The natural killer cell-activating anti-CD16/CD30 bispecific monoclonal antibody (BiMAb) had shown efficacy in a Phase I/II trial of refractory Hodgkin's disease (HD). To gain additional information on clinical efficacy and to investigate the effects of different application schedules and the concomitant application of cytokines, we performed a second randomized pilot trial using this BiMAb in patients with refractory HD. Patients received 4 x 25 mg HRS-3/A9 either as a continuous infusion for 4 days or as a 1-h infusion every other day. In case of an objective response, retreatment was attempted after 4 weeks; in case of stable disease (SD), a second course was given after prestimulation with interleukin 2 and followed by granulocyte macrophage colony-stimulating factor s.c. A total of 16 heavily pretreated patients received one to four BiMAb courses. Overall, we observed one complete remission and three partial remissions lasting 5-9 months (three of four of these responses occurred after continuous BiMAb infusion) and four cases of SD for 3 to >6 months. Interleukin 2 pretreatment before the second BiMAb course resulted in a significant increase of circulating natural killer cells in all five patients treated. This coincided with the conversion of two cases of SD into one complete remission and one partial remission. HRS-3/A9-related side effects consisted of mild fever in only six patients. In summary, this second trial confirmed the antitumor efficacy of this BiMAb against HD and the minor toxicity of this BiMAb. Coadministration of cytokines might contribute to an augmented antitumor activity, and additional clinical trials are warranted to optimize this novel treatment modality.

2000-05-22·Cancer Immunology, Immunotherapy2区 · 医学

Initiation of humoral and cellular immune responses in patients with refractory Hodgkin's disease by treatment with an anti-CD16/CD30 bispecific antibody

2区 · 医学

Article

作者: Wolfram Jung ; Frank Hartmann ; Christina Deisting ; Michael Pfreundschuh ; Christoph Renner ; Marieta Juwana

Fifteen patients with refractory Hodgkin's disease were treated in a dose-escalation trial with the bispecific monoclonal antibody (bi-mAb) HRS-3/A9, which is directed against the Fc gamma receptor III (CD16 antigen) and the Hodgkin's-associated CD30 antigen. Treatment consisted of four cycles of four bi-mAb infusions given over 1 h every 3-4 days at different dose levels ranging from 1 mg/m2 to 64 mg/m2. Measurable serum levels (above 0.1 microgram/ml) of circulating bi-mAb could be detected in patients treated with doses above 4 mg/m2, reaching peak levels of 9.5 micrograms/ml immediately after the end of antibody infusion on the highest dose level. Bi-mAb elimination corresponded to second-order kinetics with a terminal half-life time (t1/2, beta) of 28-32 h. Bi-mAb treatment induced the occurrence of human anti-(mouse Ig) antibodies (HAMA) in 6 out of 13 patients initially testing negative. All 6 patients not only developed anti-isotypic anti-(mouse Ig) but also anti-idiotypic and anti-anti-idiotypic antibodies. While no consistent changes of peripheral blood cell counts, or of any lymphocyte subpopulation including natural killer (NK) cells, has been observed, 4 out of 6 evaluable patients treated with doses of at least 4 mg/m2 showed an increase of NK cell activity within 2 weeks after treatment, which lasted for a maximum of 12 weeks. Circulating amounts of soluble CD30 antigen could be detected in the serum of 6 patients. However, like the results and time courses of all the other immunological parameters evaluated, this was not predictive for treatment outcome.

1998-01-01·Leukemia & Lymphoma4区 · 医学

Anti- CD16/CD30 Bispecific Antibodies as Possible Treatment for Refractory Hodgkin's Disease

4区 · 医学

Article

作者: Wolfram Jung ; Christoph Renner ; Frank Hartmann ; Michael Pfreundschuh

Fifteen patients with refractory Hodgkin's disease were treated in a phase I/II dose escalation trial with the NK-cell activating bispecific monoclonal antibody HRS-3/A9 which is directed against the Fcgamma-receptor III (CD16 antigen) and the Hodgkin's associated CD30 antigen, respectively. HRS-3/A9 was given four times every 3-4 days starting with 1 mg/m2. The treatment was well tolerated and the maximum tolerated dose was not reached at 64 mg/m2, the highest dose given due to limited amounts of HRS-3/A9 available. Mild to moderate side effects occured in six patients and consisted of fever, pain in involved lymph nodes, and a maculopapulous rash. Median counts of NK-cells and of all lymphocyte subsets were considerably decreased in the patients before therapy and showed no consistent changes under therapy. Eight patients developed human anti-mouse immunoglobulin antibodies, and five patients showed an allergic reaction after attempted retreatment. One complete and one partial remission (lasting 6 and 3 months, respectively), three minor responses (lasting 1 to 15 months), two disease stabilizations (for 2 and 17 months, respectively), and one mixed response were achieved. There was no clearcut dose-side effect or dose-response correlation. Our results encourage further clinical trials with this novel immunotherapeutic approach and emphasize the necessity to reduce the immunogenicity of the murine bispecific antibodies.

100 项与 HRS-3/A9 相关的药物交易

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