Clinical Effects of Monoclonal Antibodies (MAb 17-1A) in Patients with Metastatic Colorectal Carcinomas

Frödin, Jan‐Erik; Harmenberg, Ulrika; Biberfeld, Peter; Christensson, Birger; Lefvert, Ann‐Kari; Rieger, Åke; Shetye, Jayant; Wahrén, Britta; Mellstedt, Håkan

doi:10.1089/hyb.1988.7.309

Cited by 46 publications

(11 citation statements)

References 17 publications

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“…Several immunotherapeutic trials of human cancer using mAbs showed encouraging results [3,5,6,9,[16][17][18]. The mechanisms involved in such antibody-directed tumor remission remain obscure.…”

Section: Introductionmentioning

confidence: 99%

Biological activity in the human system of isotype variants of oligosaccharide-Y-specific murine monoclonal antibodies

Scholz

Lubeck

Loibner

et al. 1991

Cancer Immunol Immunother

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The capacity of isotype variants of BR55-2, an anti-tumor monoclonal antibody directed against Y oligosaccharide, to mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in the human system was evaluated using freshly isolated peripheral blood mononuclear cells, lymphocytes, monocytes and complement. The ADCC activities of the BR55-2 IgG3 isotype and its switch variants (IgG1, IgG2b, and IgG2a) with human monocytes were high for all isotypes, whereas the activity of all isotypes was lower with freshly isolated lymphocytes, IgG1 being the least effective. The CDC on the other hand was strong with IgG3, IgG2b and IgG2a and negative with the IgG1 variant. The IgG3 and IgG2a isotypes were selected for further development. Their strong ADCC and CDC activity against mammary carcinoma, colon carcinoma and small-cell lung tumor cell lines was confirmed quantitatively using proteins highly purified from tissue-culture supernatants. Significant variations in ADCC and CDC competence was observed among human donors.

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Section: Introductionmentioning

confidence: 99%

Biological activity in the human system of isotype variants of oligosaccharide-Y-specific murine monoclonal antibodies

Scholz

Lubeck

Loibner

et al. 1991

Cancer Immunol Immunother

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“…This mAb also inhibits the growth of human tumor xenografts in nude mice (3). In patients with colon and pancreatic cancer treated with mAb C017-1A, complete and partial remissions have been described (7,8,(14)(15)(16)(17). However, murine immunoglobulins administered to humans have a short half-life (12-18 hr) and induce an anti-mouse immunoglobulin response (7,8,18).…”

mentioning

confidence: 99%

Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificity.

Steplewski

Sun

Shearman

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

175

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Chimeric antibodies were constructed in which the murine variable region of anti-colorectal cancer monoclonal antibody C017-lA was joined with human'y, -y2, 'y3, and y4 constant regions. Human-mouse chimeric proteins were compared with the parental murine IgG2a antibody C017-lA for their ability to participate in tumor-cell destruction by human and murine effector cells in antibody-dependent cell-mediated cytotoxicity (ADCC) assays. All of the chimeric antibodies showed different degrees of ADCC with human lymphocytes, monocytes, and granulocytes and with murine macrophages. Monocytes and macrophages were able to utilize the chimeric IgG1 and, to a lesser degree, IgG4 and IgG3 antibodies to lyse tumor-cell targets in ADCC assays. The chimeric IgG1 and IgG4 antibodies were nearly as effective as the parental C017-1A antibody in inhibiting tumor growth in nude mice. These data indicate that chimeric IgG1 antibody is superior in its antitumor activity.Monoclonal antibody (mAb) C017-1A was developed in 1978 (1, 2) and, after characterization of its antitumor activities (3, 4) and of its selective binding to colon carcinoma cells (5, 6), was used in clinical trials by Sears et al. (7,8). C017-1A is of the IgG2a isotype and is active in antibody-dependent cell-mediated cytotoxicity (ADCC) assays with murine (3, 9, 10) and human (9-13) effector cells. This mAb also inhibits the growth of human tumor xenografts in nude mice (3). In patients with colon and pancreatic cancer treated with mAb C017-1A, complete and partial remissions have been described (7, 8, 14-17). However, murine immunoglobulins administered to humans have a short half-life (12-18 hr) and induce an anti-mouse immunoglobulin response (7,8,18). For these reasons, recombinant DNA techniques have been used to construct chimeric mAbs in which the human constant (C) region of choice is linked to the murine variable (V) region (19)(20)(21). A chimeric C017-1A protein has been constructed with the human C,,3 region (22), and its characteristics have been described (23,24). Recently, we used the cloned murine V region of C017-1A to construct chimeric molecules with human CVi, C,,2, and C, regions. The availability of the series of chimeric mAbs with the same binding specificity permits direct comparison of all four human IgG isotypes for their effects in vitro and in vivo on human tumor-cell targets. Such analyses may provide a rationale for the selection of the most promising chimeric mAbs for clinical application. MATERIALS AND METHODSChimeric Proteins. Methods for construction and characterization of yl, y2, 'y3, and 'y4 chimeric antibodies have been detailed (24). In brief, the functionally rearranged heavy-and light-chain V genes of hybridoma 17-1A were isolated and inserted into expression vectors containing genomic DNA segments encoding human y heavy-chain and K light-chain C regions. As described previously (24), transfection of these expression vectors containing mouse-human chimeric immunoglobulin genes into nonproducing mouse myeloma Sp2/0 ...

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“…They were chosen since each patient had many consecutive sera avail able and all had well-documented tumor staging. The characteristics of the patients and the treatment schedule have been described earlier [9] and are sum marized in table 1. The patients investigated were also subject to treatment with mouse monoclonal antibodies (Mab) against the tumor-associated anti gen CO 17-1A [9].…”

Section: Patientsmentioning

confidence: 99%

Significance of Alkaline Phosphatase Isozymes in the Monitoring of Patients with Colorectal Carcinoma

Harmenberg¹,

Frödin²,

Ljungdahl-Ståhle³

et al. 1989

Tumor Biol

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The clinical course of colorectal carcinoma may be monitored by tumor markers such as carcinoembryonic antigen (CEA), carcinoma antigen (CA) 19-9 and CA-50. Alkaline phosphatase isozymes were previously used to study the clinical course of testicular and gynecologic tumors. In this study we investigated 8 patients with advanced colorectal carcinoma. Their sera were analyzed for the tumor markers CEA, CA 19-9, CA-50 and three alkaline phosphatase isozymes: the nonspecific liver isozyme LAP, the intestinal isozyme IAP and the placental isozyme PLAP. Rising levels of CEA, CA 19-9 and CA-50 were seen as expected, and PLAP also showed rising levels during tumor progression. LAP remained elevated. This indicates an association between progression of colorectal carcinoma and a raised serum content of alkaline phosphatase isozymes.

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Clinical Effects of Monoclonal Antibodies (MAb 17-1A) in Patients with Metastatic Colorectal Carcinomas

Cited by 46 publications

References 17 publications

Biological activity in the human system of isotype variants of oligosaccharide-Y-specific murine monoclonal antibodies

Biological activity in the human system of isotype variants of oligosaccharide-Y-specific murine monoclonal antibodies

Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificity.

Significance of Alkaline Phosphatase Isozymes in the Monitoring of Patients with Colorectal Carcinoma

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