BackgroundHomeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.ResultsWe developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).ConclusionsWe developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.
Helicobacter suis infects the stomachs of both animals and humans, and can induce gastric mucosa-associated lymphoid tissue (MALT) lymphomas. It is known that CXC chemokine ligand 13 (CXCL13) is highly expressed in the Helicobacter-infected mice and gastric MALT lymphoma patients, but the pathway that links the activation of CXCL13 and the formation of gastric MALT lymphomas remains unclear. In this study, we examined whether CXCL13 neutralization would interfere with the formation of gastric lymphoid follicles including B cells, CD4+T cells, dendritic cells (DCs), and follicular DCs (FDCs) in germinal centers to determine the role of CXCL13 in the formation of B-cell aggregates after H. suis infection. Moreover, the expression of genes associated with the lymphoid follicle formation was also effectively suppressed by anti-CXCL13 antibody treatment. These results suggest that the upregulation of CXCL13 has an important role in the development of gastric MALT lymphomas and highlight the potential of anti-CXCL13 antibody for protection against Helicobacter-induced gastric diseases.
Semaphorin 4D (SEMA4D or CD100) is a member of the semaphorin family of proteins and an important mediator of the movement and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. Blocking the binding of SEMA4D to its receptors can result in physiologic changes that may have implications in cancer, autoimmune, and neurological disease. To study the effects of blocking SEMA4D, we generated, in SEMA4D-deficient mice, a panel of SEMA4D-specific hybridomas that react with murine, primate, and human SEMA4D. Utilizing the complementarity-determining regions from one of these hybridomas (mAb 67-2), we generated VX15/2503, a humanized IgG4 monoclonal antibody that is currently in clinical development for the potential treatment of various malignancies and neurodegenerative disorders, including multiple sclerosis and Huntington's disease. This work describes the generation and characterization of VX15/2503, including in vitro functional testing, epitope mapping, and an in vivo demonstration of efficacy in an animal model of rheumatoid arthritis.
Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including metastasis, tumor invasion, and neovascularization. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells activates RhoA and AKT signaling pathways, which promotes formation of new blood vessels and tumor growth in vivo. SEMA4D is over-expressed in a wide array of tumor types, and is also produced by inflammatory cells recruited to the tumor microenvironment, such as tumor-associated macrophages. In addition to its effects on endothelial cells, the interaction of PLXNB1 with MET and ERBB2 can lead to SEMA4D-mediated transactivation of these membrane receptor kinases with a direct effect on tumor cell migration and invasive growth. Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated inflammatory cells, functions as a crucial factor in tumor metastatic potential, and that expression of SEMA4D and/ or its high affinity receptor in tumors induces neovascularization and increases overall tumor aggressiveness. Antibody neutralization of SEMA4D represents a new therapeutic strategy for cancer treatment. We selected a humanized IgG4 antibody, VX15/2503, that binds with roughly 3 nM affinity to rat, mouse, primate, and human SEMA4D. We utilized cellular collapse, flow cytometric and other in vitro functional assays to demonstrate that this antibody blocks SEMA4D interaction with PLXNB1. Using both this antibody and its mouse IgG1 equivalent, MAb 67-2, we have demonstrated that antibody-mediated SEMA4D neutralization blocks tumor growth in CT26 tumor grafts with a tumor growth delay (TGD) of 42% and BCA34 (TGD 18%) tumor grafts, as well as RIP-Tag2, with a tumor growth inhibition (TGI) of 56%, and Tyr:NRAS (TGD 52%) spontaneous tumor models. In summary, we demonstrate that antibody mediated neutralization of SEMA4D in vivo inhibits tumor growth and tumor angiogenesis in a variety of tumor models. The humanized antibody, VX15/2503, has successfully completed IND-enabling toxicology testing and a Phase I trial is currently being conducted in adult patients with advanced solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2531. doi:1538-7445.AM2012-2531
Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including transactivation of several oncogenes, metastasis, tumor invasion, and neovascularization. Expression of SEMA4D and its receptor plexin-B1 (PLXNB1) correlates with invasive disease in humans. SEMA4D is over-expressed in a wide array of tumor types and is also produced by inflammatory cells recruited to the tumor microenvironment. SEMA4D binding to PLXNB1 on endothelial cells activates RhoA and AKT signaling pathways, which promotes formation of new blood vessels and tumor growth in vivo. In addition to its effects on endothelial cells, the interaction of PLXNB1 with MET and ERBB2 can lead to SEMA4D-mediated transactivation of these membrane receptor kinases with a direct effect on tumor cell migration and invasive growth. It is well known that tumor growth and metastasis involve a complex process of cross talk amongst the tumor cells, stroma and immune infiltrate, as well as the endothelial cells and vasculature. Our understanding of the role of SEMA4D in this process is evolving. We selected a humanized IgG4 antibody, VX15/2503, that blocks SEMA4D interaction with the high affinity receptor PLXNB1 and a lower affinity receptor, CD72, expressed on immune cells. The antibody binds with between 1-5 nM affinity to rat, mouse, primate, and human recombinant SEMA4D. Affinity to native cell-associated SEMA4D on primary human T cells was, however, determined to be 0.5 nM. We demonstrate that antibody-mediated SEMA4D neutralization delays tumor growth in several primary and metastatic in vivo models. Inhibition of SEMA4D regulates angiogenesis and vascular permeability in these models. Additionally, tumor growth delay results from modulation of the tumor microenvironment, such as infiltrating immune cells. We also demonstrate direct effects of SEMA4D/PLXNB1 interaction acting as a guidance signal for tumors, as previously described for axons, whereby tumor migration is affected ∼80%. Antibody blockade restores these functional activities. Moreover, using a genetic fingerprinting approach, we identified a unique gene signature that is related to changes in PLXNB1 expression and sensitivity to existing targeted therapies. This signature sheds light on combination therapies with anti-SEMA4D antibodies that may produce additive anti-tumor effects. In summary, blockade of SEMA4D reduces tumor growth through effects on tumor microenvironment, angiogenesis and vascular permeability, as well as direct effects on tumor. Therefore, antibody neutralization of SEMA4D represents a new therapeutic strategy for cancer treatment. The humanized antibody, VX15/2503, has successfully completed IND-enabling toxicology testing and a Phase I trial is currently being conducted in adult patients with advanced solid tumors. Citation Format: Elizabeth E. Evans, Alan S. Jonason, Mark Paris, Terrence L. Fisher, Sebold Torno, Holm Bussler, Jessica Decker, Maria Scrivens, He Huang, Laurie A. Winter, Tracy Pandina, Leslie Balch, Michael A. Doherty, Renee Kirk, Alan Howell, Jennifer Seils, Christine Reilly, Maurice Zauderer, John E. Leonard, Ernest S. Smith. Reduction of tumor growth and metastasis by a humanized IgG4 monoclonal antibody to SEMA4D (VX15/2503). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1245. doi:10.1158/1538-7445.AM2013-1245 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.