| Abstract: |
Human-mouse chimeric immunoglobulins Gl and G3 (IgGl and IgG3) (ChGl, ChG3) and “complementarity-determining regions-grafted, humanized IgGl and IgG3 (HuGl, HuG3) constructs of the mouse monoclonal antibody (mAb) M195 were characterized. M195 is a murine immunoglobulin G2a (IgG2a), anti-CD33 mAb, specifically reactive with acute myelogenous leukemia cells, that is active as an antileu-kemia agent in humans. The new mAb constructs maintained specificity and biological function, including rapid internalization after binding to the cell surface, which has been important for delivery of therapeutic isotopes in patients. Although previously reported complementarity-determining region-grafted mAbs had reduced avidities, the HuGl and HuG3 M195 showed up to an 8.6- and 4-fold higher binding avidity, respectively, than the original murine mAb. All constructs were effective at mediating rabbit complement-mediated cytotoxicity against HL60 targets. Fibroblasts transfected with CD33 genes and expressing high levels of CD33 antigen were also lysed in the presence of human complement, but HL60 cells or fibroblasts with lower CD33 levels were not killed. Thus, the inability of Ml95 and constructs to kill HL60 targets with human complement is due to the much lower antigen density on HL60 cells compared to CD33+ fibroblasts. Unlike the murine M195, the chimeric and humanized Ml95 demonstrated antibody-dependent cell-mediated cytotoxicity using human peripheral blood mononuclear cells as effectors. Because the chimeric and humanized M195 have improved avidities as compared to the original Ml95 and have, in addition, the potential to avoid human anti-mouse antibody responses and to recruit human effector functions, these new constructs may be useful therapeutically, either alone or conjugated to toxins or isotopes, in the treatment of acute myelogenous leukemia. © 1992, American Association for Cancer Research. All rights reserved. |
| Keywords: |
acute granulocytic leukemia; human cell; nonhuman; binding affinity; mouse; animal; mice; immunoreactivity; mice, inbred balb c; monoclonal antibody; membrane antigen; antibodies, monoclonal; antibody specificity; cytotoxicity, immunologic; antigens, cd; antigen binding; leukemia cell line; antibody dependent cellular cytotoxicity; antigens, differentiation, myelomonocytic; binding, competitive; radioiodination; monoclonal antibody m 195; radioassay; radioligand assay; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
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