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1.
Cancer Immunol Res ; 11(7): 962-977, 2023 07 05.
Article in English | MEDLINE | ID: mdl-37074216

ABSTRACT

IL-12 is a pleotropic inflammatory cytokine, which has broad stimulatory effects on various immune cell populations, making it an attractive target for cancer immunotherapy. However, despite generating robust antitumor activity in syngeneic murine tumor models, clinical administration of IL-12 has been limited by severe toxicity. mWTX-330 is a selectively inducible INDUKINE molecule comprised of a half-life extension domain and an inactivation domain linked to chimeric IL-12 by tumor protease-sensitive linkers. Systemic administration of mWTX-330 in mice was well tolerated, resulted in robust antitumor immunity in multiple tumor models, and preferentially activated tumor-infiltrating immune cells rather than immune cells present in peripheral tissues. Antitumor activity was dependent on in vivo processing of the protease cleavable linkers and required CD8+ T cells for full efficacy. Within the tumor, mWTX-330 increased the frequency of cross-presenting dendritic cells (DC), activated natural killer (NK) cells, skewed conventional CD4+ T cells toward a T helper 1 (TH1) phenotype, drove regulatory T cells (Treg) fragility, and increased the frequency of polyfunctional CD8+ T cells. mWTX-330 treatment also increased the clonality of tumor-infiltrating T cells by expanding underrepresented T-cell receptor (TCR) clones, drove CD8+ T and NK cells towards increased mitochondrial respiration and fitness, and decreased the frequency of TOX+ exhausted CD8+ T cells within the tumor. A fully human version of this INDUKINE molecule was stable in human serum, was reliably and selectively processed by human tumor samples, and is currently in clinical development.


Subject(s)
Interleukin-12 , Melanoma, Experimental , Mice , Humans , Animals , Interleukin-12/genetics , Killer Cells, Natural , CD8-Positive T-Lymphocytes , Peptide Hydrolases
2.
Cancer Immunol Res ; 10(5): 581-596, 2022 05 03.
Article in English | MEDLINE | ID: mdl-35286392

ABSTRACT

IL-2 is a cytokine clinically approved for the treatment of melanoma and renal cell carcinoma. Unfortunately, its clinical utility is hindered by serious side effects driven by the systemic activity of the cytokine. Here, we describe the design and characterization of a conditionally activated IL-2 prodrug, WTX-124, that takes advantage of the dysregulated protease milieu of tumors. WTX-124 was engineered as a single molecule containing an inactivation domain and a half-life extension domain that are tethered to a fully active IL-2 by protease-cleavable linkers. We show that the inactivation domain prevented IL-2 from binding to its receptors in nontumor tissues, thereby minimizing the toxicity associated with systemic exposure to IL-2. The half-life extension element improves the pharmacokinetic profile of WTX-124 over free IL-2, allowing for greater exposure. WTX-124 was preferentially activated in tumor tissue by tumor-associated proteases, releasing active IL-2 in the tumor microenvironment. In vitro assays confirmed that the activity of WTX-124 was dependent on proteolytic activation, and in vivo WTX-124 treatment resulted in complete rejection of established tumors in a cleavage-dependent manner. Mechanistically, WTX-124 treatment triggered the activation of T cells and natural killer (NK) cells, and markedly shifted the immune activation profile of the tumor microenvironment, resulting in significant inhibition of tumor growth in syngeneic tumor models. Collectively, these data demonstrate that WTX-124 minimizes the toxicity of IL-2 treatment in the periphery while retaining the full pharmacology of IL-2 in the tumor microenvironment, supporting its further development as a cancer immunotherapy treatment. See related Spotlight by Silva, p. 544.


Subject(s)
Interleukin-2 , Melanoma , Cytokines , Humans , Immunotherapy , Interleukin-2/pharmacology , Interleukin-2/therapeutic use , Peptide Hydrolases , Tumor Microenvironment
3.
Cancer Treat Res Commun ; 28: 100433, 2021.
Article in English | MEDLINE | ID: mdl-34273876

ABSTRACT

The T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) is a validated immune checkpoint protein expressed on memory CD4+T-cellls, Tregs, CD8+T-cell and natural killer (NK) cells. ASP8374 is a fully human monoclonal immunoglobulin (Ig) G4 antibody designed to block the interaction of TIGIT with its ligands and inhibit TIGIT signaling. ASP8374 exhibited high affinity binding to TIGIT and increased interferon (IFN)-γ production of cultured peripheral blood mononuclear cells (PBMCs) in a titratable manner. When used in combination with pembrolizumab, an anti-programmed death-1 (PD-1) antibody, ASP8374 induced higher T-cell activation in vitro than either treatment alone. An anti-mouse TIGIT antibody surrogate, mSEC1, displayed anti-tumor efficacy in an MC38 syngeneic mouse tumor model alone and in combination with an anti-programmed death-ligand 1 (PD-L1) antibody. In an additional syngeneic mouse tumor model (CT26), while mSEC1 alone did not demonstrate anti-tumor efficacy, mSEC1 combined with an anti-PD-1 antibody enhanced anti-tumor efficacy above that of the anti-PD-1 antibody alone. These data provide evidence that ASP8374 has therapeutic potential for advanced malignancies.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Receptors, Immunologic/antagonists & inhibitors , Animals , Antibodies, Monoclonal/pharmacology , Female , Humans , Mice
4.
J Cachexia Sarcopenia Muscle ; 7(4): 467-82, 2016 09.
Article in English | MEDLINE | ID: mdl-27239403

ABSTRACT

BACKGROUND: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. METHODS: Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. RESULTS: Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. CONCLUSIONS: The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.

5.
Mol Cancer Ther ; 14(8): 1858-67, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25995436

ABSTRACT

Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit.


Subject(s)
Antibodies, Monoclonal/pharmacology , Neovascularization, Pathologic/metabolism , Receptor, Notch1/agonists , Angiogenesis Inhibitors/pharmacology , Animals , Antibodies, Blocking/pharmacology , Antibodies, Blocking/toxicity , Antibodies, Monoclonal/toxicity , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , Female , Humans , Ligands , Mice , Phenylurea Compounds/pharmacology , Quinolines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/metabolism , Signal Transduction/drug effects , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
6.
Clin Cancer Res ; 21(5): 1106-14, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25542901

ABSTRACT

PURPOSE: ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic. EXPERIMENTAL DESIGN: We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. RESULTS: A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models. CONCLUSIONS: NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Gene Expression , Neoplasms/genetics , Neuregulin-1/genetics , Receptor, ErbB-3/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Area Under Curve , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm/genetics , Female , Humans , Ligands , Mice , Mutation , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Neuregulin-1/metabolism , Prognosis , Protein Binding , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Reproducibility of Results , Xenograft Model Antitumor Assays
7.
Cancer Res ; 70(19): 7630-9, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20709759

ABSTRACT

Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb-specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies.


Subject(s)
Antibodies, Monoclonal/pharmacology , Neoplasms/therapy , Receptor, Fibroblast Growth Factor, Type 2/immunology , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , Antibody Specificity , Cell Growth Processes/drug effects , Cell Line, Tumor , Female , Gene Amplification , Humans , Mice , Mice, SCID , Molecular Sequence Data , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/immunology , Phosphorylation/drug effects , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/genetics , Signal Transduction , Xenograft Model Antitumor Assays
9.
Proc Natl Acad Sci U S A ; 104(25): 10565-70, 2007 Jun 19.
Article in English | MEDLINE | ID: mdl-17563372

ABSTRACT

In plants and in the nematode Caenorhabditis elegans, an RNAi signal can trigger gene silencing in cells distant from the site where silencing is initiated. In plants, this signal is known to be a form of dsRNA, and the signal is most likely a form of dsRNA in C. elegans as well. Furthermore, in C. elegans, dsRNA present in the environment or expressed in ingested bacteria is sufficient to trigger RNAi (environmental RNAi). Ingestion and soaking delivery of dsRNA has also been described for other invertebrates. Here we report the identification and characterization of SID-2, an intestinal luminal transmembrane protein required for environmental RNAi in C. elegans. SID-2, when expressed in the environmental RNAi defective species Caenorhabditis briggsae, confers environmental RNAi.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/genetics , Membrane Proteins/genetics , Membrane Proteins/physiology , RNA Interference , RNA, Helminth/genetics , Amino Acid Sequence , Animals , Animals, Genetically Modified , Caenorhabditis elegans/metabolism , Conserved Sequence , Intestinal Mucosa/metabolism , Membrane Proteins/chemistry , Molecular Sequence Data , Mutation , Protein Sorting Signals , RNA, Double-Stranded/genetics , Sequence Homology, Amino Acid , Transgenes
10.
Science ; 295(5564): 2456-9, 2002 Mar 29.
Article in English | MEDLINE | ID: mdl-11834782

ABSTRACT

Double-stranded RNA-mediated gene interference (RNAi) in Caenorhabditis elegans systemically inhibits gene expression throughout the organism. To investigate how gene-specific silencing information is transmitted between cells, we constructed a strain that permits visualization of systemic RNAi. We used this strain to identify systemic RNA interference-deficient (sid) loci required to spread gene-silencing information between tissues but not to initiate or maintain an RNAi response. One of these loci, sid-1, encodes a conserved protein with predicted transmembrane domains. SID-1 is expressed in cells sensitive to RNAi, is localized to the cell periphery, and is required cell-autonomously for systemic RNAi.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/genetics , Gene Silencing , Membrane Proteins/genetics , Membrane Proteins/physiology , RNA, Double-Stranded/genetics , RNA, Helminth/genetics , Amino Acid Sequence , Animals , Animals, Genetically Modified , Caenorhabditis elegans/embryology , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/chemistry , Calmodulin-Binding Proteins/genetics , Cytoplasm/metabolism , Embryo, Nonmammalian/physiology , Genes, Helminth , Germ Cells/metabolism , Green Fluorescent Proteins , Intestinal Mucosa/metabolism , Luminescent Proteins/genetics , Membrane Proteins/chemistry , Molecular Sequence Data , Mosaicism , Muscle Proteins/genetics , Muscles/metabolism , Mutation , Protein Structure, Tertiary , RNA, Double-Stranded/metabolism , RNA, Helminth/metabolism , Recombinant Fusion Proteins/metabolism , Transgenes
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