35 results about "Neonatal Fc receptor" patented technology

The compositions and methods of the present invention are based, in part, on our discovery that an effector function mediated by an Fc-containing polypeptide can be altered by modifying one or more amino acid residues within the polypeptide (by, for example, electrostatic optimization). The polypeptides that can be generated according to the methods of the invention are highly variable, and they can include antibodies and fusion proteins that contain an Fc region or a biologically active portion thereof.

The invention provides novel heterodimeric fusion proteins comprising a first polypeptide including an alpha subunit of FSH (αFSH) linked directly or indirectly to a binding partner of neonatal Fc receptor (FcRn) and a second polypeptide including a beta subunit of FSH (βFSH) linked directly or indirectly to an FcRn binding partner. In one embodiment the FcRn binding partner includes an Fc fragment of an immunoglobulin, e.g., an Fc fragment of IgG. Also provided are methods making and using the fusion proteins of the invention. The invention provides a method for increasing fertility in a subject and a method for treating a subject having a disease state responsive to treatment by FSH.

The compositions and methods of the invention are based in part on our discovery that effector functions mediated by Fc-containing polypeptides can be altered by modifying one or more amino acid residues in the polypeptide (by, eg, electrostatic optimization). Polypeptides that can be produced according to the methods of the invention are highly variable and they can include antibodies and fusion proteins comprising Fc regions or biologically active portions thereof.

A composition comprising at least one AAV vector formulated for intrathecal delivery to the central nervous system is described. The composition comprises at least one expression cassette which contains sequences encoding an immunoglobulin construct linked to expression control sequences therefor and a pharmaceutically acceptable carrier. The immunoglobulin construct may be an immunoglobulin modified to have decreased or no measurable affinity for neonatal Fc receptor (FcRn).

The present invention is directed to methods of inducing a phenotypic change in a population of monocytes and / or macrophages. The method includes administering to the population of monocytes and / or macrophages, a macrophage stimulating agent coupled to a carrier molecule, wherein the carrier molecule facilitates macropinocytic uptake of the agent by monocytes and macrophages in the population and is defective in neonatal Fc receptor binding, wherein the administering induces a phenotypic change in the monocytes and macrophages in the population.

The compositions and methods of the present invention are based, in part, on our discovery that an effector function mediated by an Fc-containing polypeptide can be altered by modifying one or more amino acid residues within the polypeptide (by, for example, electrostatic optimization). The polypeptides that can be generated according to the methods of the invention are highly variable, and they can include antibodies and fusion proteins that contain an Fc region or a biologically active portion thereof.

A composition comprising at least one AAV vector formulated for central nervous system delivery is described. The composition comprises at least one expression cassette which contains sequences encoding an anti-neoplastic immunoglobulin construct for delivery to the brain operably linked to expression control sequences therefor and a pharmaceutically acceptable carrier. The anti-neoplastic immunoglobulin construct may be an immunoglobulin modified to have decreased or no measurable affinity for neonatal Fc receptor (FcRn). Also provided are methods of using these constructs in preparing pharmaceutical compositions and uses thereof in anti-neoplastic regimens, particularly for primary and / or metastatic cancers of the brain.

The invention is directed to methods of purifying Fc-containing molecules using a soluble neonatal Fc receptor (sFcRn). Native FcRn binds Fc-containing proteins at or below about pH 6.5 and releases them at or above about pH 7 and provides a much milder approach for capturing and purifying Fc-containing proteins, in particular, therapeutic Fc-containing proteins. Other embodiments of the invention provide modifications to alter the pH for binding and elution to the sFcRn, to modulate Fc-containing protein binding affinity, to affect sFcRn linkage to a support surface, or to improve the stability of sFcRn to conditions utilized in the methods of the invention.

The invention provides novel heterodimeric fusion proteins comprising a first polypeptide including an alpha subunit of FSH (αFSH) linked directly or indirectly to a binding partner of neonatal Fc receptor (FcRn) and a second polypeptide including a beta subunit of FSH (βFSH) linked directly or indirectly to an FcRn binding partner. In one embodiment the FcRn binding partner includes an Fc fragment of an immunoglobulin, e.g., an Fc fragment of IgG. Also provided are methods making and using the fusion proteins of the invention. The invention provides a method for increasing fertility in a subject and a method for treating a subject having a disease state responsive to treatment by FSH.

The invention provided herein includes isolated polypeptides that specifically block the interaction between neonatal Fc receptor (FcRn) and albumin. Blocking the interaction treats diseases and conditions caused by increased amounts of albumin or modified albumin that possesses pathogenic properties wherein it is deemed desirable to decrease albumin levels. Accordingly, also provided are methods of using these isolated polypeptides to treat various diseases and conditions caused by increased amounts of albumin or modified albumin that possesses pathogenic properties. The invention provided herein also includes isolated polypeptides capable of binding to a non-IgG and non-albumin competitive site on an FcRn alpha 3 domain. These can be useful for tracking FcRn without inhibiting IgG or albumin binding or function. Accordingly, the invention also includes methods and systems to track FcRn without inhibiting IgG or albumin binding or function.

A composition comprising at least one AAV vector formulated for central nervous system delivery is described. The composition comprises at least one expression cassette which contains sequences encoding an anti-neoplastic immunoglobulin construct for delivery to the brain operably linked to expression control sequences therefor and a pharmaceutically acceptable carrier. The anti-neoplastic immunoglobulin construct may be an immunoglobulin modified to have decreased or no measurable affinity for neonatal Fc receptor (FcRn). Also provided are methods of using these constructs in preparing pharmaceutical compositions and uses thereof in anti-neoplastic regimens, particularly for primary and / or metastatic cancers of the brain.

The present invention provides a method for producing a transgenic (Tg) non-human animal capable of developing an enhanced humoral immune response against an antigen as compared to a non-transgenic control animal of the same species, comprising introducing into said non-human animal a genetic construct providing for enhanced MHC class I-related neonatal Fc receptor (FcRn) activity. Also provided a Tg non-human animal comprising a genetic construct providing for enhanced FcRn activity, as well as the use of such animal in a non- therapeutical method. Therapeutic genetic constructs and methods are also provided. The present invention further provides methods for producing immunoglobulins.

The present disclosure relates to an isolated anti-FcRn antibody, which is an antibody binding to FcRn (stands for neonatal Fc receptor, also called FcRP, FcRB or Brambell receptor) that is a receptor with a high affinity for IgG or a fragment thereof, a method of preparing thereof, a composition for treating autoimmune disease, which comprises the antibody, and a method of treating and diagnosing autoimmune diseases using the antibody. The FcRn-specific antibody according to the present disclosure binds to FcRn non-competitively with IgG to reduce serum pathogenic auto-antibody levels, and thus can be used for the treatment of autoimmune diseases.

A method is disclosed for the treatment of human subjects diagnosed with immune thrombocytopenia (ITP). The method comprises administering to a human subject a human neonatal Fc receptor (hFcRn) antagonist, optionally in combination with standard-of-care ITP treatment. In certain embodiments, the hFcRn antagonist is efgartigimod (ARGX-113). Standard-of-care ITP treatment may comprise administration of corticosteroids, immunosuppressants, and / or thrombopoietin receptor (TPO-R) agonists.

The invention provided herein includes isolated polypeptides that specifically block the interaction between neonatal Fc receptor (FcRn) and albumin. Blocking the interaction treats diseases and conditions caused by increased amounts of albumin or modified albumin that possesses pathogenic properties wherein it is deemed desirable to decrease albumin levels. Accordingly, also provided are methods of using these isolated polypeptides to treat various diseases and conditions caused by increased amounts of albumin or modified albumin that possesses pathogenic properties. The invention provided herein also includes isolated polypeptides capable of binding to a non-IgG and non-albumin competitive site on an FcRn alpha 3 domain. These can be useful for tracking FcRn without inhibiting IgG or albumin binding or function. Accordingly, the invention also includes methods and systems to track FcRn without inhibiting IgG or albumin binding or function.

Described herein are hybrid antibodies targeted for the treatment of cancer. The antibodies have binding ability to Fc epsilon receptor and neonatal Fc receptor, which can be achieved, for example, by replacing the sequence or amino acid in the IgE constant domain with the corresponding sequence and amino acid derived from IgG.

Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and / orpharmacodynamic properties of such a therapeutic agent in genetically modified rodents). In some embodiments the genetically modified rodents express antibodies comprising a human Fc (e.g., a human IgG1 Fc, a human IgG4 Fc). In some embodiments, the rodents express fully human antibodies (i.e., antibodies having human heavy chains and human light (gamma or kappa) chains). In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn), a beta-2-microglobulin polypeptide (beta 2Mu), a Fc epsilon receptor 1 alpha (Fc[epsilon]R1[alpha]), a Fc gamma receptor 1 alpha (Fc[gamma]R1a), a Fc gamma receptor 2a (Fc[gamma]R2a), a Fc gamma receptor 2b (Fc[gamma]R2b), a Fc gamma receptor 3a (Fc[gamma]R3a),a Fc gamma receptor 3b (Fc[gamma]R3b), a Fc gamma receptor 2c (Fc[gamma]R2c)). The transmembrane and cytoplasmic domain of such receptors can be human or non-human (e.g., rodent).

The present invention provides a method for producing a transgenic (Tg) non-human animal capable of developing an enhanced humoral immune response against an antigen as compared to a non-transgenic control animal of the same species, comprising introducing into said non-human animal a genetic construct providing for enhanced MHC class I-related neonatal Fc receptor (FcRn) activity. Also provided a Tg non-human animal comprising a genetic construct providing for enhanced FcRn activity, as well as the use of such animal in a non- therapeutical method. Therapeutic genetic constructs and methods are also provided. The present invention further provides methods for producing immunoglobulins.

Herein is reported a method for selecting a full length antibody comprising the steps of a) generating from a parent full length antibody a plurality of full length antibodies by randomizing one or more amino acid residues selected from the amino acid residues at positions 1-23 in the heavy chain variable domain (numbering according to Kabat), at positions 55-83 in the light chain variable domain (numbering according to Kabat), at positions 145-174 in the first heavy chain constant domain (numbering according to EU index) and at positions 180-97 in the first heavy chain constant domain (numbering according to EU index), b) determining the binding strength of each of the full length antibodies from the 10 plurality of antibodies to the human neonatal Fc receptor (FcRn), and c) selecting a full length antibody from the plurality of full length antibodies that has a different binding strength to the FcRn than the parent full length antibody.

The present invention relates to anti-PSMA antibodies comprising a heavy chain constant region containing one or more amino acid substitutions as compared to wild-type IgG wherein the one or more amino acid substitutions reduce the affinity of the antibody for neonatal Fc receptor (FcRn) as compared to an IgG-based wild-type antibody, thereby reducing the serum half-life of the modified antibody. The one or more amino acid modifications, which have the effect of reducing FcRn binding, are selected from the group consisting of positions His310, His433, His435, His436, Ile253. The antibodies of the invention are particularly suitable for use in radioimmunotherapy.

The present invention relates to targeted prevention of vertical transmission of infection between mother and foetus. More particularly, the invention relates to methods of preventing neonatal Fc receptor (FcRn)-mediated transmission of virus, preferably flavivirus, more preferably Zika virus (ZIKV), from a mother immune to a cross-reactive virus e.g. Dengue virus (DENY) to her foetus, and to reagents that block or inhibit said FcRN-mediated transmission of virus.

Herein is reported a method for selecting a full length antibody comprising the steps of a) generating from a parent full length antibody a plurality of full length antibodies by randomizing one or more amino acid residues selected from the amino acid residues at positions 1-23 in the heavy chain variable domain (numbering according to Kabat), at positions 55-83 in the light chain variable domain (numbering according to Kabat), at positions 145-174 in the first heavy chain constant domain (numbering according to EU index), and at positions 180-97 in the first heavy chain constant domain (numbering according to EU index), b) determining the binding strength of each of the full length antibodies from the 10 plurality of antibodies to the human neonatal Fc receptor (FcRn), and c) selecting a full length antibody from the plurality of full length antibodies that has a different binding strength to the FcRn than the parent full length antibody.

The present disclosure relates to dimers of engineered polypeptides having a binding affinity for the neonatal Fc receptor FcRn, and provides an FcRn binding dimer, comprising a first monomer unit, a second monomer unit and an amino acid linker, wherein the first and second monomer units each comprises an FcRn binding motif. The FcRn binding dimer binds FcRn with higher capacity compared to the first monomer unit or second monomer unit alone. The present disclosure also relates to the use of the FcRn binding dimer as an agent for modifying pharmacokinetic and pharmacodynamic properties and as a therapeutic agent.

The invention relates to anti-PSMA antibodies comprising a heavy chain constant region comprising one or more amino acid substitutions compared to a wild-type IgG, wherein the one or more amino acid substitutions reduce the affinity of the antibody for the neonatal Fc receptor (FcRn), thereby reducing the serum half-life of the modified antibody compared to a wild-type antibody of class IgG. The one or more amino acid modification having the effect of reducing FcRn binding is selected from positions His310, His433, His435, His436, Ile253. Antibodies of the present invention are particularly suited for use in radioimmunotherapy.