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Enhanced Antitumor Effects of CD20 over CD19 Monoclonal Antibodies in a Nude Mouse Xenograft Model¹

Department of Immunology [E. H., P. C. M. v. d. B., J. J. S., R. W. d. B. A. H.] and Department of Radiotherapy [A. A. M. H.], The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Innotherapie, BP 1985, Besançon, F25020 Cedex, France [J. W.]; and Academic Hospital Leiden, POB 9600, 2300 RC Leiden, the Netherlands [C. J. M. M.]

We used a nude mouse xenograft tumor model to compare the efficacy of unconjugated CD19 and CD20 mAbs (IgG2a subclass) in mediating antilymphoma effects. Treatment with the CD20 mAbs NKI-B20 and BCA-B20 resulted in a drastic decrease in tumor take rate (P < 0.0001) in comparison to controls, whereas the CD19 mAb CLB-CD19 was ineffective. Tumor growth rates were reduced by both CD19 and CD20 (P < 0.0001). The decrease in growth rate induced by NKI-B20 or BCA-B20 was larger than that induced by CLB-CD19 (P = 0.0022). In vitro experiments showed that NKI-B20 or BCA-B20 are more powerful than CLB-CD19 in mediating lysis by interleukin 2-activated natural killer cells. No difference was observed between different isotypes (IgG1, IgG2a, IgG2b) of the switch variants of NKI-B20 or CLB-CD19. A positive correlation between antigen density and the sensitivity to antibody-dependent cellular cytotoxicity was demonstrated with human lymphoblastoid B cells, JY, transfected with cDNA encoding the human CD19 antigen that expressed high levels of this antigen. These cells are more efficiently killed by natural killer cells when coated with CLB-CD19 mAbs than JY wild-type cells that express 1 log lower levels of the CD19 antigen. Antibody-dependent cellular cytotoxicity experiments with thioglycolate-activated macrophages show a more complex relationship between antigen density, isotype of the mAb, and cytotoxicity. BCA-B20 (IgG2a) and CLB-CD19 (IgG2a) and all isotypes of NKI-B20 mediated strong cytotoxicity, whereas CLB-CD19 isotypes IgG1 and IgG2b were associated with limited cytotoxicity. Proliferation of Daudi cells was inhibited with high concentrations of all isotypes of CLB-CD19, but not with any of the CD20 mAbs. To our knowledge this is the first report showing that the antitumor effects in vivo of unconjugated CD20 mAbs are far superior to those of CD19 mAbs.

¹ Supported by Grant NKI 89-06 from the Koningin Wilhelmina Fonds (The Dutch Cancer Society) to E. H. and P. C. M. v. d. B.

² To whom correspondence should be addressed, at Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

Received 8/ 3/94. Accepted 12/13/94.

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