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AssigneesThe Salk Institute for Biological Studies, The Regents of the University of California
InventorsIan S. Trowbridge, Raymond Taetle, Suhaila N. White
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Combinations of monoclonal antibodies which are highly effective for inhibiting cell growth and methods for inhibiting cell growth employing novel combinations of monoclonal antibodies are disclosed. The antibodies employed are capable of binding to the human transferrin receptor glycoprotein and, in combination, usually exhibit a substantially greater inhibition of cell growth than either of the antibodies individually when administered in comparable amounts, e.g. at saturation conditions. In preferred combinations, at least one member of the combination is individually highly effective to inhibit cell growth and at least one other member of the combination is individually substantially ineffective to inhibit cell growth. Combinations are selected based upon an in vitro screening test using CCRF-CEM cells which express the human Tf receptor.
A therapeutic composition for inhibiting proliferation of transferrin-receptor-positive tumor cells expressing the transferrin receptor on their surfaces, said composition comprising a combination of a first and a second monoclonal antibody and a pharmaceutically acceptable carrier, wherein each of said antibodies is an anti-human-transferrin-receptor monoclonal antibody which binds to an epitope of the external domain of the human transferrin receptor glycoprotein and which first and second monoclonal antibodies simultaneously bind the transferrin receptor, wherein in vitro screening of the CCRF-CEM leukemic cell line with said first and second monoclonal antibodies individually and with said combination of said first and second monoclonal antibodies shows that said combination inhibits cell proliferation to a greater extent than either of said antibodies individually and also inhibits cell proliferation by at least about 80%, and wherein said combination of antibodies inhibits in vivo proliferation of cells expressing the transferrin receptor on their surfaces selected from the group consisting of human hematopoietic tumor cells and human melanoma cells by binding the transferrin receptor and thereby blocking transferrin receptor function.
A composition for inhibiting the proliferation of transferrin-receptor-positive tumor cells expressing the human transferrin receptor on their outer surfaces, which composition comprises first and second monoclonal antibodies in a pharmaceutically acceptable carrier,
A method of inhibiting proliferation of transferrin-receptor-positive cells expressing the transferrin receptor on their surfaces in a human, which method comprises administering to said human an effective dose of a combination containing a first and a second monoclonal antibody, which dose is effective to halt proliferation of said cells, wherein each of said antibodies is an anti-human-transferrin-receptor monoclonal antibody which binds to an epitope of the external domain of the human transferrin receptor glycoprotein and which first and second monoclonal antibodies simultaneously bind the transferrin receptor, said first and second antibodies being such that a comparison of in vitro screening of the CCRF-CEM leukemic cell line with said first and second monoclonal antibodies individually and in vitro screening thereof with said combination of said first and second monoclonal antibodies shows that said combination inhibits cell proliferation to a greater extent than either of said antibodies individually and also inhibits cell proliferation by at least about 80%, and wherein said dose of said combination of antibodies inhibits in vivo cell proliferation of cells expressing the transferrin receptor on their surfaces selected from the group consisting of human hematopoietic tumor cells and human melanoma cells by binding the transferrin receptor and thereby blocking transferrin receptor function.
A method of inhibiting proliferation of tumor cells expressing the transferrin receptor on their surfaces in a human, which method comprises administering to said human an effective dose of a combination containing a first monoclonal antibody and a second monoclonal antibody which dose is effective to halt proliferation of said cells, wherein each of said antibodies binds to an epitope of the external domain of the human transferrin receptor glycoprotein, said first monoclonal antibody being one obtained from the cell line designated A27.15 and assigned ATCC Accession No. HB-10395 or an antibody-producing reclone thereof which reclone produces antibodies that bind to epitopes of the external domain of said human transferrin receptor glycoprotein, and said second monoclonal antibody being one obtained from the cell line designated E2.3 and assigned ATCC Accession No. CRL 10746 or an antibody-producing reclone thereof which reclone produces antibodies that bind to epitopes of the external domain of said human transferrin receptor glycoprotein, wherein said first and second monoclonal antibodies simultaneously bind the human transferrin receptor and wherein said dose of said combination of antibodies inhibits in vivo cell proliferation of cells expressing the transferrin receptor on their surfaces selected from the group consisting of human hematopoietic tumor cells and human melanoma cells by binding the transferrin receptor and thereby blocking transferrin receptor function.
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