Abstract
Human anti-murine antibody (HAMA) response is a serious problem in the repeated infusion of murine monoclonal antibodies (MoAbs). HAMA positive sera were obtained from seven patients with colorectal cancer, pancreas cancer, malignant melanoma or myocardial infarction who had previously received radiolabelled MoAbs. The nature of HAMA was analysed using size exclusion high performance liquid chromatography (HPLC) after incubating with radiolabelled MoAbs including IgG, Fab or human/mouse chimeric Abs. Immune complexes composed of HAMA and MoAbs were formed. The percentage of radioactivity with a high molecular weight was related to HAMA levels determined by enzyme linked immunosorbent assay. Most radioactivity present in immune complex shifted to the antibody fraction after the addition of normal murine serum. All of seven sera were reactive with all four murine IgGs and this suggests that HAMA in these patients recognised the constant region of MoAbs. In one patient, HAMA was considered to recognise the variable region and to be anti-idiotypic. There was no significant binding with human/mouse chimeric Abs in any HAMA positive serum, although five out of seven patients were reactive with murine MoAb Fab, indicating that HAMA was composed of Abs responsive to the CH1 or CL region of murine IgG. These results suggest that (1) HAMA was composed of Ab responsive to Fc portion and/or CH1 or CL region of murine IgG, and (2) human/mouse chimeric Abs look promising in the repeated infusion of MoAb in HAMA positive patients.
Highlights
NL-1 is a murine IgG2a antibody directed against common acute lymphocytic leukaemia antigen (CALLA) identical with CDI0 (Letarte et al, 1988; Monod et al, 1989)
Human/mouse chimeric NL-1 antibody was obtained by ligating the human heavychain enhancer element to the chimeric heavy- and lightchain genes as previously reported (Nishimura et al, 1987; Saga et al, 1990)
With Human anti-murine antibody (HAMA) positive sera, examined using five radiolabelled murine IgG; ZCE-025, 96.5, NL-1, SF-25 or Fab fragment of RI 1D10, the radioactivity was associated with an entity having a higher molecular weight than original IgG (Figure Ic) or Fab peaks, forming immune complexes composed of HAMA-antibody
Summary
Monoclonal antibodiesThe MoAb designated ZCE-025 is a murine IgGI recognisingCEA and was provided by Hybritech Inc. (San Diego, CA)Correspondence: M. (Tokyo, Japan) in a purified DTPAcoupled form. MoAb 96.5 is a murine IgG2a recognising melanoma cell surface antigen p97. SF-25 antibody, generated by fusing myeloma cells and spleen cells of mice immunised with human hepatocellular carcinoma cells, is an IgG, antibody reactive with the 125 kilodalton antigen on the cell surface of some hepatocellular carcinoma and colon cancers (Takahashi et al, 1988). This antibody and its human/mouse chimeric counterpart were provided by Centocor through Toray Industries, Inc. This antibody and its human/mouse chimeric counterpart were provided by Centocor through Toray Industries, Inc. (Tokyo, Japan)
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