Antitumor x anti-CD3 bifunctional antibodies redirect T-cells activated in vivo with staphylococcal enterotoxin B to neutralize pulmonary metastases.
T-cell antitumor activities are limited by the requirement of two specific major histocompatibility complex restricted steps, T-helper cell activation and cytotoxic T-lymphocyte targeting. The aim of this study was to investigate whether bypassing these major histocompatibility complex restricted steps using nonspecific in vivo activation of T-cells with staphylococcal enterotoxin-B (SE-B) and retargeting with antitumor x anti-CD3 bifunctional antibody (BFA) could provide an effective antitumor response. C3H/HeN mice were injected i.v. with CL-62 melanoma cells, which express the human melanoma antigen p97, and were treated 10 min later with SE-B and/or anti-CD3 (500A2) x anti-p97 (96.5) BFA. Pulmonary metastases were counted 14 days following injections. SE-B alone induced a dose-dependent activation of T-cells as measured by increased interleukin-2 receptor expression and enhanced proliferative responses. SE-B doses greater than 10 micrograms significantly reduced the number of pulmonary metastases versus control (P < 0.01). Combined treatment with SE-B (50 micrograms) and BFA (5 to 50 micrograms) significantly decreased pulmonary metastases compared to treatment with SE-B alone (P < 0.05). Similar reductions in metastases were observed with the F(ab')2 BFA but not with the unconjugated antitumor component of the BFA. Combined treatments with SE-B plus BFA accomplished better tumor neutralization than adoptively transferred in vitro activated splenocytes (4 x 10(7)) retargeted with BFA (5-100 micrograms; P < 0.05). These studies demonstrate that T-cells can be activated in vivo by SE-B and retargeted with small doses of BFA. In this immunocompetent syngeneic pulmonary metastasis model, SE-B plus BFA provided a dramatic antitumor response.
Penna
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Department of Surgery, Mayo Clinic, Rochester, Minnesota 55905.
Dean
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PA
Nelson
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H
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology*; D000912:Antibodies, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004768:Enterotoxins / Q000276:immunology*; D005260:Female; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary*; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D017252:CD3 Complex; D004768:Enterotoxins; D015375:Receptors, Interleukin-2; C031818:enterotoxin B, staphylococcal