Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease.
For the treatment of Hodgkin lymphoma, bispecific monoclonal antibodies (bi-mAbs) were established which recognize the Hodgkin-associated CD30 antigen with one arm and the CD3 or CD28 antigen on T lymphocytes or the CD16 antigen on natural killer (NK) cells with the second arm. The NK cell-activating alpha-CD16/CD30 antibody was able to retarget human NK cells toward CD30- target cells and induce their lysis. Sixty percent of Hodgkin tumor-bearing severe combined immunodeficient mice responded to a combined treatment with bi-mAb and human NK cells, leading to a final cure rate of 20%. T cell-activating bi-mAbs were more effective, resulting in the cure of all mice treated. The in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 antibodies resulted in the specific activation of resting human T cells infiltrating the CD30+ Hodgkin tumors. Tumor-infiltrating lymphocytes in the group of mice treated with both T cell-activating bi-mAbs expressed high levels of cytokines and cytotoxic molecules such as perforin and the cytotoxic serine esterases granzyme A and B. More importantly, activated T cells did not home to CD30 tissue and did not enter the circulation. Encouraged by these preclinical data, 15 patients with treatment-refractory Hodgkin lymphoma were included in a phase I/II dose-escalation study and treated four times every 3 or 4 days with increasing doses of the alpha-CD16/CD30 bi-mAb ranging from 1 mg/m2 to 128 mg/m2. No dose-limiting toxicity occurred even at the highest doses. Of these 15 patients, one had a complete response, one a partial response, three a mixed response, two stable disease, and eight patients had progressive disease. Treatment with immunological effector cell-recruiting bi-mAbs is a promising new approach to the treatment of Hodgkin disease refractory to standard therapy.
da Costa
L
L
Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
Renner
C
C
Hartmann
F
F
Pfreundschuh
M
M
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D017730:Ki-1 Antigen / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017452:Receptors, IgG / Q000276:immunology; D016539:Reed-Sternberg Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D017730:Ki-1 Antigen; D017452:Receptors, IgG