32 results about "Delta-like ligand 4" patented technology

The present invention provides methods of using a DLL4 modulator to modulate vascular development. Furthermore, methods of treatment using DLL4 modulators, such as DLL4 antagonists, are provided.

Improved DLL4 binding proteins are described, including antibodies, CDR-grafted antibodies, human antibodies, and DLL4 binding fragments thereof, proteins that bind DLL4 with high affinity, and DLL4 binding proteins that neutralize DLL4 activity. The DLL4 binding proteins are useful for treating or preventing cancers and tumors and especially for treating or preventing tumor angiogenesis, and/or other angiogenesis-dependent diseases such as ocular neovascularization, or angiogenesis-independent diseases characterized by aberrant DLL4 expression or activity such as autoimmune disorders including multiple sclerosis.

The invention relates to targeted binding agents against DLL4 and uses of such agents. More specifically, the invention relates to fully human monoclonal antibodies directed to DLL4. The described targeted binding agents are useful in the treatment of diseases associated with the activity and/or overproduction of DLL4 and as diagnostics.

A therapeutic method for treating ischemic or vascular disorders by administering an agent capable of inhibiting human delta-like ligand 4 (Dll4) activity to a subject in need thereof. In one embodiment, the agent is an anti-Dll4 antibody or antibody fragment capable of inhibiting the binding of Dll4 to a Notch receptor. The method of the invention is useful for treating eye disorders such as ischemic retinopathy, diabetic retinopathy, age related macular degeneration, corneal neovascularization, neovascular glaucoma, or retinopathy of prematurity. The method is also useful or treating ischemic or vascular disorders such as ischemic injury, cerebral ischemia, cardiac ischemia, ischemic conditions affecting the limbs and other organs or tissues, arteriovenous malformations, wound healing, organ or tissue transplantation, placental insufficiency, arterial narrowing and occlusion, atherosclerosis, and systemic or pulmonary hypertension.

DLL4-binding antibodies, specifically antibodies preventing Notch signaling and internalization of DLL4, can: more efficiently than inhibitors only preventing DLL4-mediated Notch-signaling disrupt angiogenesis and pathological processes including tumor growth.

The present invention provides methods of treating a disease or disorder, in which increasing the number of regulatory T cell (Treg) is beneficial, by administering to a subject suffering from such a disease or disorder a therapeutically effective amount of DII4 antagonists that block DII4-Notch signal pathways, thereby increasing the number of Treg. Diseases or disorders treatable by the methods of the invention include autoimmune diseases or disorders, such as multiple sclerosis (MS), diabetes, and the like. Suitable DII4 antagonists for the invention include antibodies or antibody fragments that specifically bind DII4 and block DII4-Notch interactions, the extracellular domain of DII4, and the like. The invention also provides methods of preventing an occurrence or recurrence of such diseases or disorders in a subject predisposed or susceptible to developing such diseases or disorders. Furthermore, the methods of the invention are useful in preventing or treating organ transplant rejections or graft-versus-host disease.

The present invention provides methods of preventing, treating or ameliorating diabetes by administering to a subject in need thereof a therapeutically effective amount of Dll4 antagonists that block Dll4-Notch signal pathways. As observed in a mouse model of diabetes, Dll4 antagonists exhibit protective effects on pancreatic islets, lower blood glucose levels, and block the production of auto-antibodies, including those against insulin and glutamic acid decarboxylase 65 (GAD65), via the expansion of regulatory T cells (Tregs). Thus, the present invention further provides methods of lowering the levels of blood glucose, and/or reducing or blocking the production of auto-antibodies, by administering to a subject in need thereof a therapeutically effective amount of Dll4 antagonists. Suitable Dll4 antagonists for the invention include antibodies or antibody fragments that specifically bind Dll4 and block Dll4-Notch interactions, the extracellular domain of Dll4, and the like.

An isolated antibody that specifically binds to an extracellular domain of human DLL4 and affects growth of a tumor comprising cancer stem cells is described. Also described is a method of treating cancer comprising administering a therapeutically effective amount of an anti-DLL4 antibody.

The present invention relates to pharmaceutical combinations comprising dual Angiopoietin-2/DII4 binders and anti-VEGF-R agents for use in treating diseases like cancer and ocular diseases.

The invention provides anti-DLL4 antibodies, and compositions comprising and methods of using these antibodies.

The invention belongs to the field of antibodies. A bispecific antibody targeting to both VEGF and DLL4 is characterized in that the antibody comprises four chains, namely, an amino acid sequence shown by SEQ ID NO: 1, an amino acid sequence shown by SEQ ID NO: 2, an amino acid sequence shown by SEQ ID NO: 3 and an amino acid sequence shown by SEQ ID NO: 4 in sequence. The dual-targeted VEGF and DLL4 bispecific antibody HB-32 is constructed for the first time, and the antibody can be bound with the antigens VEGF and DLL4 respectively and has good antitumor activity.

The present invention relates to a dual-targeted protein comprising: a novel protein specifically binding to delta like ligand 4 (DLL4); and an antibody specifically binding to a vascular endothelial cell growth factor (VEGF).

The invention provides anti-DLL4 antibodies, and compositions comprising and methods of using these antibodies.

The invention provides a bombyx mori recombinant baculovirus Bm-CMV-DLL4-DAF. The recombinant baculovirus adopts a recombinant baculovirus expression vector Pfastbacdual as a vector, and comprises a CMV-IE promoter, a DLL4 gene, a gp64 signal peptide gene, a DAF protein gene and a gp64 transmembrane domain gene. Preparation of the recombinant baculovirus includes steps of: subjecting the CMV-IE promoter sequence, the DLL4 protein bases, the gp64 signal peptide gene sequence, the gp64 transmembrane domain gene sequence and the DAF gene sequence to PCR amplification, constructing a Pfastbacdual-CMV-DLL4-DAF recombinant plasmid, and extracting viral genome. The recombinant baculovirus is good in stability, high in host infection rate, high in expression capability and capable of efficiently expressing DLL4 protein in mammal animal cells, thus provoking high and effective immunoreactions. The recombinant baculovirus is suitable for application in preparation of cancer vaccines.

Methods are provided for generating DLL4-expressing immune cells. The invention also includes cellular compositions of dendritic and T cells produced by these methods. The immune cells of the invention can be used widely as components in many diagnostic and therapeutic systems, including improved vaccines to reduce the risk of graft versus host disease.

The present invention discloses application of DLL4 cytokine in preparation of a medicine for treating fulminant hepatic failure, the medicine includes a DLL4 cytokine pharmaceutically acceptable excipient, an antioxidant and a carrier, the form of medicine can be an injection liquid or frozen dry powder or a suspension, the application temperature of the medicine including the DLL4 cytokine is 15 DEG C-30 DEG C, and the humidity is 45%-75%. Studies on the aspects of biochemical indexes, immunohistochemistry, gene expression level, proteomics and the like show that the DLL4 cytokine can be used in preparation of the medicine for effectively treating fulminant hepatic failure, and different dosages and forms of medicines can be produced by compounding the DLL4 cytokine with different solvents and stabilizers.

The invention discloses an anti-human DLL4 monoclonal antibody 3F9 which is obtained through secretion of a hybridoma cell strain preserved in CGMCC (China General Microbiological Culture Collection Center) at yard 3, No. 1 Beichen west road, Chaoyang District, Beijing City on June 7, 2017 with the preservation number of CGMCC No.14283. The anti-human DLL4 monoclonal antibody 3F9 is named as hybridoma cell strain 3F9 for secreting the anti-human DLL4 monoclonal antibody. The hybridoma cell strain has the classification and name of hybridoma cell strain 3F9 for secreting the anti-human DLL4 monoclonal antibody. The capability of DLL4+DC for inducing Na-ve T cells to differentiate in the Th1 direction cannot be blocked through binding of the monoclonal antibody 3F9 and DC as compared with commercialized MHD4-46.

The invention discloses a preparation method of an anti-human DLL4 monoclonal antibody 3F9 which is obtained through secretion of a hybridoma cell strain preserved in CGMCC (China General Microbiological Culture Collection Center) at yard 3, No. 1 Beichen west road, Chaoyang District, Beijing City on June 7, 2017 with the preservation number of CGMCC No.14283. The anti-human DLL4 monoclonal antibody 3F9 is named as hybridoma cell strain 3F9 for secreting the anti-human DLL4 monoclonal antibody. The hybridoma cell strain has the classification and name of hybridoma cell strain 3F9 for secretingthe anti-human DLL4 monoclonal antibody. The capability of DLL4+DC for inducing Na-ve T cells to differentiate in the Th1 direction cannot be blocked through binding of the monoclonal antibody 3F9 and DC as compared with commercialized MHD4-46.

The disclosure provides methods of treating cancer, tumors, and neoplasias by administering ionizing radiation and an anti-DLL4 antibody or a DLL4-binding fragment.

The invention belongs to the biotechnical field and particularly discloses a recombinant anti-HGF/DLL4 bispecific antibody and a preparation method and application thereof. The anti-human HGF/DLL4 bispecific antibody can be combined with both HGF and DLL4. The antibody disclosed by the invention has amino acid sequences shown in SEQ ID NO:2 and SEQ ID NO:4. The recombinant anti-human HGF/DLL4 bispecific antibody has an excellent anti-tumor effect.