Enhanced antitumor effects of CD20 over CD19 monoclonal antibodies in a nude mouse xenograft model (original) (raw)
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Cancer research, 1995
Since antibody-dependent cellular cytotoxicity is considered an important mechanism by which mAbs may exert their antitumor effects, it seems likely that these antitumor effects can be enhanced by the activation of the appropriate effector cell populations. We have used nude mice xenografted with human Daudi tumor cells as a model to compare the antilymphoma effects of unconjugated CD19 (CLB-CD19) and CD20 (BCA-B20) mAbs (IgG2a subclass) alone or in combination with recombinant human interleukin 2 (rhIL-2) or recombinant mouse granulocyte-macrophage-colony-stimulating factor (rmGM-CSF). Treatment of established tumors with BCA-B20 or rhIL-2 or rmGM-CSF as a single agent, all resulted in highly significant decreases of tumor growth rates, but did not increase the number of complete regressions. The combination of CLB-CD19 or BCA-B20 mAbs with rhIL-2 or rmGM-CSF resulted in larger decreases of growth rates than either of the agents alone. Complete eradication of large Daudi tumors cou...
Journal of Immunotherapy, 2008
The role played by B cells in cancer biology is complex and somewhat controversial. Previous studies using genetically engineered mice suggest that B cells may be immunosuppressive and inhibit tumor rejection. However, the effects of B-cell depletion employing an antibody in mice bearing solid tumors has not been tested owing to difficulties in making an effective antimouse CD20 antibody (similar to rituximab). Injection of a newly developed antimouse CD20 antibody was effective in depleting circulating B cells from blood and lymph nodes, although depletion was less complete in the spleen. B-cell depletion slowed the growth of new solid tumors (not expressing CD20) and retarded the growth of established tumors but did not induce tumor regression. However, when the antibody was combined with an active immunotherapy approach using an adenovirus vaccine expressing the human papilloma virus-E7 gene (Ad.E7) in mice bearing TC1 tumors (murine lung cancer cells expressing human papilloma virus-E7), we noted enhanced antitumor effects and increased numbers of tetramer + /CD8 + T cells within the spleens and activated CD8 + T cells within tumors. B-cell depletion using an anti-CD20 antibody was thus effective in retarding tumor growth in multiple solid tumor models and augmenting immunotherapy in a tumor vaccine model. These studies raise the possibility that B-cell depletion may be a useful adjunct in human immunotherapy trials.
OncoImmunology, 2015
Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor FcgRIIIa represents a major effector function of many therapeutic antibodies. In an attempt to further enhance natural killer (NK) cellmediated ADCC, we combined therapeutic antibodies against CD20 and CD38 with recombinant immunoligands against the stimulatory NK cell receptors NKG2D or NKp30. These immunoligands, respectively designated as ULBP2:7D8 and B7-H6:7D8, contained the CD20 scFv 7D8 as a targeting moiety and a cognate ligand for either NKG2D or NKp30 (i.e. ULBP2 and B7-H6, respectively). Both the immunoligands synergistically augmented ADCC in combination with the CD20 antibody rituximab and the CD38 antibody daratumumab. Combinations with ULBP2:7D8 resulted in higher cytotoxicity compared to combinations with B7-H6:7D8, suggesting that coligation of FcgRIIIa with NKG2D triggered NK cells more efficiently than with NKp30. Addition of B7-H6:7D8 to ULBP2:7D8 and rituximab in a triple combination did not further increase the extent of tumor cell lysis. Importantly, immunoligand-mediated enhancement of ADCC was also observed for tumor cells and autologous NK cells from patients with hematologic malignancies, in which, again, ULBP2:7D8 was particularly active. In summary, co-targeting of NKG2D was more effective in promoting rituximab or daratumumab-mediated ADCC by NK cells than co-ligation of NKp30. The observed increase in the ADCC activity of these therapeutic antibodies suggests promise for a 'dual-dual-targeting' approach in which tumor cell surface antigens are targeted in concert with two distinct activating NK cell receptors (i.e. FcgRIIIa and NKG2D or B7-H6).
Natural killer cells and immunotherapy based on monoclonal antibodies
Biomedical Reviews, 2020
Natural killer (NK) cells are effector lymphocytes of innate immunity needed to protect against stressed cells and to destroy tumor cells and virus-infected cells. These cells play an important role in the immune surveillance of malignant cells, preventing their uncontrolled growth. Natural killer cells recognize target cells directly through their receptors, which bind to various determinants on the surface of the target cell. The receptor-ligand (secretory or membrane-bound) interaction between the NK cells and the target cells determines NK's cell activity. The use of monoclonal antibodies in tumor therapy has increased significantly in the recent years. These antibodies are intended to block inhibitory receptors (immune checkpoint inhibitors) expressed by immune cells or to block their ligands expressed by tumor cells. Examples of such immune checkpoint molecules are the following receptors: cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and others. This blocking inhibits tumor growth by enabling immune system reactivation. The advances in cellular immunobiology that have provided the establishment of blocking monoclonal antibodies (ipilimumab, nivolumab, etc.) and increased NK cell proliferative activity are promising therapies for neoplasms.
Frontiers in Immunology, 2013
In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.
Differential Action of Anti-CD20 Monoclonal Antibodies: Role in Induction of Cell Death
Journal of Cancer Science & Therapy, 2018
Purpose: To study and assess to the sensitivity of Burkitt's lymphoma cells harboring differential levels of cell surface CD20 for anti-CD20 monoclonal Antibodies. Material and methods: Burkitt's lymphoma cell line 'Daudi' was used during present study. Cells were exposed to single dose of γ-radiation (0.5 Gy) and thereafter incubated with rituximab (Rtx) or tositumomab (Tst) (0.5 µg/ ml concentration each). The changes in expression of RelA, Akt and Bax/Bcl-2 ratio was measured to assess sensitivity of cells in term of cell death. Results: During the present investigation, we found that cells incubated with anti-CD20 mAbs at +20 hrs post radiation exposure showed higher levels of cell death in term of Bax/Bcl-2 ratio. In addition, we also found the significant changes in expression of pro-survival signaling proteins such as RelA and Akt pathways. Moreover, we found that tositumomab is a potent inducer of apoptotic cell death. Conclusion: These findings suggested that the efficacy of anti-CD20 mAbs depends on the number of CD20 molecules expressed on cell surface and type of antibody used. It may provide new treatment options for selection of anti-CD20 mAbs even in aggressive B-cell lymphoma, which harbors low levels of CD20 or even resistant to current therapies in vivo.
International Journal of Cancer, 1993
In order to target NK cells against the Hodgkin's-derived cell line L540, we developed bispecific monoclonal antibodies (Bi-MAbs) by somatic hybridization of the 2 mouse hybridoma cell lines HRS-3 and A9 which produce monoclonal antibodies (MAbs) with reactivity against the Hodgkin and Reed-Sternberg cell-associated CD30 antigen and the CD 16 antigen (FcγIII receptor), respectively. The CD 16 MAb-producing cell line A9 was selected as a partner for HRS-3 because of its efficiency in inducing lysis of the A9 hybridoma cells by resting NK cells. The hybrid hybridoma cell line HRS-3/A9 produced the supernatant with the strongest bispecific reactivity and was repeatedly subcloned and used for ascites production. Crude supernatant and purified HRS-3/A9 Bi-MAb triggered specific lysis of the CD30+ Hodgkin's-derived cell line L540, but not of the CD30− cell line HPB-ALL by unstimulated peripheral-blood lymphocytes and NK-cell-enriched populations. Moreover, treatment of SCID mice bearing heterotransplanted human Hodgkin's tumors with HRS-3/A9 and human peripheral blood lymphocytes induced specific complete tumor regression in 10/10 animals. We thus report successful tumor treatment in an in vivo model using NK-cell-associated Bi-MAbs and show that the Bi-MAb HRS-3/A9 is an efficient promoter of the anti-tumor effects of NK cells in vitro and in vivo.