivo suggests the use of this MAb in cancer patients with less tumor burden to determine the tumoricidal efficacy of this antibody.

Animals↗
PubMed1989

Detection of the tumor-associated glycoprotein antigen (TAG-72) in premalignant lesions of the colon.

We used monoclonal antibody B72.3 to study the expression of the colorectal carcinoma-associated antigen TAG-72 in premalignant colonic lesions with the immunoperoxidase technique. This antigen, which is rarely detectable in the normal colonic epithelium, was expressed in 13 of 19 adenomas with moderate to severe dysplasia and nine of nine cases of inflammatory bowel disease. The antibody reacted with the normal-appearing mucosa adjacent to a carcinoma in 10 of 12 cases, although only eight of the tumors expressed the antigen. The expression of the TAG-72 antigen in the colonic epithelium may be an early marker of malignant transformation.

Antibodies, Monoclonal↗
PubMed1989

The expression of colorectal carcinoma-associated antigens in the normal colonic mucosa. An immunohistochemical analysis of regional distribution.

Immunohistologic studies were performed to evaluate the expression and regional distribution of 20 colorectal carcinoma-associated antigens in the colonic mucosa of 12 normal adults. A distinct regional variation was seen in the expression of blood group A, B, Lewis(b), and extended Lewis(y) antigens, which were expressed predominantly in the right colon, whereas Lewis(a), Lewis(y), and H-type 2 were prevalent throughout. Lewis(x) and X-like antigens were only occasionally expressed. Two antibodies against sialylated Lewis(a) showed different staining patterns, with CA19.9 positive in only two biopsies and CO29.11 intensely positive in most. Two of the three antibodies detecting carcinoembryonic antigen epitopes (3d6 and COL-4) stained many biopsies, whereas COL-12 was rarely detected. No regional gradient was found in the expression of the other antigens studied (B72.3, ME491; GA73.3, ND1, and ND4). This mapping data will provide an important baseline for future studies of epitope distribution in the colon in premalignant and neoplastic conditions.

ABO Blood-Group System↗
PubMed1988

A cell surface glycoprotein expressed by colorectal carcinomas including poorly differentiated, noncarcinoembryonic antigen-producing colorectal tumors.

A monoclonal antibody to a cell surface glycoprotein on human colorectal carcinomas was raised using the undifferentiated colon carcinoma cell line MIP 101 as the immunogen. This antibody, ND4, is an IgG2a which does not cross-react with carcinoembryonic antigen (CEA), non-specific cross-reacting antigen, or blood group substances A, B, and H. Immunoprecipitation using lysates of cells grown in [35S]methionine or [3H]glucosamine and lysates of cells surface labeled with 125I showed binding to a cell surface glycoprotein with a molecular weight of approximately 160,000. Indirect immunofluorescence showed binding to the cell surface of 14 of 15 human colorectal carcinoma cell lines including six of six that do not secrete CEA. Two of seven human noncolorectal carcinoma lines and one of six nonhuman cell lines also bound antibody. Immunoperoxidase staining of formalin-fixed tissues showed prominent antibody binding with 19 of 33 (58%) human colorectal carcinomas, including five of six poorly differentiated tumors, five of 43 (12%) normal colonic mucosal biopsies, and one of 17 (6%) normal noncolonic tissues. One of 11 (9%) noncolonic tumors, a gastric adenocarcinoma, stained with ND4. Preliminary data obtained by a nonquantitative nitrocellulose dot-immunoassay have tentatively identified this glycoprotein in the serum of 15 of 37 (41%) patients with colorectal cancer. Three of the 15 patients had early stage disease and normal CEA levels (less than 2.5 ng/ml). Three patients had circulating antigen detectable preoperatively but not after tumor resection. Only one of 11 (9%) sera samples from normal subjects was positive. The characteristics of ND4 suggest that it may be of value in monitoring patients with colorectal carcinomas who do not have plasma CEA elevations. It may also be of value in the differential diagnosis of metastatic, poorly differentiated adenocarcinomas of unknown primary origin.

Animals↗
PubMed1987

Human immune response to monoclonal antibody administration is dose-dependent.

When mouse monoclonal antibodies (MAbs) are injected into patients they usually induce an immune response. The resultant human anti-mouse-immunoglobulin antibody (Hu-aMAb) limits multiple injections of these reagents. A strategy to decrease the production of Hu-aMAb was tested in 20 patients with advanced gastrointestinal carcinoma. Ten patients received 700 mg of MAb as their initial exposure to mouse immunoglobulin, while the other ten patients received 100-mg of immunoglobulin initially. Each group received the same maintenance regimen until Hu-aMAb or disease progression was detected. Six patients in the high-dose group did not produce detectable Hu-aMAb for up to five months after initial exposure. All ten of the patients who received the low initial dose developed Hu-aMAb. Allergic reaction did not occur in the absence of Hu-aMAb. This larger initial dose in vivo injection strategy may allow repetitive exposure to MAb reagents without Hu-aMAb limiting further diagnostic or therapeutic use of murine immunoglobulin.

Animals↗
PubMed1986

A radioimmunoassay for the detection of a human tumor-associated glycoprotein (TAG-72) using monoclonal antibody B72.3.

Monoclonal antibody (MAb) B72.3 was generated against a carcinoma metastasis and has been shown to bind with a high degree of selectivity to a tumor-associated glycoprotein (TAG-72) found in human colon and breast carcinomas, while showing minimal reactivity to any normal adult tissues. Competition radioimmunoassays have been developed for the detection of TAG-72 in tumors and sera from both athymic mice bearing human carcinoma xenografts and patients with colon, breast and other carcinomas. The distribution of TAG-72 in human tumor xenografts was restricted to tumors originating from the LS-174T human colon carcinoma, with no significant reactivity being detected in human tumor xenografts from a different colon carcinoma, a human breast carcinoma, or a human melanoma. The levels of TAG-72 in clinical material obtained from surgery were examined; high levels were found in colon carcinomas and to a lesser extent in breast carcinomas, while no detectable levels were found in normal tissues. Sera from apparently normal patients contained a mean level of 2.2 units per ml of TAG-72. A level of 3 standard deviations above the mean level of TAG-72 found in normals was employed as a cut-off value to indicate a positive test result in subsequent studies. No patient with inflammatory disease or other benign colon disease exhibited elevated levels of TAG-72. Seven out of 20 patients with other carcinomas had elevated serum levels of TAG-72. The serum TAG-72 levels were compared with the serum levels of antigens recognized by the MAbs currently used to screen sera of carcinoma patients (CEA, GICA, and OC125). It was clearly demonstrated that TAG-72 is different from these antigens and can be found in some sera in which no antigen is detected by otherwise available MAb RIAs.

Animals↗
PubMed1986

Bilateral breast carcinoma: prospective evaluation of factors assisting diagnosis.

Bilateral primary breast cancers occur commonly enough to justify adoption of special pre- and post-initial therapy screening. A 13.2% incidence of bilateral breast carcinoma has been found in the breast cancer patients who presented to the Fox Chase Cancer Center with an operatively manageable primary in an arbitrarily defined 30-month period and who have been followed for at least 20 months thereafter. Of the 287 patients seen in those 30 months, 4.5% had synchronously detectable lesions. Xeroradiography is helpful in the initial and follow-up evaluation of the patient for detection of a second primary and may lead to the discovery of an earlier-stage lesion. A history of a family member having a breast cancer was shown to be significant, 26% and 24% for primary and secondary relatives, respectively, and warrant a special screening strategy. Recognition of these factors may lead to earlier detection of curable breast cancers.

Adenocarcinoma↗
PubMed1986

Biologic effects of gamma interferon pre-treatment followed by monoclonal antibody 17-1A administration in patients with gastrointestinal carcinoma.

Twenty-seven patients with metastatic adenocarcinoma of the colon or pancreas were treated with 400mg of monoclonal antibody 17-1A. This antibody, which binds to a cell surface glycoprotein moiety preferentially expressed by adenocarcinomas of the rectum, colon, pancreas, and stomach, is postulated to induce antibody-dependent monocyte cytotoxicity (ADMC) as a mechanism of tumor lysis. Therapy was preceded by four days of gamma interferon infusions, with the intent of activating peripheral blood monocytes, enhancing monocyte Fc receptor expression and increasing the likelihood of tumor lysis as reflected by enhanced ADMC directed against a colon carcinoma cell line (SW1116) which expresses 17-1A's target antigen. In this Phase I study patients were treated daily at one of the following gamma interferon dose levels (X 10(6) U/M2/day): 0.001, 0.01, 0.1, 1.0, 10.0, 40.0, 60.0, 80.0. Addition of 100 U/ml of rIFN-gamma in vitro to monocytes isolated from normal controls or from patients prior to treatment significantly enhanced monocyte Fc receptor expression and ADMC. in vitro tumor cell killing by monocytes and monoclonal antibody was enhanced by treatment with low doses of rIFN-gamma, while treatment with high doses of rIFN-gamma did not enhance ADMC. No objective clinical responses were noted, although serum tumor markers dropped transiently in 36% of the treated patients. Seven of 11 assayed patients developed human anti-idiotype antibodies. With better scheduling of rIFN- and 17-1A we hope to duplicate optimal in vitro conditions for antibody-mediated cytotoxicity, hopefully enhancing in vivo antibody mediated tumor lysis.

Adenocarcinoma↗
PubMed1986

Multiparameter evaluation of the expression in situ of normal and tumor-associated antigens in human colorectal carcinoma.

The immunoreactivity of a panel of monoclonal antibodies (MoAb) was studied in a series of patients with colorectal carcinomas to test the association of antigen expression with other parameters such as histopathologic stage, differentiation, and clinical outcome. Low-level binding to normal tissue and high-level binding to malignant tissue were observed with MoAb defining, respectively, a gastrointestinal cancer antigen (GICA), Leb (distal colon only), A, H type 2 antigen, X-like antigen, and the 200-kilodalton (Kd) protein of carcinoembryonic antigen (CEA). The degree of histologic differentiation correlated with the expression of Lea antigen, A, and Y haptens, whereas a progressive loss of these antigens coincided with loss of differentiation. Two undifferentiated carcinomas expressed only two, H type 2 antigen and a highly glycosylated protein of 20-50 Kd, of the 14 antigens investigated. An interesting, but not significant, association between Leb antigen expression and more extensive disease was found: Whereas 71% of Dukes C tumors were positive for Leb, only 48% of patients with Dukes A and B2 tumors showed the presence of Leb antigen. On the other hand, the presence of B72.3-defined antigen is significantly associated with an earlier stage of disease. Chi-square tests to assess the association of antigen positivity with disease recurrence indicated a significant binding association with tumor recurrence over a broad range of percent positive cells for two MoAb defining different determinants of GICA. Similar associations, but over a narrow range of positive cells, were found for H type 2 antigen and the 200-Kd protein of CEA.

ABO Blood-Group System↗
PubMed1986

Detection of murine immunoglobulin in human tissues following therapeutic infusion of monoclonal antibody.

A class switch variant of hybridoma CO19-9 secreting IgG2a antibodies was shown to have the same immunoperoxidase binding pattern in human tissue as the IgG1 antibody secreted by the parental hybridoma. The IP tissue binding of GA73.3 and 17-1A monoclonal antibodies which have been suggested to bind to structurally related antigens were compared; although quite similar in distribution, some differences were noted. GA73.3 bound to 12/12 colon carcinomas compared to 17-1A which reacted with 11/12 tumors. In several cases, the percentage of cells reactive with GA73.3 (90-100%) exceeded those reactive with 17-1A (10-25%). Additionally, the intensity of reactivity for GA73.3 was consistently greater than that seen with 17-1A. The detection of murine antibody bound to human tissues following therapeutic infusion of 19-9 IgG2a or GA73.3 differed. Detection of antibody-antigen complexes was seen less often in patients who had received 19-9 IgG2a (2/6) than in patients who had received GA73.3 (5/5). Additionally, the presence of murine immunoglobulin was seen only in the extracellular mucin of the patients receiving 19-9 IgG2a, whereas strong cellular binding of murine immunoglobulin was noted following infusion with GA73.3.

Animals↗
PubMed1986

Trial of therapy with monoclonal antibody 17-1A in pancreatic carcinoma: preliminary results.

Monoclonal antibody 17-1A was administered to 25 patients with advanced unresectable carcinoma of the pancreas. Ten patients received 17-1A alone in 400 mg doses delivered intravenously, while 15 patients received 400 mg 17-1A absorbed on to autologous peripheral blood mononuclear cells collected by leukapheresis (usual yield greater than 10(9) cells). No toxicity was observed. Twenty-three patients developed circulating anti-murine immunoglobulin within three weeks of treatment, and 11 patients developed circulating anti-idiotypic immunoglobulin. Four out of 19 clinically evaluable patients (21%) showed objective regressions of tumor. Response did not correlate with the presence or absence of anti-idiotypic antibody and did not correlate with the method of treatment with 17-1A alone or 17-1A and mononuclear cells, at the time of current analysis.

Antibodies, Monoclonal↗
PubMed1985

Selection of monoclonal antibodies detecting serodiagnostic human tumor markers.

Monoclonal antibodies (MAbs) were selected for specific binding to spent media of cultured tumor cells. Out of more than 12,000 hybridomas screened, 19 were selected in preliminary inhibition assays for secretion of MAbs which detected antigens in cancer patients' sera. Antibody CO 29.11, which was studied in detail, bound to an antigen shed and expressed by adenocarcinoma cells of colon, stomach, pancreas and urinary bladder. CO 29.11 bound to purified sialylated Lewis a (Lea) antigen but to a different epitope and with a higher binding affinity than the MAb CA 19-9. CO 29.11 but not CA 19-9 bound weakly to unsialylated Lea antigen. In double-determinant radioimmunoassay with sera of patients with colorectal carcinoma, CO 29.11 was found to be a more sensitive marker than CA 19-9 for the detection in serum of sialylated Lea antigen.

Antibodies, Monoclonal↗
PubMed1985

Characterization of Lewis antigens in normal colon and gastrointestinal adenocarcinomas.

The Lewis a antigen (Lea)- and Lewis b antigen (Leb)-active glycolipids and glycoproteins in normal colon mucosa, colon carcinoma tumors, and gastrointestinal tumor cell lines were studied by using monoclonal antibodies against Lewis determinants in solid-phase radioimmunoassay, chromatogram binding assay, and immunoprecipitation/PAGE. Lea-5 was a major component of the purified non-acid glycolipid fraction from normal colon mucosas from four patients examined and Lea-7 was a minor component in three of these four cases. Lea in colon carcinoma of the same patients was expressed as Lea-5 in all four cases and as both Lea-5 and Lea-7 in one of the four cases. All normal colon mucosa samples expressed Lea but not Leb. Leb-6 was expressed in all tumors obtained from the same patients as normal colon mucosa (Leb negative) samples and in the gastrointestinal tumor cell lines. These findings indicate that Leb is a colon adenocarcinoma-associated antigen and that Lea and Leb are coexpressed in tumor tissue. Evidence is presented for the coexistence of Lea and Leb carbohydrate determinants in both glycolipid and glycoprotein forms in the same cells.

Adenocarcinoma↗