There is provided inter alia a polypeptide comprising an immunoglobulin chain variable domain which binds to IL-6R, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1-CDR3 and FR1-FR4 are as defined in the specification.

Provided are attenuated immunostimulatory bacteria with genomes that are modified to, for example, reduce toxicity and improve the anti-tumor activity, such as by increasing accumulation in the tumor microenvironment, particularly in tumor-resident myeloid cells, improving resistance to complement inactivation, reducing immune cell death, promoting adaptive immunity, and enhancing T-cell function. The increase in colonization of phagocytic cells improves the delivery of encoded therapeutic products to the tumor microenvironment and tumors, and permits, among other routes, systemic administration of the immunostimulatory bacteria.

The invention relates to a bispecific antibody targeting TfR1 and a soluble antigen. The inventors demonstrate that the unique mode of interaction of the bispecific antibody with TfR1 increases its persistence in vivo through an FcRn-like mechanism. It has been demonstrated on MCF7 cell line that the bispecific antibody induces soluble antigen (IL6) uptake through TfR1 mediated endocytosis. Effects of the bispecific antibody on XG6 cell lines viability have been demonstrated, notably on iron and IL-6 deprivation. Hence, the inventors design an improved sweeping antibody which can specifically target tumors and inflammatory cells expressing TfR1. By its unique mode of interaction with TfR1, its ability to induce soluble uptake antigen through TfR1 mediated endocytosis and its capacity to deprive cells of iron, known for being required in tumors growth and progression and development of inflammatory pathologies, the bispecific antibody can be used in the treatment of cancer and inflammatory pathologies.

The present invention is directed to antibodies and fragments thereof and humanized versions thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V.sub.H, V.sub.L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

The invention provides novel bispecific monoclonal antibodies carrying a different specificity for each binding site of the immunoglobulin molecule and methods for producing novel bispecific monoclonal antibodies carrying a different specificity for each binding site of the immunoglobulin molecule. The antibodies are composed of a single heavy chain and two different light chains, one containing a Kappa constant domain and the other of a Lambda constant domain. The invention provides methods for the isolation of antibodies of different specificities but sharing a common heavy chain. The invention also provides methods for the controlled co-expression of two light chains and a single heavy chain leading to the assembly of monospecific and bispecific antibodies. The invention provides a mean of producing a fully human bispecific and bivalent antibody that is unaltered in sequence and does not involve the use of linkers or other non-human sequences, as well as antibody mixtures of two monospecific antibodies and one bispecific antibody. The invention also provides the means of efficiently purifying the bispecific antibody.

The present inventors discovered that problems of existing antibody pharmaceuticals can be solved by producing antigen-binding molecules that contain an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. Use of antigen-binding molecules of the present invention enables various diseases that originate from a target tissue to be treated in a manner specific to the target tissue.

This invention provides fully human monoclonal antibodies that recognize the IL-6/IL-6R complex. The invention further provides methods of using such monoclonal antibodies as a therapeutic, diagnostic, and prophylactic.

The present disclosure relates to uses of an anti-IL-6 antibody, e.g., clazakizumab in order to prevent, stabilize, reduce, or otherwise treat acute or chronic respiratory distress syndrome (ARDS or CRDS) and symptoms thereof such as lung damage, and also to treat cytokine storm syndrome, in patients with or suspected of having a bacterial, viral, or fungal infection, such as a coronavirus infection, e.g., COVID-19, SARS, MERS, or another bacterial or viral infection which may cause acute or chronic respiratory distress syndrome or cytokine storm syndrome.

A pharmaceutical composition to induce bone marrow stem cell mobilization from the bone marrow to peripheral blood in patients suffering from pathological conditions, such as diabetes, or subjected to treatments that impair cell mobilization, or in patients suffering from the so called “poor mobilizer” condition, includes at least one therapeutic agent that inhibits production and/or action of the human cytokine oncostatin M (OSM), a macrophage derived factor, that prevents mobilization of stem cells.

Administration regimens for therapeutic proteins (e.g., T cell-activating bispecific antibodies) that mitigate cytokine release syndrome and infusion-related reaction are disclosed. The methods employ initial fractional dosing with optional administration of additional agents such as steroids or cytokine antagonists that are discontinued with maximal weekly dosing over the course of the dosing regimen.