A mouse/human chimeric monoclonal antibody (mAb) composed of the variable regions of murine 17-4A mAb and the constant regions of human IgG-1K immunoglobulin was administered to 10 patients with metastatic colon cancer. Four patients received single infusions of 10 mg (n = 2) or 40 mg (n = 2). Six patients received three infusions of 10 mg (n = 3) or 40 mg (n = 3) at 2-week intervals. The pharmacokinetics were similar at both dose levels and at the second and third infusions. The plasma disappearance curves were best fit by a two-compartment model having a mean aT l2 of 17.5 hr (range 13-23 hr) and a mean fTf2 of 100.5 hr (range 65-139 hr).

Two human T-cell leukemias carrying a t(8;14)(q24;q11) chromosome translocation were studied for rearrangements and expression of the c-myc oncogene. For one leukemia, rearrangement was detected in a region immediately distal (3') to the c-myc locus; no rearrangements of c-myc were observed in the second case (DeF). However, studies with hybrids between human and mouse leukemic T cells indicated that in the leukemic cells of DeF, the breakpoint in chromosome 14 occurred between genes for the variable (V alpha) and the constant (C alpha) regions for the alpha chain of the T-cell receptor. The C alpha locus had translocated to a region more than 38 kilobases 3' to the involved c-myc oncogene. Since human c-myc transcripts were expressed only in hybrids carrying the 8q+ chromosome but not in hybrids containing the normal chromosome 8, it is concluded that the translocation of the C alpha locus 3' to the c-myc oncogene can result in its transcriptional deregulation.

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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A summary of the properties of CGP 51901 is shown in Table 3. On the basis of its binding to IgE and IgE-secreting cells and its activity in vitro and in vivo, CGP 51901 is expected to be able to decrease serum IgE by direct clearance of IgE and by reduction of the numbers and productivity of IgE-secreting cells. The end result of reduction of IgE in the circulation and on mast cells is expected to be the attenuation of IgE-mediated reactions and the improvement in allergy symptoms. The effective serum concentration of CGP 51901 is expected to be in the range 1-10 micrograms/ml. Because CGP 51901 is an antibody specific for IgE, it is expected to be highly selective in its activity. Because IgE does not appear to be essential and because CGP 51901 has been rigorously tested to confirm its non-anaphylactic nature, this treatment is not expected to have any adverse effects. Therefore, CGP 51901 is expected to be safe and to have a good probability of being effective when it is tested in human clinical trials.