Antibody-interferon-alpha fusion protein (IGN002) for the treatment of b-cell non-Hodgkin lymphomas: A phase 1, first-in-human, dose-escalation trial.

Author: Nastoupil, Loretta J. ; Minning, Dena ; Young, Patricia Ann ; Timmerman, John ; Dang, Nam H. ; Gresser, Michael J.

TPS3109Background: Interferon alpha (IFNα) has anti-proliferative and pro-apoptotic effects against many cancers, including NHL, and promotes both innate and adaptive anti-tumor immunity, but the c...

01 Jan 2016·Cancer Immunology Research

Abstract B182: IGN004 is an antibody-interferon-alpha fusion protein against a novel tumor-associated antigen with both direct anti-tumor and immunostimulatory effects

Author: Steward, Kristopher ; Khare, Sanjay ; Gresser, Michael ; Sachdev, Raj

AbstractBackground: Antibody-IFNα fusion proteins represent a cancer therapeutic with properties of an antibody-drug conjugate and an immunotherapeutic agent, having both direct anti-tumor and immune-activating effects. These powerful molecules have the potential to target the anti-tumor cytotoxic effects of IFN to the tumor and to change the immunosuppressive tumor microenvironment to activate anti-tumor immunity. We previously reported the activity of IGN002, a recombinant anti-CD20-IFNα fusion protein, against human non-Hodgkin B-cell lymphomas (Yamada et al, JCO 2013). We now report the in vitro and in vivo anti-tumor activity of IGN004, an antibody-IFNα fusion protein against a novel tumor associated antigen expressed by many solid and liquid tumors.Methods: IGN004 was evaluated against a panel of human non-small cell lung cancer (NSCLC), melanoma, multiple myeloma (MM), and acute myeloid leukemia (AML) cell lines. Antigen expression was assessed by flow cytometry and immunohistochemistry (IHC). Anti-proliferative activity was measured by MTS assay. MHC, costimulatory, and coinhibitory molecule expression was assessed by flow cytometry. T-cell killing of tumor cells by TALL-104 effector cells was assessed by MTS assay. Human tumor cell line and patient-derived xenografts were grown in immunodeficient mice.Results: IGN004 antibody bound to the majority of tumor cell lines investigated, including melanoma, NSCLC, AML, and MM. In addition, IGN004 antibody also bound to nearly 100% of the primary solid tumor samples tested by IHC. IGN004 induced stronger growth inhibition than the unfused antibody and IFNα. Incubation of tumor cells with IGN004 caused an increase in surface expression of MHC class I, PD-L1, and OX-40L. In an in vitro T-cell killing assay using TALL-104 cells as effectors and NSCLC cells as targets, treatment of tumor cells with IGN004 led to increased effector cell killing of tumor targets (69.2% killing without IGN004 vs. 100% killing with IGN004; p = 0.001). The enhanced T-cell killing was observed even with concentrations at the sub-picomolar level (EC50 = 0.87 pM). Importantly, IGN004 demonstrated robust in vivo efficacy against MM, AML, melanoma, and NSCLC xenografts, including patient-derived tumors. Against U266 MM xenografts, IGN004 fusion protein caused complete regression of all established tumors and achieved long-term survival in 62.5% of mice. IGN004 unfused antibody caused a significant delay in tumor progression (p=0.002 vs. vehicle) but did not achieve long-term survival (p=0003 vs. IGN004 fusion protein). When efficacy was tested against a panel of patient-derived NSCLC xenografts, IGN004 fusion protein demonstrated efficacy against 7/11 tumor models, including tumor regression in 3. Against a patient-derived xenograft model of melanoma, IGN004 unfused antibody was ineffective while IGN004 fusion protein inhibited the growth of the tumors. In a patient-derived xenograft model of AML, IGN004 treatment caused a reduction in the percentage of AML cells in the blood, spleen and bone marrow, compared to PBS treated animals.Conclusions: IGN004 demonstrated robust in vitro and in vivo anti-tumor activity against both solid and liquid tumors. Treatment of tumor cells with IGN004 caused an increase in surface expression of MHC class I, PD-L1, and OX-40L. IGN004 demonstrated the ability to enhance the effector T-cell-mediated killing of NSCLC cells in an in vitro assay using the TALL-104 cell line as effectors and NSCLC cell lines as targets. Against both cell line and patient-derived human xenograft tumors IGN004 had robust in vivo anti-tumor efficacy. These results support the further development of IGN004 as a potent targeted cancer immunotherapeutic agent that also has direct anti-tumor effects.Citation Format: Kristopher Steward, Michael Gresser, Raj Sachdev, Sanjay Khare. IGN004 is an antibody-interferon-alpha fusion protein against a novel tumor-associated antigen with both direct anti-tumor and immunostimulatory effects. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B182.

03 Dec 2015·Blood

Antibody-Interferon-Alpha Fusion Protein Therapy for the Treatment of B-Cell Non-Hodgkin Lymphoma: Enhanced ADCC, Inhibition of Proliferation, and In Vivo Eradication of CD20+ Human Lymphomas

Author: Minning, Dena M. ; Timmerman, John M. ; Steward, Kristopher K ; Gresser, Michael J ; Khare, Sanjay D ; Morrison, Sherie L ; Sachdev, Raj K ; Young, Patricia A ; Yamada, Reiko E

AbstractBackground: Interferon-alpha (IFNα) is a pleiotrophic cytokine with direct anti-tumor and immunostimulatory effects. Currently IFNα is approved for the treatment of multiple hematologic malignancies, including non-Hodgkin lymphoma (NHL). However, its clinical utility has been hindered by dose-limiting toxicitiy due to systemic activation of the interferon receptor. To overcome this limitation, we engineered anti-tumor antibody-IFNα fusion proteins to selectively increase delivery of IFN to the tumor site and reduce systemic toxicity. We previously reported that IGN002, an anti-CD20-IFNα fusion protein, exhibits enhanced complement-dependent cytotoxicity (CDC) compared to rituximab, and inhibits proliferation and induces apoptosis of human B-cell NHL (Yamada et al, ASCO 2013). We now extend these previous findings and show that IGN002 possesses enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function and superior in vivo anti-tumor activity against B-cell NHL, compared to rituximab.Methods: IGN002 was evaluated against a panel of human Burkitt and diffuse large B-cell lymphoma (DLBCL) cell lines. Proliferation was measured by [3 H]-thymidine incorporation, STAT1 activation by flow cytometry, ADCC by lactate dehydrogenase release using human PBMC effectors, and IFN bioactivity by encephalomyocarditis (EMC) viral protection assay. NHL xenografts were grown in SCID mice.Results: IGN002 more potently inhibited the growth of NHL cell lines expressing CD20 than rituximab or unfused IFNα. Intrinsic IFNα activity of IGN002 was reduced in viral protection and anti-proliferation assays using cells lacking CD20 expression. STAT1 activation by IGN002 was enhanced on cells expressing the target antigen, whereas a control antibody-IFNα fusion protein showed reduced STAT activation activity compared to unfused IFNα. Together, these results indicate that fusion of IFNα to the antibody results in reduced IFN effects on cells not bearing the tumor antigen target. IGN002 exhibited enhanced ADCC activity compared to rituximab against Daudi, Ramos, and Raji NHL cells in long-term (overnight incubation) assays, demonstrating both higher potency and higher maximal cytotoxicity. This result is possibly due to activation of the effector cell populations by the fused IFNα moiety, as IFN is known to activate both NK cells and monocytes. The in vivo anti-tumor efficacy of IGN002 was compared to rituximab and a control antibody-IFNα fusion protein against 10-day established Raji NHL xenografts. IGN002 was superior to both rituximab and the control fusion protein, achieving a longer median survival and higher long-term survival rate (p = 0.0015 and < 0.0001 vs. rituximab and control fusion protein, respectively). The in vivo anti-tumor efficacy of IGN002 was also compared to rituximab at three equimolar dose levels (5 mg/kg, 1 mg/kg, and 0.2 mg/kg antibody) against 10-day established Daudi NHL xenografts. IGN002 showed superior efficacy compared to rituximab at all doses (p < 0.001), achieving tumor eradication (100% long-term survival) in all mice treated at all three dose levels, whereas rituximab only delayed tumor progression.Conclusions: IGN002 demonstrated more robust direct anti-proliferative and antibody effector functions than rituximab against human NHL cells in vitro, and also showed the ability to eradicate established NHL xenografts in vivo. Against cells expressing the CD20 target antigen, IGN002 exhibited greater anti-proliferative potency than unfused IFNα. In contrast, the anti-proliferative and anti-viral potency of IGN002 was reduced against cells lacking CD20, compared to unfused IFNα. These findings support the hypothesis that tumor antigen-targeted IFN therapeutics may possess a broader therapeutic index than unfused IFNα, inhibiting tumor growth by multiple mechanisms while reducing systemic toxicity. These results support the further development of IGN002 for the treatment of B-cell NHL, and a first-in-human phase I clinical study will begin later this year in the United States.DisclosuresTimmerman: Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Valor Biotherapeutics: Research Funding. Steward:ImmunGene, Inc.: Employment. Minning:Valor Biotherapeutics, LLC: Consultancy. Sachdev:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gresser:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Khare:Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Morrison:ImmunGene, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Drug(Targets)	Indications	Global Highest Phase

IGN-004 ( IFN α x IFNAR )	Neoplasms More	Preclinical
IGN-005	Leukemia More	Pending
IGN-003	Multiple Myeloma More	Pending
IGN-006	Solid tumor More	Pending

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