Abstract
Abstract 422
Antibody-dependent cell-mediated cytotoxicity (ADCC), largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells following activation, including NK cells. We hypothesized that the anti-lymphoma activity of rituximab could be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb.
Rituximab induced upregulation of CD137 on NK cells was assessed using lymphoma cell lines and primary lymphoma patient samples. In-vitro NK cell degranulation and cytotoxicity were assessed by CD107a mobilization and chromium release. A murine lymphoma tumor model targeted by mouse anti-mouse CD20 mAb was used to assess in-vivo synergy of anti-CD20 and anti-CD137 mAbs. Mechanism of synergy was explored by T cell, NK cell, and macrophage depletion in the immune competent mouse model. A xenotransplant model in SCID mice with disseminated, luciferase-labeled lymphoma was used to demonstrate efficacy of anti-CD137 mAb and rituximab, and sufficiency of an innate immune response.
NK cells in human primary lymphoma samples do not express CD137 at baseline, however these cells highly upregulate CD137 when encountering rituximab-coated tumor B cells. Rituximab-induced NK cell degranulation and cytotoxicity as measured by CD107a mobilization (p=.006) and chromium release (p=.01) are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution (p<.001) and prolonged survival (p=.048). Sequential administration of anti-CD20 mAb followed by anti-CD137 mAb (p=.027) is required for the synergistic effect. In-vivo administration of anti-CD20 mAb induces upregulation of CD137 on mouse NK cells (p=0.001), allowing subsequent targeting with anti-CD137 mAb. NK cell depletion completely abrogates the therapeutic effect of anti-CD20 plus anti-CD137 mAb combination (p<.001). In a xenotransplant disseminated lymphoma model (Figure 1A), rituximab plus anti-CD137 mAb provided superior reduction in tumor burden, as quantified by bioluminescence (p=.001; Figure 1B), and prolonged overall survival (p=.013; Figure 1C).
Our results demonstrate the synergy of anti-CD137 mAb and rituximab by stimulation of rituximab-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against B cell malignancies by targeting first the tumor and then the host immune system.
No relevant conflicts of interest to declare.
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