Characterization of a Series of Isotype Switch Variants of a New CD20 Monoclonal Antibody

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Abstract
A series of heavy chain switch variants has been isolated from a new B cell-specific monoclonal antibody belonging in the CD20 cluster. The antibodies NKI-B20/1, NKI-B20/2b, and NKI-B20/2a (of isotype IgG, IgG2b, and IgG2a, respectively) have been used to study the influence of isotype and of the target antigen on the capacity to mediate cytotoxicity with a number of effector mechanisms. Unlike many mouse MAbs, NKI-B20/2b and NKI-B20/2a were cytolytic with human complement on human target cells that did not express the complement regulatory factor HRF20. All 3 isotypes of NKI-B20 mediated antibody-dependent cell-mediated cytotoxicity (ADCC) with rIL-2-activated NK cells from mouse spleen. Here the antigen density seemed the most important factor in determining the level of cell kill. With mouse peritoneal macrophages as effector cells again all 3 isotypes of NKI-B20 mediated cytotoxicity. For the IgG1 and IgG2b variants of NKI-B20 this is at variance to what has been reported for MAbs of other specificities. Despite the high activity with murine effector cells none of the NKI-B20 MAbs mediated ADCC with human peripheral blood NK cells, with or without stimulation with rIL-2, due to the lack of interaction of the murine MAbs with the human Fc receptor. The CD20 antigen appears to be a good target antigen for various forms of cytotoxicity, to which its relatively high antigenic density, its resistance to antibody-induced modulation, and its unusual structure all contribute.