The present invention discloses an monoclonal antibody, which can bind to HyIL-6 with the binding constant 2.86×10.sup.−10 and significantly inhibit IL-6/IL-6R/gp130 complex formation. In addition, the monoclonal antibody of the present invention effectively inhibits HyIL-6-stimulated signal transducer and activator of transcription 3(STAT3) activation and related vascular endothelial growth factor (VEGF) induction. Data from hydrogen deuterium exchange mass spectrometry (HDX-MS) demonstrate that the antibody of the present invention mainly binds to site IIIa of IL-6 and blocks the final step in the interaction between gp130 and IL-6/IL-6R complex. Additionally, data from ELISA binding assays and kinetics assays indicate that the antibody of the present invention interacts simultaneously with IL-6 and IL-6R, while it does not interact with IL-6R alone. The unique features of the antibody of the present invention offer a novel alternative for IL-6 blockade and illuminate a better therapeutic intervention targeting IL-6.

This invention provides methods of subcutaneous administration of anti-CD3 monoclonal antibodies (mAbs) either alone or in combination with monoclonal antibodies, that recognize the Interleukin-6 (IL-6) and IL-6 receptor (IL-6R) complex for the treatment, prevention or alleviating a symptom of a disease.

Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin.sup.− and/or pagP.sup.−. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd.sup.−, purI.sup.−, and msbB.sup.−. The immunostimulatory bacteria, such as Salmonella species, are modified to encode immunostimulatory proteins that confer anti-tumor activity in the tumor microenvironment, and/or are modified so that the bacteria preferentially infect immune cells in the tumor microenvironment, or tumor-resident immune cells, and/or are modified to induce less cell death in immune cells than in other cells. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the immunostimulatory bacteria.

This document relates to methods and materials for treating a mammal having an autoimmune disease. For example, materials and methods for producing a T cell comprising a FOXP3 polypeptide and one or more transcription factors are provided herein. Methods and materials for treating a mammal having an autoimmune disease comprising administering to a mammal having an autoimmune disease an effective amount of a T cell are also provided herein.

A population of immune cells comprising modified immune cells co-expressing a chimeric antigen receptor comprising, inter alia, an IB-2Kβ cytoplasmic signaling domain. Also provided herein are genetically engineered immune cells having reduced production of interferon gamma (IFNy). Such genetically engineered immune cells may have a disrupted endogenous IFNy gene, a disrupted endogenous IFNy receptor (IFNyR) gene, or both. Alternatively, the immune cells may express an IFNy antagonist.

The present invention relates to medical combination products comprising (i) at least one antibody construct comprising at least one domain which binds to a target antigen expressed on the surface of a cell and at least one other domain which binds to CD3 as well as (ii) at least one molecule that is inhibitor/antagonist of TNF/TNFR reducing TNF/TNFR signaling and/or an inhibitor/antagonist of IL6/IL6R that reduces IL6/IL6R signaling, wherein a first dose of said inhibitor/antagonist is administered before administration of a first dose of said antibody construct. Furthermore, the invention provides therapeutic and preventive methods and medical uses of said combination products, as well as a kit comprising said at least one antibody construct and at least one antagonist/inhibitor of TNF or IL6 or its cognate receptor, wherein the interaction of said antagonist/inhibitor of TNF or an inhibitor/antagonist of IL6 with its cognate receptor reduces, mitigates, prevents, or treats cytokine release syndrome.

Embodiments of the present disclosure are directed to methods and compositions for inhibiting cytomegalovirus (CMV) in a transplant recipient. In some embodiments, the methods are directed to inhibiting CMV reactivation in a transplant recipient with a CMV-seropositive serological status, the method comprising administering an effective amount of a compound to block IL-6 function. In some embodiments, the methods are directed to preventing CMV infection in a transplant recipient, wherein a transplant donor has a CMV-seropositive serological status, the method comprising administering an effective amount of a compound to block IL-6 function. In still other embodiments, a composition comprising a compound to block IL-6 function is administered to a transplant recipient with a CMV-seropositive serological status to prevent CMV reactivation.

The present disclosure relates to an improved method for the manufacture of polypeptides comprising at least three or at least four immunoglobulin single variable domains (ISVDs). More specifically, an improved method is provided of producing, purifying and isolating polypeptides comprising at least three or at least four ISVDs in which an undesired product-related conformational variant is reduced or absent.

Disclosed is a method for producing an antibody, comprising culturing in a presence of a polyanionic compound an animal cell into which a gene encoding an antibody has been introduced whereby the animal cell produces the antibody, wherein the polyanionic compound is at least one selected from the group consisting of an anionic polysaccharide and an anionic polyamino acid, and the antibody is an antibody in which at least 3 amino acid residues of framework region 3 (FR3) are substituted each independently with an arginine residue or a lysine residue.

This invention relates generally to monoclonal antibodies or antigen binding fragments thereof that specifically bind Toll-like Receptor 4 (TLR-4), to methods of using the anti-TLR4 antibodies to treat or prevent symptoms of Acute Respiratory Distress Syndrome (ARDS). This invention also relates to monoclonal antibodies or antigen binding fragments thereof that specifically bind to IP-10 and methods of using anti-IL-10 antibodies to treat or prevent symptoms of ARDS. The invention further provides routes of administrations and formulations for said methods.