Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy

Abstract

Treatment of patients with B-NHL with rituximab and CHOP has resulted in significant clinical responses. However, a subset of patients develops resistance to further treatments. The mechanism of unresponsiveness in vivo is not known. We have reported the development of rituximab-resistant clones derived from B-NHL cell lines as models to investigate the mechanism of resistance. The resistant clones exhibit hyper-activated survival/anti-apoptotic pathways and no longer respond to a combination of rituximab and drugs. Recent studies reported the therapeutic efficacy in mice bearing B-cell lymphoma xenografts following treatment with the anti-CD20-hIFNα fusion protein. We hypothesized that the fusion protein may bypass rituximab resistance and inhibit survival signaling pathways. Treatment of the rituximab-resistant clones with anti-CD20-hIFNα, but not with rituximab, IFNα, or rituximab+IFNα resulted in significant inhibition of cell proliferation and induction of cell death. Treatment with anti-CD20-hIFNα sensitized the cells to apoptosis by CDDP, doxorubicin and Treanda. Treatment with anti-CD20-hIFNα inhibited the NF-κB and p38 MAPK activities and induced the activation of PKC-δ and Stat-1. These effects were corroborated by the use of the inhibitors SB203580 (p38 MAPK) and Rottlerin (PKC-δ). Treatment with SB203580 enhanced the sensitization of the resistant clone by anti-CD20-hIFNα to CDDP apoptosis. In contrast, treatment with Rotterin inhibited significantly the sensitization induced by anti-CD20-hIFNα. Overall, the findings demonstrate that treatment with anti-CD20-hIFNα reverses resistance of B-NHL. These findings suggest the potential application of anti-CD20-hIFNα in combination with drugs in patients unresponsive to rituximab-containing regimens.

Converting Lymphoma Cells into Potent Antigen-Presenting Cells for Interferon-Induced Tumor Regression

“…Linking type I IFN to tumor antigen-associated Abs increased the antitumor effect of type I IFN in a xenograft model by direct killing of IFNα-sensitive 38C13-hCD20 tumor cells (15). Treatment with anti-hCD20-hIFNα reversed rituximab resistance of B-NHL in vitro, resulting in inhibition of cell proliferation and induction of cell death (16). Because many lymphomas are resistant to anti-CD20- or IFN-mediated apoptosis, we wondered whether targeting tumor cells with IFNα could mobilize the adaptive immune system for tumor control.…”

“…Targeted delivery of IFNα to the tumor microenvironment by hCD20 mAb induces tumor cell apoptosis in vitro and could lead to tumor control in vivo (15). Treatment with anti-hCD20-hIFNα can reverse the rituximab resistance of B-NHL in vitro by inhibiting cell proliferation and inducing cell death (16). However, not all lymphomas respond to anti-CD20 or IFN with apoptosis.…”

Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL

“…In colorectal cancer, CD10 degrades Met-enkephalin, accelerating the tumor growth and liver metastasis [ 66 ]. Meanwhile, CD20 is a tetraspanin with ability to form calcium channels and regulate cell cycle progression and activation, differentiation and proliferation of B cells [ 67 ].…”

Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing

“…Immunocytokines share a similar development concept, so it is predicted that they could improve the therapeutic window of cytokines. In cases of IFNs, various conjugates with monoclonal antibody (mAb) targeted against tumor-associated proteins, such as EGFR, HER2, CD20, CD38, and CD137, showed antiproliferative effects in murine models of either hematological malignancies or solid tumors ( Huang et al, 2007 ; Rossi et al, 2009 ; Dubrot et al, 2011 ; Trinh et al, 2013 ; Yang et al, 2014 ; Vega et al, 2015 ; Pogue et al, 2016 ). Tumor suppression was mediated by IFN α/β receptor on the cells ( Xuan et al, 2010 ) and/or through a more effective tumor antigen presentation by DCs to CD8 + T cells ( Yang et al, 2014 ).…”