Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease.

Abstract

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.

• Authors: L da Costa, C Renner, F Hartmann, M Pfreundschuh
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 46 Suppl Pg. S33-6 ( 2000) ISSN: 0344-5704 [Print] Germany
• PMID: 10950145 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal
• CD28 Antigens
• CD3 Complex
• Ki-1 Antigen
• Receptors, IgG

Topics

• Animals
• Antibodies, Bispecific (immunology, therapeutic use)
• Antibodies, Monoclonal (immunology, therapeutic use)
• CD28 Antigens (immunology)
• CD3 Complex (immunology)
• Hodgkin Disease (immunology, therapy)
• Humans
• Ki-1 Antigen (immunology)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation (immunology)
• Mice
• Mice, SCID
• Neoplasm Transplantation
• Receptors, IgG (immunology)
• Reed-Sternberg Cells (immunology)
• T-Lymphocytes (immunology)
• Tumor Cells, Cultured