Treatment of Refractory Hodgkin's Disease With an Anti-CD16/CD30 Bispecific Antibody

Abstract

Fifteen patients with refractory Hodgkin's disease were treated in a phase I/II trial with the natural killer (NK)-cell–activating bispecific monoclonal antibody HRS-3/A9, which is directed against the Fcγ-receptor III (CD16 antigen) and the Hodgkin's-associated CD30 antigen, respectively. Median counts of NK cells and of all lymphocyte subsets were considerably decreased in the patients before therapy. HRS-3/A9 was administered 4 times every 3 to 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 administered because of the limited amounts of HRS-3/A9 available. Side effects were rare and consisted of fever, pain in involved lymph nodes, and a maculopapulous rash. A total of 9 patients developed human antimouse Ig antibodies, and 4 patients developed an allergic reaction after attempted retreatment. A total of 1 complete and 1 partial remission (lasting 16 and 3 months, respectively), 3 minor responses (1 to 11+ months), and 1 mixed response were achieved. There was no clear-cut 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.

Early lymphocyte recovery post‐autologous haematopoietic stem cell transplantation is associated with better survival in Hodgkin's disease

“…However, natural killer (NK) cells return to normal as early as 2 weeks post ASCT (Porrata et al, 2001c). NK cells have shown activity against HD (Hartmann et al, 1997). Thus, NK cells may play an immuno-surveillance role early after ASCT in HD.…”

A recombinant bispecific single‐chain Fv antibody against HLA class II and FcγRIII (CD16) triggers effective lysis of lymphoma cells

“…Because of its restricted expression on potential effector cells, CD16 represents an interesting target for the recruitment and induction of cytolysis. Studies with CD16‐directed conventionally coupled bsAb demonstrated efficient lysis of malignant cells in vitro and in animal models (Garcia de Palazzo et al , 1992; Hombach et al , 1993; Kipriyanov et al , 2002), and clinical trials were initiated (Weiner et al , 1995; Hartmann et al , 1997). However, these trials were hampered by limited amounts of available bsAb, by the induction of human anti‐mouse antibodies (HAMA), and by the presence of an Fc‐portion in these hybrid‐hybridoma antibodies, which may have contributed to their toxicity.…”

Locoregional treatment of low-grade B-cell lymphoma with CD3�CD19 bispecific antibodies and CD28 costimulation: I. Clinical phase I evaluation

“…When 2 patients at a dose level had devel- 1 Follicular lymphoma. 2 Mantle-cell lymphoma. 3 Chronic lymphocytic leukemia (B-cell type).…”

“…In the treatment of human malignancies with bispecific antibodies, 2 major strategies have been investigated so far. Anti-FcR␥ϫanti-TAA antibodies were used to redirect Fc receptor-bearing effector cells such as macrophages and NK cells toward the tumor cells, [2][3][4] circumventing additional (pre-) activation of the effector cells, as crosslinking of the FcR␥ molecules results in sufficient tumor-cell lysis.…”