85 results about "Effector functions" patented technology

Described herein are polypeptides and related antibodies comprising a variant Fc domain. The variant Fc domain provide for stabilized Fc:Fc interactions when the polypeptide(s), antibody or antibodies are bound to its target, antigen or antigens on the surface of a cell, thus providing for improved effector functions, such as CDC-response.

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.

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.

Herein are antibodies or antigen-binding fragments specifically binding to GPRC5D. Additionally, monovalent antibodies or antigen-binding fragments specifically binding to GPRC5D are also included. The Fc region of these antibodies contains K248E and T437R mutations (designated as "RE mutations") per the EU numbering system. The described antibodies, expressed in host cells that lack fucosylation capabilities, exhibit enhanced antibody¬ dependent cellular cytotoxicity (ADCC) and enhanced complement-dependent cytotoxicity (CDC).

Provided herein are methods for reducing the likelihood and / or severity of peripheral neuropathy, anemia, and / or neutropenia in an individual being treated with an antibody-drug conjugate (ADC). Also provided herein are methods for increasing dosing amount and / or frequency of an antibody-drug conjugate (ADC) in an individual. In some embodiments, the methods comprise administering to the individual an effective amount of an ADC that comprises an antibody conjugated to a drug moiety via a linker, wherein the antibody comprises a heavy chain comprising a human Fc region with reduced or eliminated effector function. Compositions, uses, and kits related thereto are also provided.

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.

Herein are antibodies or antigen-binding fragments specifically binding to GPRC5D. Additionally, monovalent antibodies or antigen-binding fragments specifically binding to GPRC5D are also included. The Fc region of these antibodies contains K248E and T437R mutations (designated as “RE mutations”) per the EU numbering system. The described antibodies, expressed in host cells that lack fucosylation capabilities, exhibit enhanced antibody-dependent cellular cytotoxicity (ADCC) and enhanced complement-dependent cytotoxicity (CDC).

The invention discloses an anti-tumor pharmaceutical composition based on NBDHEX and application of the anti-tumor pharmaceutical composition in treatment of immunosuppressive malignant tumors. The pharmaceutical composition comprises NBDHEX (6-(7-nitro-2, 1, 3-benzoxadiazol-4-ylthio) hexanol) and a PD-1 (programmed death-1) inhibitor, and is characterized in that the NBDHEX (6-(7-nitro-2, 1, 3-benzoxadiazol-4-ylthio) hexanol) and the PD-1 inhibitor are used as raw materials. The NBDHEX can induce tumor cells to generate immunogenic death and promote tumor antigen release, DAMPs signal activation and dendritic cell maturation, so that an immunosuppressive tumor microenvironment is remodeled, and CD8 + T cell infiltration and effector functions are enhanced. The pharmaceutical composition can significantly improve the anti-tumor immune response intensity and the treatment response rate. Animal experiments and cell experiments verify the synergistic anti-tumor effect of the composition in a lymphoma model. The immunosuppressive malignant tumors are suitable for treatment of various immunosuppressive malignant tumors including lymphoma, and are especially suitable for patients with poor single-drug reaction or drug resistance to immune checkpoint inhibitors, and a new way is provided for clinical treatment of tumors.

The present disclosure relates to anti-human CD154 antibodies having a modified effector function. The present disclosure also relates to the use of these anti-human CD154 antibodies in the treatment of conditions associated with CD154 activation, the conditions associated with CD154 activation are, for example, transplant rejection, inflammatory conditions and diseases, dysfunctional immune responses associated with viral infections and diseases, autoimmune conditions and diseases, allergic conditions, atherosclerotic conditions, or neurodegenerative conditions and diseases. The present disclosure also relates to the use of these anti-human CD154 antibodies in inducing central tolerance and hematopoietic cell chimerism in transplanted patients.

The present disclosure provides methods and compositions related to the modification of immune effector cells to increase therapeutic efficacy. In some embodiments, immune effector cells modified to reduce expression of one or more endogenous target genes, or to reduce one or more functions of an endogenous protein to enhance effector functions of the immune cells are provided. In some embodiments, immune effector cells further modified by introduction of transgenes conferring antigen specificity, such as exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs) are provided. Methods of treating a cell proliferative disorder, such as a cancer, using the modified immune effector cells described herein are also 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.

This document relates to methods and materials for modulating (e.g., reducing) T cell activation (e.g., T cell proliferation, T cell effector functions, and / or cytokine secretion) using a TRAILshort polypeptide, a variant TRAILshort polypeptide, or a TRAILshort fusion polypeptide. For example, a TRAILshort polypeptide, a variant TRAILshort polypeptide, or a TRAILshort fusion polypeptide can be administered to a mammal in need thereof, e.g., a human with an autoimmune disorder, graft versus host disease, lichen planus or other disorder characterized by excessive T cell activation, to reduce excessive T cell activation (e.g., excessive T cell proliferation, excessive T cell effector functions, and / or excessive cytokine secretion).

The present invention provides an antibody against the hepatitis B virus. The antibody has enhanced Fc-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.

To provide therapies, methods and uses that overcome the drawbacks of existing therapies of neurodegenerative pathologies.SOLUTION: The present specification discloses modified anti-PD-L1 antibodies that abolish Fc-related effector function and enhance clearance rate while maintaining therapeutic efficacy for neurodegenerative disease modification. The present specification also discloses a nucleic acid sequence and an expression construct encoding the modified anti-PD-L1 antibodies, as well as a method for producing the modified anti-PD-L1 antibodies. In addition, the present specification discloses methods of treatment and uses that employ an administration regime of the disclosed anti-PD-L1 antibodies that ensures the antibodies are present for only a specific period of time and then are sufficiently cleared from the body to ensure treatment efficacy is maintained.SELECTED DRAWING: Figure 32

Provided herein are anti-MIC antibodies comprising one or more Fc domain mutations to eliminate Fc effector functions. Also provided herein are methods of use in treating cancer by administering the anti-MIC antibodies described herein.

The present invention relates to a method of producing an immune cell devoid of endogenous effector functions from pluripotent stem cells. Further, the present invention relates to a method of producing an immune cell devoid of endogenous effector functions, but comprising one or more exogenous modifications, wherein each of the one or more exogenous modifications introduces a predetermined effector function; an immune cell or a population of immune cells obtainable or obtained by the methods of the invention, a pharmaceutical composition comprising the immune cells or the population of immune cells, as well as to the immune cell or the population of immune cells obtainable or obtained by the methods of the invention, or the pharmaceutical compositions for use in medicine.

The invention relates to a specialized subpopulation of natural killer cells that have enhanced effector functions and the potential to kill malignant tumor cells or infected cells when the natural killer cells are exposed to an antibody bound to the tumor cells or the infected cells.

The invention relates to chimeric antigen receptor constructs and their use for treatments and therapies. Further disclosed are methods of treating and / or preventing a disease, such as e.g. a cancer, an infectious disease, an inflammatory or inflammation-induced disease, a chronic disease or an autoimmune disease.

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.

To provide antibody compositions with Fc mutations and site-specific conjugation properties.SOLUTION: Disclosed herein is an antibody that binds to Her2, EGFR, Trop2, CDH3, or other TAA containing a triple mutation at L234A, L235A and L328C, and a method for preparing such a triple mutated antibody. Consequently, the triple mutated antibody contains a modified effector function through Fc silencing and is capable of site-specific conjugation at L328C to form an antibody-drug-conjugate (ADC), which can be administered to a patient and can provide a method of treating cancer, immunological and neurological disorders.SELECTED DRAWING: Figure 8

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).

Lassa fever is a zoonotic viral hemorrhagic disease caused by Lassa virus (LASV), endemic in multiple west African countries where the multimammate rat is a main virus reservoir. The broad geographic range of the rodent host places a large population at risk of serious illness. LASV is also a bioterrorism threat. A LASV vaccine is an unmet need. Applicants advance a vaccine based on a live vesicular stomatitis virus vector for immunizing against the LASV surface glycoprotein. Preclinical evaluation exhibited high efficacy in cynomolgus macaques. The animals developed serum antibodies that could mediate antiviral effector functions including direct neutralization of virus infectivity. This vaccine candidate elicited robust protective immunity in cynomolgus macaques that prevented development of detectable viremia and disease for at least 1 year after vaccination. These protective immune response features provide valuable data for comparison to an ongoing phase 1 clinical trial and planned phase 2b / 3 clinical trials.

The present invention provides an Fc fusion protein construct which has a higher serum half-life compared to native / native molecules as a monovalent dimer, thus facilitating obtaining a higher protein titer during production, obtaining higher stability during storage, and obtaining improved efficacy when used as a therapeutic agent. Also provided are Fc fusion protein constructs having mutations that reduce effector function in the Fc region, which have increased activity to inhibit tumor growth, and thus are advantageous when used as cancer therapy.

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.

To provide antibodies having increased Fc effector functions or decreased Fc effector functions, to provide the use of such antibodies in combination, and to provide compositions comprising such antibodies.SOLUTION: Provided are combinations of first and second antibodies having modified Fc effector functions resulting from amino acid substitutions in an Fc region, the amino acid substitutions allowing for co-dependent activation of effector functions such as CDC or ADCC, or agonistic activity or enhanced agonistic activity.SELECTED DRAWING: None

The present invention relates to FcRn antagonists or Fc variant proteins and their preparation. The Fc variants have an altered binding affinity for FcRn. In one aspect, the Fc variants according to the invention comprise amino acid substitutions of L234A, L235A, T307N, V308P, L309Y, P329G, H433R, N434W. In another aspect, the Fc variants according to the invention comprise amino acid substitutions of T307N, V308P, L309Y, H433R, N434W, M252Y, S254T, T256E. In yet another aspect, the Fc variants of the present invention comprise amino acid substitutions of T307N, V308P, L309Y, H433R, N434W, M252Y, S254T, T256E, L234A, L235A, P329G. The Fc variant prepared according to the invention can be used for preparing an FcRn antagonist composition or can be used for preparing a drug or molecule containing the Fc variant with a changed effector function.

The present invention relates to anti-oxMIF antibodies and their use in treating oxMIF-related disorders, said anti-oxMIF antibodies having 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 enhanced effector function due to further substitutions in the heavy chain constant region.