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Chimeric Murine-Human Antibodies Directed against Folate Binding Receptor Are Efficient Mediators of Ovarian Carcinoma Cell Killing¹

From Centocor, Malvern, Pennsylvania 19355 [L. R. C., D. S., V. R. Z., Jr.]; Istituto Nazionale Per Lo Studio E La Cura Dei Tumori, via Venezian 1, Milan, Italy [D. M., P. C., M. I. C.]; and the Department of Obstetrics and Gynecology, Harvard Medical School, Boston, Massachusetts 02114 [V. R. Z., Jr.]

The MOv18 (1,) and MOv19 (2a,) murine monoclonal antibodies (MAbs) recognize different epitopes on the human folate binding receptor which is overexpressed on 90% of nonmucinous epithelial ovarian tumors. A chimeric murine-human (human 1,) version of both antibodies was constructed and expressed. The genes encoding the murine heavy and light chain variable regions of the MOv18 and MOv19 MAbs were cloned from the parental hybridomas, fused with genes encoding the human heavy (1) and light () chain constant regions, respectively, and expressed in the SP2/0 murine myeloma cell line. Using human peripheral blood mononuclear cells as effector cells and conditions that provide for maximum lysis (effector target = 50:1, saturating antibody concentration), the murine MOv18 MAb (IgG1) mediated variable levels of specific cytolysis of the target ovarian cancer cell line IGROV1. In contrast, the chimeric MOv18 MAb mediated higher and more consistent lysis even at a 10–100-fold lower antibody concentration. The murine MOv19 MAb (IgG2a) mediated specific lysis of IGROV1 cells, and the chimeric version of this antibody mediated an amount of lysis at least equal to that mediated by its murine counterpart. A comparison of the ED₅₀ values obtained for the murine MOv19 and chimeric MOv19 antibodies indicates that the chimeric MOv19 MAb was 3 to 10 times more potent than the murine MOv19 antibody. In addition, the ED₅₀ values obtained for the chimeric MOv18 and chimeric MOv19 MAbs were similar, indicating that these MAbs are equally potent. The level of maximal lysis obtained was dependent on the number of target molecules/cell; the same high level of lysis mediated by cMOv18, MOv19, and cMOv19 was observed with both IGROV1 and OvCA432 target cells. However, only low levels of lysis were obtained when the SW626 cell line, which expresses 1 x 10⁴ folate binding protein sites/cell, was used as a target. An equimolar mixture of the chimeric MOv18 and MOv19 MAbs was no more effective in the mediation of lysis than an equivalent amount of either chimeric MAb alone. These data suggest that the folate binding receptor is expressed on IGROV1 cells at a density sufficient to provide for optimal levels of antibody-mediated lysis using a single chimeric antibody directed at the folate binding receptor.

¹ Research supported in part by Associazione Italian Ricerca Cancro and CNR-ACRO (Committee of National Research-of the Cancer Research Oncologic).

² To whom requests for reprints should be addressed, at Apollon, Inc., One Great Valley Parkway, Malvern, PA 19355.

³ Present address: Apollon, Inc., One Great Valley Parkway, Malvern, PA 19355.

Received 8/ 9/93. Accepted 3/ 1/94.

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