725 Pre-clinical development of TNFR2 ligand-blocking BI-1808 for cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A768-A768
Author(s):  
Linda Mårtensson ◽  
Mathilda Kovacek ◽  
Petra Holmkvist ◽  
Monika Semmrich ◽  
Carolin Svensson ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Therapeutic Effect ◽  
Cytokine Release ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Cynomolgus Monkeys ◽  
Range Finding ◽  
Cellular Expression ◽  
Toxicological Studies

BackgroundThe pleiotropic TNF-alpha:TNFR axis plays a central role in the immune system. While the cellular expression of TNFR1 is broad, TNFR2 expression is mainly restricted to immune cells. The therapeutic potential of targeting TNFR2 for cancer treatment has been previously indicated and to gain further insight, we characterized a wide panel antibodies, generated from the n-CoDeR F.I.R.S.T™ target and antibody discovery platform. We identified parallel human and mouse TNFR2 specific, complete ligand (TNF-alpha) blocking antibodies and could show potent anti-tumor activity in several immune-competent models, both as single agent and in combination with anti-PD1 using a BI-1808 murine surrogate. The mechanism-of-action was shown to be FcgR dependent and likely mediated through a combination of intra-tumor T reg depletion, CD8+ T cell expansion and modulation of tumor-associated myeloid cells. These findings were confirmed using BI-1808 in a humanized mouse model.MethodsTo address safety of the human lead-candidate BI-1808 two toxicological studies were performed in cynomolgus monkeys. The first study was a dose-range-finding study and the second a GLP study where three doses (2, 20 and 200 mg/kg) were given weekly for four consecutive weeks followed by a recovery period of eight weeks. In addition, cytokine release was further studied in T cell stimulation assays and in a humanized mouse model. Moreover, the BI-1808 murine surrogate was used to study the relationship between dose, receptor occupancy (RO) and efficacy in immune competent mouse cancer experimental models.ResultsFour weekly administrations of BI-1808 to cynomolgus monkeys were well tolerated at all doses, with no associated clinical signs, and no histopathological changes. Non-adverse and reversible increases in neutrophil counts and decreases in T cells were observed at all dose levels. No drug-related adverse events were observed and consequently the NOAEL for BI-1808 was determined to be 200 mg/kg. Pharmacokinetic studies demonstrated an expected half-life of two weeks at receptor saturation. There were no indications of cytokine release in any of the systems tested. Finally, we could show that to achieve max therapeutic effect, sustained RO was needed for approximately two weeks, covering the time it takes to generate a full adaptive Immune response.ConclusionsThere is a clear association between RO and therapeutic effect and BI-1808 is well tolerated at doses associated with high and sustained RO. Collectively, these studies were used to determine the starting dose in upcoming phase I/II study in solid cancer aiming for first-patient in during December 2020.Ethics ApprovalThe study on cynomolgous monkeys was conducted by Citox/Charles River Laboratories in compliance with animal health regulations, in particular: Council Directive No. 2010/63/EU of 22 September 2010 and French decree No. 2013-118 of 01 February 2013 on the protection of animals used for scientific purposes. Studies in mice were approved by the Swedish Animal Experiment Ethics Board, ethical permit/ethical license numbers 5.2.18-17196/2018 and 5.8.18-03333/2020

203 Preclinical characterization and development of MG1124, a Novel Immune Checkpoint inhibitor targeting CEACAM1 for NSCLC patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A218-A218
Author(s):  
Jae-Chul Lee ◽  
Woo Seok Yang ◽  
Hye-Young Park ◽  
Hye-mi Nam ◽  
Hyun-Jung Cho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Mouse Model ◽  
Mouse Models ◽  
Nk Cell ◽  
Cytotoxic T Cell ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Cynomolgus Monkeys ◽  
Homophilic Interaction

BackgroundCEACAM1 is the only member of CEACAM family which is expressed on lymphocytes such as T cells and NK cells that mediate suppression of inflammatory T cell response. It is known that CEACAM1-CEACAM1 homophilic interaction induces downregulation of ZAP70 phosphorylation in response to T cell receptor (TCR) stimulation. There is a wealth of research demonstrating the correlation between CEACAM1 expression and cancer progression, in a wide range of indications. We developed a fully human monoclonal antibody (mAb) MG1124 that specifically binds to CEACAM1 but not to other CEA family members, thereby exerting anti-tumor effect via triggering immune response.MethodsT cell activation of MG1124 was determined by an NFAT-luciferase reporter assay with CEACAM1 overexpressing Jurkat stable cells. In vitro efficacy of MG1124 was examined using an NK cell- or cytotoxic T cell-mediated tumor cell killing assay. The anti-tumor efficacy of MG1124 alone or in combination was studied in a humanized mouse model. As MG1124 binds to monkey CEACAM1 with high affinity, pharmacokinetics assessment of MG1124 was performed in cynomolgus monkeys.ResultsAn anti-CEACAM1 antibody MG1124 bound to CEACAM1 but not to other CEA family members. MG1124 blocked CEACAM1 homophilic interaction by binding to the N domain of CEACAM1. Especially the homophilic interaction induced downregulation of ZAP70 phosphorylation in response to TCR stimulation in a CEACAM1 overexpressing Jurkat stable cell line, which was rescued by MG1124 resulting in augmentation of NFAT activity and IL-2 expression. NK cell or cytotoxic T cell-mediated tumor lysis was increased by MG1124 in a CEACAM1 expression-dependent manner. MG1124 inhibited tumor growth in CEACAM1 expressing NSCLC CDX humanized mouse models. In an NSCLC PDX humanized mouse model, MG1124 dose-dependently inhibited tumor growth as monotherapy. Moreover, MG1124 showed synergistic anti-cancer activity with pembrolizumab in NSCLC huPDX models. Pharmacokinetic (PK) analysis in cynomolgus monkeys showed that the half-life (T1/2) of MG1124 was estimated to range from 14 to 17 days, and the peak plasma concentration (Cmax) and overall exposure (AUC) were found to be generally dose proportional. Following this PK study, a toxicity study in cynomolgus monkeys is ongoing.ConclusionsMG1124, a novel anti-CEACAM1 mAb, blocked CEACAM1-mediated negative regulation and restored NK or cytotoxic T cell activities. MG1124 showed effective anti-tumor activity in in vivo mouse models and its combination with PD-1 blockade further enhanced treatment efficacy. The data presented herein support further advancement of MG1124 towards clinical development. MG1124 is a potential therapeutic candidate for immune checkpoint blockade in cancer therapy.ReferencesScott D Gray-Owen, Richard S Blumberg. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 2006; 6(6): 433–46.Anka Thies. et al., CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 2002; 20(10): 2530–6.Sebastian Dango, et al., Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer. Lung Cancer 2008; 60(3): 426–33.Matthew Dankner, et al., CEACAM1 as a multi-purpose target for cancer immunotherapy. OncoImmunology 2017;6(7):e1328336.

scholarly journals Antigen-Conjugated Human IgE Induces Antigen-Specific T Cell Tolerance in a Humanized Mouse Model

2014 ◽  
Vol 192 (7) ◽  
pp. 3280-3288 ◽  
Author(s):  
Günther Baravalle ◽  
Alexandra M. Greer ◽  
Taylor N. LaFlam ◽  
Jeoung-Sook Shin
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Humanized Mouse ◽  
Humanized Mouse Model

scholarly journals 767. A Novel Humanized Mouse Model for Testing Anti-HIV T-Cell Gene Therapy Strategies

2016 ◽  
Vol 24 ◽  
pp. S304
Author(s):  
Kevin G. Haworth ◽  
Christina Ironside ◽  
Hans-Peter Kiem
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Mouse Model ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Therapy Strategies ◽  
Cell Gene ◽  
Anti Hiv

scholarly journals An EBNA3A-Mutated Epstein-Barr Virus Retains the Capacity for Lymphomagenesis in a Cord Blood-Humanized Mouse Model

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
James C. Romero-Masters ◽  
Makoto Ohashi ◽  
Reza Djavadian ◽  
Mark R. Eichelberg ◽  
Mitchell Hayes ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
Cord Blood ◽  
Wild Type ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) causes B cell lymphomas and transforms B cells in vitro. The EBV protein EBNA3A collaborates with EBNA3C to repress p16 expression and is required for efficient transformation in vitro. An EBNA3A deletion mutant EBV strain was recently reported to establish latency in humanized mice but not cause tumors. Here, we compare the phenotypes of an EBNA3A mutant EBV (Δ3A) and wild-type (WT) EBV in a cord blood-humanized (CBH) mouse model. The hypomorphic Δ3A mutant, in which a stop codon is inserted downstream from the first ATG and the open reading frame is disrupted by a 1-bp insertion, expresses very small amounts of EBNA3A using an alternative ATG at residue 15. Δ3A caused B cell lymphomas at rates similar to their induction by WT EBV but with delayed onset. Δ3A and WT tumors expressed equivalent levels of EBNA2 and p16, but Δ3A tumors in some cases had reduced LMP1. Like the WT EBV tumors, Δ3A lymphomas were oligoclonal/monoclonal, with typically one dominant IGHV gene being expressed. Transcriptome sequencing (RNA-seq) analysis revealed small but consistent gene expression differences involving multiple cellular genes in the WT EBV- versus Δ3A-infected tumors and increased expression of genes associated with T cells, suggesting increased T cell infiltration of tumors. Consistent with an impact of EBNA3A on immune function, we found that the expression of CLEC2D, a receptor that has previously been shown to influence responses of T and NK cells, was markedly diminished in cells infected with EBNA3A mutant virus. Together, these studies suggest that EBNA3A contributes to efficient EBV-induced lymphomagenesis in CBH mice. IMPORTANCE The EBV protein EBNA3A is expressed in latently infected B cells and is important for efficient EBV-induced transformation of B cells in vitro. In this study, we used a cord blood-humanized mouse model to compare the phenotypes of an EBNA3A hypomorph mutant virus (Δ3A) and wild-type EBV. The Δ3A virus caused lymphomas with delayed onset compared to the onset of those caused by WT EBV, although the tumors occurred at a similar rate. The WT EBV and EBNA3A mutant tumors expressed similar levels of the EBV protein EBNA2 and cellular protein p16, but in some cases, Δ3A tumors had less LMP1. Our analysis suggested that Δ3A-infected tumors have elevated T cell infiltrates and decreased expression of the CLEC2D receptor, which may point to potential novel roles of EBNA3A in T cell and NK cell responses to EBV-infected tumors.

Abstract 3569: Humanized mouse model of MAGE-A1-targeted anti-melanoma T cell therapy

2018 ◽  
Author(s):  
Megan S. McAfee ◽  
Trisha Sippel ◽  
Daniel Hunter ◽  
Jean Campbell ◽  
Thomas Schmitt ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Cell Therapy ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
T Cell Therapy
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