39 results about "Effector functions" patented technology

Antibodies, antigen-binding proteins and Fc-fusion proteins that comprise recombinant polypeptides containing a chimeric heavy chain constant region sequence are provided that bind to certain Fc receptors however have reduced effector functions. Methods of making constructs for expression of such chimeric Fc-containing antibodies, antigen-binding proteins and Fc-fusion proteins in cell systems, and methods of producing and isolating the chimeric Fc-containing proteins are provided.

The present disclosure provides compositions, methods of making, and use of a circular ribonucleic acid (circRNA) therapeutic for targeted delivery to immune cells, including T cells, for effector functions such as B cell depletion, providing, among other things, methods of treating B cell-mediated diseases such as autoimmune disease and cancer, meeting the medical need for efficacious and safe therapies that overcome the disadvantages of ex vivo CAR T therapy. Provided by the present disclosure is a circRNA therapeutic comprising: (i) a circRNA comprising a ribosome recruiting element, and a coding sequence encoding a CAR comprising, for example, an anti-CD19 antibody or antigen-binding fragment thereof, and (ii) a targeting moiety (e.g., anti-CD5) that binds to an immune cell (e.g., a T cell), wherein the circRNA is in a delivery vehicle, and a targeting moiety that binds to a T cell is conjugated to the delivery vehicle (e.g., a lipid nanoparticle).

The present invention relates to antibodies capable of binding to human OX40 and to variants thereof comprising a modified Fc region comprising at least one mutation that enhances the Fc-Fc interaction of the antibody and at least one mutation that reduces the Fc effector functions of the antibody. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

T lymphocytes play a key role in the immune response and their functions are intimately linked to metabolic programs. During immune responses, T cells undergo a metabolic reprogramming notably characterized by an increased aerobic glycolysis. Using a quantitative phosphoproteomic approach, the inventors have identified a new transcription factor called Foxk1 as being highly phosphorylated in T cells upon T Cell Receptor (TCR) engagement. The results also indicate that Foxk1 phosphorylation and nuclear translocation is dependent of the AKT-mTOR kinase activities. Using T-cell specific Foxk1 deficient mice (Foxk1- / -), we demonstrated that Foxk1 is required for full T cell activation. Foxk1-deficient T cells exhibited reduced proliferation and cytokine secretion following TCR stimulation. Furthermore, T cells from Foxk1- / - mice were less prone to acquire an effector like phenotype than wild-type cells when challenged in vivo. Conversely, Foxk1 overexpression in T cells enhanced their effector functions in a TCR-dependent manner. In CD8+ T cells, this effect also results into enhanced cancer cell killing capacity in vitro, and improved tumor rejection in vivo. Altogether, these results indicated that Foxk1 is a major regulator of T cell metabolism and thus, of T cell effector functions. Thus, the present invention relates to host immune cells engineered to overexpress a Foxk1 polypeptide and their use of the treatment of cancer.

The invention relates to lymphocytes which are genetically engineered to overexpress one or more maintenance factor(s), wherein, as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s), the lymphocytes exhibit enhanced stem-like or memory phenotype and a comparable or greater level of one or more effector functions in response to immune stimulation and a comparable or greater level of proliferation. The invention also relates to use of said lymphocytes in therapy, to methods for identifying said lymphocytes, and to methods for producing said lymphocytes.

Provided are proteins and molecules comprising a variant Fc region or a variant CH2 domain with significantly reduced binding to FcγR family receptors and reduced effector functions. Methods of producing and using such proteins and molecules are also provided.

This article describes antibodies or antigen-binding fragments that specifically bind to GPRC5D. Additionally, it includes monovalent antibodies or antigen-binding fragments that specifically bind to GPRC5D. The Fc regions of these antibodies contain K248E and T437R mutations (referred to as “RE mutations”) according to the EU numbering system. The described antibodies, when expressed in host cells lacking fucosylation capacity, exhibit enhanced antibody-dependent cytotoxicity (ADCC) and enhanced complement-dependent cytotoxicity (CDC).

The invention discloses an Fc variant with an enhanced effector function and application of the Fc variant, and relates to a modified human IgG1 Fc region polypeptide which respectively contains amino acid substitutions of D, L, A and L at sites S239, F243, R292 and Y300 according to an EU numbering system. The present invention provides Fc variants, i.e., direct interface optimization and allosteric induced endogenous defucosylation, synergistically greatly enhancing binding affinity to Fc [gamma] RIIIa, thereby obtaining unprecedented ADCC activity, antibodies or Fc fusion proteins comprising the Fc variants, nucleic acids encoding them, expression vectors and host cells, as well as methods for preparing such Fc variants and methods for preparing such Fc variants. The invention also relates to application of the compound in preparation of medicines for treating diseases such as cancers or infectious diseases.

The present disclosure provides super-repressors capable of inhibiting the transcription of NR4A1, NR4A2, and NR4A3 target genes. The super-repressors can be used to enhance the effector functions of immune cells, e.g., for adoptive cell therapy. Methods of treating disorders using the modified immune cells are also provided.

The invention provides antibody heavy chain constant regions with a hinge region modified to reduce binding to Fcγ receptors. The modification occurs within positions 233-236 by replacement of natural residues by glycine(s) and / or deletion(s). Such modifications can reduce binding of an antibody bearing such a constant region to Fcγ receptors to background levels. The constant regions can be incorporated into any format of antibody or Fc fusion protein. Such antibodies or fusion proteins can be used in methods of treatment, particularly those in which the mechanisms of action of the antibody or Fc fusion protein is not primarily or at all dependent on effector functions, as is the case when an antibody inhibits a receptor-ligand interaction or agonizes a receptor.

The present invention relates to antibodies capable of binding to human OX40 and to variants thereof comprising a modified Fc region comprising at least one mutation that enhances the Fc-Fc interaction of the antibody and at least one mutation that reduces the Fc effector functions of the antibody. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

This invention relates to IgG1 Fc variants that do not elicit antibody effector functions such as CDC, ADCP, and ADCC. In particular, this invention relates to IgG1 Fc variant peptides comprising mutants L234A, L235A, A327G, P329A, A330S, and P331S according to EU designations, molecules comprising such IgG1 Fc variant peptides, and the use of such molecules to reduce antibody effector functions.

The present disclosure relates to novel constructs, particularly modified immune cell receptor proteins and polynucleotides encoding said modified immune cell receptor proteins, and uses of said constructs. Said modified immune cell receptor protein is designated Engineered Valency-Enhanced CD16A (EVE16), which is intended for expression on the surface of various immune cells, including but not limited to Natural Killer (NK) cells, Natural Killer T (NKT) cells, T cells, monocytes, and others. EVE16 is a chimeric protein receptor designed to exploit the endogenous signal transduction pathways inherent to immune cells, notably NK cells, NKT cells, T cells, monocytes, and others, thereby facilitating the modulation of cellular signaling, particularly to initiate activating signaling. The present disclosure describes constructs comprising optimized leader peptides, target-binding domains, linker domains as well as cytoplasmic domains that demonstrate improved surface expression and activation signaling of EVE16, resulting in more potent cytotoxicity and other effector functions of immune cells. Additionally, this disclosure encompasses vectors harboring the aforementioned constructs (including expression constructs), cells, such as human immune cells, specifically NK cells, NKT cells, T cells, or monocytes expressing said constructs, and their use in disease treatment, particularly cancer and autoimmune diseases.

The invention refers to anti-oxMIF antibodies with improved properties such as reduced aggregation potential and reduced hydrophobicity due to selected amino acid substitutions in the light and heavy chain variable domains and optionally increased effector functions due to further substitutions in the heavy chain constant regions, and their use in the treatment of oxMIF-related conditions.

The present invention is directed to chimeric antigen receptor (CAR) compositions and methods of their use in cancer and anti-viral immunotherapy. In particular, the CAR of the invention comprises a costimulatory signal (CSS) domain comprising herpes virus entry mediator protein (HVEM) or a functional fragment or variant thereof. CARs comprising such a HVEM CSS exhibit enhanced effector function.

The present invention provides an antibody against the hepatitis B virus. The antibody has enhanced Fe-mediated effector functions, such as ADCC and ADCP activity, and optionally further has a prolonged half-life. Also disclosed are a method and a cell for producing the antibody, and use of the antibody.

The present invention relates to CH3 domain-containing binding agents, such as antibodies, that have altered Fc-mediated effector functions resulting from one or more amino acid modifications in the Fc domain. The invention further relates to polynucleotides encoding such binding agents, cells capable of producing such binding agents and the use of the binding agents of the invention for the treatment of diseases.

The present specification discloses modified anti-PD-Ll antibodies that eliminate Fc- associated effector functions and enhance clearance while maintaining therapeutic efficacy on neurodegenerative disease alterations. The present specification also discloses nucleic acid sequences and expression constructs encoding such modified anti-PD-Ll antibodies, and methods of making such modified anti-PD-Ll antibodies. In addition, the present specification discloses methods of treatment and uses employing administration regimens of the disclosed anti-PD-Ll antibodies that ensure that the antibodies are only present for a specific period of time and then are sufficiently cleared from the body to ensure maintenance of therapeutic efficacy.

The invention belongs to the field of immunology, and particularly relates to a method for constructing an animal model and application thereof. The method comprises the following steps: firstly, providing a method for constructing a mouse model, namely constructing four transgenic mice by using artificial chromosomes, two different DNA recombinase and three different reporter genes, and mating to obtain the transgenic mice carrying the three different reporter genes at the same time, the mouse can be used for tracking Th1 cell differentiation and central memory T cell development in an animal body. The invention also provides a method for evaluating the immune efficacy of the vaccine, which comprises the following steps: immunizing a mouse according to an immune procedure and a dose capable of causing immune response, extracting lymphocytes of the mouse, performing flow cytometry staining, and observing a result. Through a constructed mouse model, it is found that differentiated Th1 type effector cells capable of stably expressing T-bet can be developed into CCR7 + CD4 + TCM cells, and analysis of functions and development differentiation of the cells can provide a new thought for development of cellular immune vaccines with higher effector functions and long protection periods.

The present invention relates to human IgG Fc region variants with improved effector functions and uses thereof.

The invention provides antibody heavy chain constant regions with a hinge region modified to reduce binding to Fcγ receptors. The modification occurs within positions 233-236 by replacement of natural residues by glycine(s) and / or deletion(s). Such modifications can reduce binding of an antibody bearing such a constant region to Fcγ receptors to background levels. The constant regions can be incorporated into any format of antibody or Fc fusion protein. Such antibodies or fusion proteins can be used in methods of treatment, particularly those in which the mechanisms of action of the antibody or Fc fusion protein is not primarily or at all dependent on effector functions, as is the case when an antibody inhibits a receptor-ligand interaction or agonizes a receptor.

Provided herein are methods for: (1) rapidly depleting circulating B cells and remodeling one or more B cell compartments, (2) treating B cell-related autoimmune diseases, and (3) B cell malignancies, using B cell depleting antibodies that are directed to CD19 or CD20 and one or more target antigens. Further provided herein is a CD19 / CD20 bispecific antibody with dual Fc domains that mediate enhanced effector functions and B cell depletion. HB2198 demonstrated enhanced binding to Fcγ receptors, potent effector functions, and efficient depletion of B cells in vitro and in vivo.

The present invention relates to a novel immunoglobulin Fc domain variant protein and use thereof, and when expressed in the form of a fusion protein with another biologically active protein, an immunoglobulin Fc domain variant protein according to an embodiment of the present invention can prolong the half-life in vivo of the biologically active protein as well as effectively suppress effector functions such as ADCC or CDC to minimize unexpected side effects.

Feline, canine, and equine antibody variants and uses thereof, as well as compositions and methods for improving therapeutic monoclonal antibodies by modulating immune effector functions and antibody variants using those methods and compositions.

The invention relates to lymphocytes which are genetically engineered to overexpress one or more maintenance factor(s), wherein, as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s), the lymphocytes exhibit enhanced stem-like or memory phenotype and a comparable or greater level of one or more effector functions in response to immune stimulation and a comparable or greater level of proliferation. The invention also relates to use of said lymphocytes in therapy, to methods for identifying said lymphocytes, and to methods for producing said lymphocytes.

To provide antibodies containing Fc regions with altered effector functions, and antigen-binding portions thereof, and to provide antibody drug conjugates, compositions, and methods using the antibodies.SOLUTION: Antibodies containing an Fc region with altered effector function as a result of one or more amino acid substitutions in the Fc region are used. The antibodies and antibody-drug conjugates described herein are useful, inter alia, for depleting cells and treating various hematopoietic diseases, metabolic disorders, cancers (e.g., acute myeloid leukemia (AML)), and autoimmune diseases.SELECTED DRAWING: Figure 11E

Provided herein are combinations of first and second antibodies having modified Fc effector functions resulting from amino acid substitutions in the Fc region, the amino acid substitutions allow for co-dependent activation of effector functions such as CDC and / or ADCC. Also provided are combinations of first and second antibodies having agonistic activity or enhanced agonistic activity resulting from amino acid substitutions in the Fc region where the agonistic activity is co-dependent of both a first and second antibodies.

Provided are proteins comprising a variant IgG Fc region, wherein the proteins exhibit significantly reduced binding to human FcγRI when compared with a reference protein comprising the amino acid substitutions L234A / L235A / P329G. Also provided are compositions, methods of treatment and methods to reduce Fc-induced effector functions in a parent protein.

The present disclosure provides compositions and methods for inhibiting T cell senescence and improving T cell immunotherapies. In particular, inhibitors of group IV A phospholipase A2 are disclosed as useful in modulating the lipid metabolism of cells, in particular effector T cells, such that T reg- and tumor cell-induced cell senescence is abrogated. These methods may be employed with particular utility in adoptive T cell therapies and / or enhanced T cell effector functions in vivo, including those performed in combination with checkpoint blockade therapies.

Provided herein are antibodies or antigen-binding fragments thereof that specifically bind to MICA / B having heavy chain, light chain, variable heavy chain domains (VH), variable light chain domains (VL), and complementarity determining regions (CDRs) disclosed herein, as well as methods and uses thereof. In certain aspects, the antibodies or an antigen-binding fragment thereof comprise one or more amino acid modifications to enhance effector function compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or lacks fucosylation or comprises reduced fucosylation.