Anti-KIR3D antibodies

The present invention provides antigen-binding proteins capable of binding to KIR3D polypeptides. The antibodies have increased activity in the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sézary Syndrome.

Enzymatic conjugation of antibodies

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.

Balun transformer

A balun includes a dielectric layer having first and second sides, an electrically conductive plate on the second side of the dielectric layer, a first electrically conductive line on the first side and comprising a first end electrically connected to a first terminal and a second end, a second electrically conductive line on the second side and comprising a third end electrically coupled to a second terminal and a fourth end connected to an unbalanced terminal and a micro strip line comprising a fifth end electrically connected to the third end and a sixth end. The first electrically conductive line overlaps the second electrically conductive line. The second and the sixth ends are electrically coupled to the electrically conductive plate. The electrically conductive plate is hollowed in at least a region corresponding to an overlap area of the first electrically conductive line and second electrically conductive line.

Integrated circuit device, wireless communication unit and method of manufacture therefor

An integrated circuit device (200) comprising at least one radio frequency (RF) transceiver module (210) The at least one RF transceiver module (210) comprises a plurality of low noise amplifiers (LNAs) (220, 223, 226) operably coupled at inputs (221, 22, 227) thereof to external contacts (202, 204) of the integrated circuit device (200) and arranged to receive an RF signal from the respective external contact (202, 204), amplify the received RF signal, and to output (222, 225. 228) the amplified RF signal The at least one transceiver module (210) further comprises a plurality of power amplifier (PA) modules (230, 235) operably coupled at outputs (231, 236) thereof to the external contact (202, 204) of the integrated circuit device, and arranged to receive at inputs (232, 237) thereof an RF signal to be transmitted, amplify the received RF signal to be transmitted, and output (231, 236) the amplified signal The plurality of LNAs (220, 223, 226) and the plurality of PAs (230, 235) are selectively ...

Enzymatic conjugation of polypeptides

The present application relates to methods for the enzymatic functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.

BALUN TRANSFORMER

A balun includes a dielectric layer having first and second sides, an electrically conductive plate on the second side of the dielectric layer, a first electrically conductive line on the first side and comprising a first end electrically connected to a first terminal and a second end, a second electrically conductive line on the second side and comprising a third end electrically coupled to a second terminal and a fourth end connected to an unbalanced terminal and a micro strip line comprising a fifth end electrically connected to the third end and a sixth end. The first electrically conductive line overlaps the second electrically conductive line. The second and the sixth ends are electrically coupled to the electrically conductive plate. The electrically conductive plate is hollowed in at least a region corresponding to an overlap area of the first electrically conductive line and second electrically conductive line. 1. A balun for transforming signals between an unbalanced impedance and a balanced impedance , comprising:a stack of at least an electrically conductive plate, and a dielectric layer having a first side and a second side opposite to the first side;a first electrically conductive line comprising a first end and a second end, arranged on the dielectric layer at the first side of the dielectric layer;a second electrically conductive line comprising a third end and a fourth end, arranged on the dielectric layer at the second side of the dielectric layer such that the first electrically conductive line substantially overlaps the second electrically conductive line; anda micro strip line comprising a fifth end electrically coupled to the third end and a sixth end electrically coupled to the electrically conductive plate; whereinthe electrically conductive plate is arranged on the dielectric layer at the second side,the first end is electrically coupled to the balanced impedance, the second end is electrically coupled to the electrically conductive plate, ...

ENZYMATIC CONJUGATION OF POLYPEPTIDES

The present application relates to methods for the enzymatic functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions. 1. A method for conjugating a hydrophobic compound to an antibody , comprising:a) providing an antibody having at least one acceptor glutamine residue; andb) reacting said antibody with a linker comprising a primary amine and a reactive group (R), in the presence of a TGase, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to a reactive group (R) via said linker, wherein the reaction mixture is free of organic solvent or contains less than 10% (v/v) organic solvent; and (i) an antibody of process (b) comprising an acceptor glutamine linked to a reactive group (R) via a linker comprising a primary amine, with', '(ii) a compound comprising a moiety of interest (Z), wherein (Z) is a hydrophobic compound, and a reactive group (R′) capable of reacting with reactive group R, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to moiety of interest (Z) via a linker comprising a primary amine., '(c) reacting, in the presence of organic solvent2. The method of claim 1 , wherein Z is a pyrrolobenzodiazepine.3. The method of claim 1 , wherein Z is a pyrrolobenzodiazepine dimer.4. The method of claim 1 , wherein Z is a C8/C8′-linked pyrrolobenzodiazepine dimer.5. The method of claim 1 , wherein the antibody comprises human heavy and light chain constant regions claim 1 , wherein the heavy chain constant regions comprise a N297Q substitution and a Q295X substitution claim 1 , wherein X is any amino acid other than glutamine.6. The method of claim 1 , wherein the antibody obtained comprises a functionalized acceptor glutamine residue having Formula IVc claim 1 ,{'br': None, '(Q)-NH—C—X-L-RR′-L′-V—Y—Z\u2003\u2003Formula IVc'}or a ...

TLR3 BINDING AGENTS

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like. 1. A method for treating or preventing a disease selected from the group consisting of autoimmunity , inflammation , allergy , asthma , infection , cirrhosis and sepsis , said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide , wherein said antibody inhibits signaling by said human TLR3 polypeptide without blocking binding of a double-stranded ribonucleic acid (dsRNA) TLR3 ligand to said human TLR3 polypeptide.2. A method for treating or preventing a disease selected from the group consisting of autoimmunity , inflammation , allergy , asthma , infection , cirrhosis and sepsis , said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide , wherein said antibody specifically binds to said human TLR3 polypeptide under acidic conditions with a sub-nanomolar Kfor its bivalent binding affinity.3. A method for treating or preventing a disease selected from the group consisting of autoimmunity , inflammation , allergy , asthma , infection , cirrhosis and sepsis , said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide , wherein said antibody has ...

PROCESS FOR PREPARING ELECTROACTIVE INSERTION COMPOUNDS AND ELECTRODE MATERIALS OBTAINED THEREFROM

A process for preparing an at least partially lithiated transition metal oxyanion-based lithium-ion reversible electrode material, which includes providing a precursor of said lithium-ion reversible electrode material, heating said precursor, melting same at a temperature sufficient to produce a melt including an oxyanion containing liquid phase, cooling said melt under conditions to induce solidification thereof and obtain a solid electrode that is capable of reversible lithium ion deinsertion/insertion cycles for use in a lithium battery. Also, lithiated or partially lithiated oxyanion-based-lithium-ion reversible electrode materials obtained by the aforesaid process. 2. A process according to claim 1 , wherein prior to said high-energy milling claim 1 , said process comprises pre-milling said solid electrode material.3. A process according to claim 2 , wherein said pre-milling produces about millimeter size powder.4. A process according to claim 1 , wherein said high-energy milling is high-energy ball milling.5. A process according to claim 1 , wherein said high-energy milling is high-energy wet ball milling.6. A process according to claim 1 , wherein said high-energy milling is high-energy ball milling that is performed with milling balls having a size of about 3 to about 20 mm.7. A process according to claim 1 , wherein said high-energy milling is high-energy ball milling that is performed with zirconia milling balls.8. A process according to claim 1 , wherein said high-energy milling is performed with milling balls claim 1 , using a solid electrode material:balls ratio (wt./wt.) of about 0.4:1 to about 17:1.9. A process according to claim 1 , wherein said high-energy milling is performed for a time duration of about 10 minutes to about 90 minutes.10. A process according to claim 1 , wherein said solid electrode material is reduced to a powder having an individual mean particle size between 20 nanometers and 5 microns and agglomerate mean particle size between ...

TLR3 BINDING AGENTS

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like. 1. A monoclonal antibody that specifically binds a TLR3 polypeptide , wherein said antibody inhibits signaling by the TLR3 polypeptide without blocking binding of a dsRNA TLR3 ligand to the TLR3 polypeptide.2. A monoclonal antibody that specifically binds a human TLR3 polypeptide , wherein said antibody specifically binds to the TLR3 polypeptide under acidic conditions with a sub-nanomolar Kfor its bivalent binding affinity.3. The antibody of claim 2 , wherein said antibody modulates TLR3 signaling without blocking binding of a dsRNA TLR3 ligand to the TLR3 polypeptide.4. The antibody of claim 2 , wherein said antibody inhibits TLR3 signaling.5. The antibody of claim 3 , wherein said antibody inhibits TLR3 signaling.6. The antibody of claim 2 , wherein said acidic conditions comprise a pH between 4.5 and 6.5.7. The antibody of claim 6 , wherein said antibody specifically binds to a TLR3 polypeptide under neutral conditions with a sub-nanomolar Kfor bivalent binding affinity.8. The antibody of claim 7 , wherein said neutral conditions comprise a pH between 6.6 and 7.4.9. An isolated antibody which competes for binding to a TLR3 polypeptide claim 7 , optionally under acid and/or neutral conditions claim 7 , with an antibody having respectively a VH and VL region of SEQ ID NOS 2 and 3 (31C3).10. An isolated antibody which competes for binding to a TLR3 polypeptide with an antibody selected from the group consisting of:(a) an ...

DIVERSITY RECEIVER AND TRANSCEIVER

A diversity receiver comprises a plurality of receiving paths connected to a receiver circuit. Each of the receiving paths comprises an antenna receiving a signal, connected to a matching network connected to a receive amplifier. The receiver circuit is connected to a signal level comparison circuit for providing a relative comparison value indicating one of the receiving paths receiving the signal with a relative maximum strength. The signal level comparison circuit comprises a comparator circuit connected to the receiver circuit receiving a currently received signal level, and to a logic control unit being arranged to select one of the receive paths to provide the currently received signal to the receiver circuit. 1. A diversity receiver , comprising: each of said receiving paths comprises configured to receive a signal,', 'each antenna is connected to a matching network,', 'each matching network is connected to a receive amplifier; and, 'a plurality of receiving paths connected to a receiver circuit, wherein'} a comparator circuit connected to said receiver circuit and configured to receive a currently received signal level, and', 'a logic control unit, coupled to the comparator circuit, configured to select one of said receive paths to provide said currently received signal to said receiver circuit., 'a signal level comparison circuit, coupled to the receiver circuit, and configured to provide a relative comparison value indicating one of said receiving paths receiving said signal with a relative maximum strength, said signal level comparison circuit comprising'}2. The diversity receiver as claimed in claim 1 , wherein said signal level comparison circuit comprises at least one sample & hold buffer circuit claim 1 , connected to said receiver circuit and said comparator circuit claim 1 , and configured to receive control signals from said logic control unit.3. The diversity receiver as claimed in claim 1 , wherein said currently received signal comprises at ...

Human anti-kir antibodies

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.

COMPOSITIONS AND METHODS FOR DETECTING TLR3

The present invention relates to antibodies, antibody fragments, and derivatives thereof that specifically bind to TLR3 cell receptors present on the surface of cells. The invention also relates to hybridomas producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to detect TLR3 levels on the surface of cells, and the use of such antibodies and compositions for diagnostic or therapeutic purposes in subjects. 1. A method of treating a patient , said method comprising: i) variable light chain region CDRs: KSSQSLLDSDGKTYLN (SEQ ID NO:5; CDR1); LVSKLDS (SEQ ID NO:6; CDR2); and WQGIHLPYT (SEQ ID NO:7; CDR3) and variable heavy chain region CDRs: YTFTNYGMN (SEQ ID NO:8; CDR1); NANTGEPTYAEEFKG (SEQ ID NO:9; CDR2); and DYDY (SEQ ID NO:10; CDR3); or', 'ii) variable light chain region CDRs: KSSQSLLDSDGKTYLN (SEQ ID NO:5; CDR1); LVSKLDS (SEQ ID NO:6; CDR2); and WQGIHLPYT (SEQ ID NO:7; CDR3) and variable heavy chain region CDRs: KASGYTFTNYGMN (SEQ ID NO:11; CDR1); NANTGEPTYAEEFKG (SEQ ID NO:9; CDR2); and DYDY (SEQ ID NO:10; CDR3); and, 'a) providing a paraffin-embedded tissue section from a patient and detecting TLR3 levels in said tissue section with a monoclonal antibody that specifically binds to TLR3 in paraffin-embedded tissue sections, said monoclonal antibody comprisingb) administering a TLR3 ligand to a patient positive for the presence of TLR3 in said tissue section.2. The method of claim 1 , wherein the TLR3 ligand is selected from the group consisting of a dsRNA claim 1 , polyIC claim 1 , polyAU claim 1 , an anti-TLR3 antibody and an agent capable of inducing apoptosis of TLR3-expressing cells. This application is a divisional of U.S. Ser. No. 13/119,341, filed May 11, 2011, now allowed, which is the U.S. national stage application of International Patent Application No. PCT/EP2009/061902, filed Sep. 15, 2009, which claims the ...

Process for preparing electroactive insertion compounds and electrode materials obtained therefrom

A process for preparing an at least partially lithiated transition metal oxyanion-based lithium-ion reversible electrode material, which includes providing a precursor of said lithium-ion reversible electrode material, heating said precursor, melting same at a temperature sufficient to produce a melt including an oxyanion containing liquid phase, cooling said melt under conditions to induce solidification thereof and obtain a solid electrode that is capable of reversible lithium ion deinsertion/insertion cycles for use in a lithium battery. Also, lithiated or partially lithiated oxyanion-based-lithium-ion reversible electrode materials obtained by the aforesaid process.

ENZYMATIC CONJUGATION OF POLYPEPTIDES

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions 1. An antibody or antibody fragment comprising a functionalized acceptor glutamine residue , the functionalized acceptor glutamine residue having Formula IVa ,{'br': None, 'sub': n', 'z', 'q', 'q', 'r, '(Q)-NH—(C)—X-L-(V—(Y—(Z))))\u2003\u2003Formula IVa'}or a pharmaceutically acceptable salt or solvate thereof,wherein:Q is glutamine residue present in an antibody or antibody fragment;{'sub': 'n', '(C)is a substituted or unsubstituted alkyl or heteroalkyl chain, optionally wherein any carbon of the chain is substituted with an alkoxy, hydroxyl, alkylcarbonyloxy, alkyl-S—, thiol, alkyl-C(O)S—, amine, alkylamine, amide, or alkylamide;'}n is an integer selected from among the range of 2 to 20;X is NH, O, S, absent, or a bond;L is independently absent, a bond or a continuation of a bond, or a carbon comprising framework of 5 to 200 atoms substituted at one or more atoms;r is an integer selected from among 1, 2, 3 or 4;q is an integer selected from among 1, 2, 3 or 4;z is an integer selected from among 1, 2, 3 or 4; andV is independently absent, a bond or a continuation of a bond, a non-cleavable moiety or a conditionally-cleavable moiety;Y is independently absent, a bond or a continuation of a bond, or a spacer system which is comprised of 1 or more spacers; andZ is a moiety that improves pharmacokinetic properties, a therapeutic moiety or a diagnostic moiety, wherein Z is an organic compound that is electrically negatively charged, hydrophobic and/or that has a molecular weight of at least 400 g/mol.2. The antibody of claim 1 , wherein n is an integer selected from among the range of 10 to 20.3. The antibody of claim 1 , wherein (C)is a heteroalkyl chain that comprises a (CH—CH—O—)group claim 1 , wherein x is ...

INTEGRATED CIRCUIT DEVICE, WIRELESS COMMUNICATION UNIT AND METHOD OF MANUFACTURE THEREFOR

An integrated circuit device comprising at least one radio frequency (RF) transceiver module. The at least one RF transceiver module includes a plurality of low noise amplifiers (LNAs) operably coupled to external contacts of the integrated circuit device and arranged to receive an RF signal from the respective external contact, amplify the received RF signal, and to output the amplified RF signal. Each transceiver module further includes a plurality of power amplifier (PA) modules operably coupled to the external contact of the integrated circuit device, and arranged to receive an RF signal to be transmitted, amplify the received RF signal to be transmitted, and output the amplified signal. The plurality of LNAs and the plurality of PAs are selectively configurable to operate in at least a first, multi-antenna configuration and a second, single antenna high transmit power configuration. 1. An integrated circuit device comprising: a plurality of low noise amplifiers (LNAs) having respective input ports operably coupled to at least one external contact of the integrated circuit device and arranged to receive a first RF signal from the at least one external contact and output an amplified received first RF signal, and', 'the plurality of LNAs and the plurality of PAs are selectively configurable to operate in at least a first, multi-antenna configuration and a second, single antenna high transmit power configuration.', 'a plurality of power amplifiers (PAs) having respective output ports operably coupled to the at least one external contact of the integrated circuit device, and arranged to receive at respective power amplifier input ports a second RF signal and output an amplified second RF signal to be transmitted, wherein'}], 'at least one radio frequency (RF) transceiver module, wherein the at least one RF transceiver module comprises2. The integrated circuit device of wherein the plurality of LNAs and the plurality of PAs are selectively configurable to operate in ...

HUMAN ANTI-KIR ANITBODIES

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects. 150-. (canceled)51. An isolated human , humanized , or chimeric antibody , or antigen-binding fragment thereof , that binds to each one of human KIR2DL1 , human KIR2DL2 , and human KIR2DL3 , but which does not bind human KIR2DS4 , said antibody comprising:(a)(i) a heavy chain CDR1 amino acid sequence corresponding to residues 31-35 of SEQ ID NO:17;(a)(ii) a heavy chain CDR2 amino acid sequence corresponding to residues 50-65 of SEQ ID NO:17;(a)(iii) a heavy chain CDR3 amino acid sequence corresponding to residues 99-112 of SEQ ID NO:17;(a)(iv) a light chain CDR1 amino acid sequence corresponding to residues 24-34 of SEQ ID NO:15;(a)(v) a light chain CDR2 amino acid sequence corresponding to residues 50-56 of SEQ ID NO:15; and(a)(vi) a light chain CDR3 amino acid sequence corresponding to residues 89-97 or SEQ ID NO:15; or(b) a VL region comprising SEQ ID NO: 15 and a VH region comprising SEQ ID NO: 17.52. The isolated antibody or antigen-binding fragment of claim 51 , which further does not bind to human KIR2DS3.53. The isolated antibody or antigen-binding fragment of claim 52 , which antibody has a Kd for human KIR2DL3 of no more than about 0.025 nM.54. The isolated antibody or antigen-binding fragment of claim 51 , which antibody or antigen-binding fragment blocks the binding of at least one of human KIR2DL 1 claim 51 , human KIR2DL2 claim 51 , and human KIR2DL3 to a human HLA-C ...

TLR3 BINDING AGENTS

The invention provides anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies. 1. A monoclonal antibody that specifically binds a TLR3 polypeptide , wherein said antibody:(i) inhibits signaling by the TLR3 polypeptide signaling without blocking binding of a dsRNA TLR3 ligand to the C-terminal dsRNA binding site of the TLR3 polypeptide,(ii) is capable of being internalized by a TLR3-expressing cell, and{'sup': '−9', '(iii) has a Kd of less than 10M for binding to a TLR3 polypeptide at acidic pH.'}2. The antibody of claim 1 , wherein said antibody binds to a TLR3 polypeptide within the segment corresponding to residues 102 to 204 and does not bind residue 116 and/or residue 145 of the TLR3 polypeptide of SEQ ID NO: 1.3. The antibody of claim 1 , wherein said antibody comprises a human IgG4 heavy chain comprising a serine to proline mutation in residue 241 claim 1 , corresponding to position 228 according to the EU-index.48.-. (canceled)9. The antibody of claim 1 , wherein said antibody does not have a significant reduction in binding to a TLR3 polypeptide having a mutation at residues 116 claim 1 , 145 claim 1 , 171 and/or residue 196 of the TLR3 polypeptide of SEQ ID NO: 1 claim 1 , relative to binding between the antibody and a wild-type TLR3 polypeptide of SEQ ID NO: 1.10. The antibody of claim 1 , wherein said antibody has a significant reduction in binding to a TLR3 polypeptide having a mutation at residue 182 of the TLR3 polypeptide of SEQ ID NO: 1 claim 1 , relative to binding between the antibody and a wild-type TLR3 polypeptide of SEQ ID NO: 1.11. The antibody of claim 1 , wherein said antibody binds to a TLR3 polypeptide within the segment corresponding to residues 174 to 191 and does not bind residue 116 and/or residue 145 of the TLR3 polypeptide of SEQ ID NO: 1.12. A monoclonal antibody that specifically binds a TLR3 ...

CD73 BLOCKING ANTIBODIES

The present invention relates to antibodies, and fragments thereof, that bind and inhibit CD73. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer. 1. An antibody or antibody fragment capable of specifically binding to a human CD73 polypeptide , wherein:a) the antibody or antibody fragment comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 42 (2H4+ chain), and a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 43 (2L1 chain), 44 (2L2 chain), 45 (2L3 chain) and 46 (2L4 chain).2. The antibody of claim 1 , wherein the antibody is a full-length antibody.3. The antibody or antibody fragment of claim 1 , wherein the antibody is an antibody fragment.4. A pharmaceutical composition comprising an antibody or antibody fragment according to .5. A nucleic acid or set of nucleic acids encoding a heavy and/or light chain or a VH and/or VL domain of an antibody or antibody fragment according to .6. A recombinant host cell comprising a vector encoding the antibody or antibody fragment according to .7. A method for the treatment or prevention of a disease in a patient in need thereof claim 1 , the method comprising administering to said patient an effective amount of an antibody or antibody fragment according to or a composition comprising said antibody or antibody fragment.8. The method of claim 7 , wherein said disease is cancer or infectious disease.9. The method of claim 7 , wherein the disease or cancer is a leukemia claim 7 , bladder cancer claim 7 , glioma claim 7 , glioblastoma claim 7 , ovarian cancer claim 7 , melanoma claim 7 , prostate cancer claim 7 , thyroid cancer claim 7 , stomach cancer claim 7 , esophageal cancer claim 7 ...

Immunomodulatory antibody drug conjugates binding to a human mica polypeptide

The present invention provides antigen-binding proteins capable of binding to human MICA polypeptides, conjugated to cytotoxic agents. Said conjugates have increased activity in the treatment of disorders characterized by MICA-expressing cells, particularly tumor cells.

COMPOSITIONS AND METHODS FOR TREATING CANCER

The present invention relates to antigen-binding compounds that inhibit the enzymatic activity of soluble human CD. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer. 1. An antibody or antibody fragment that binds a human CD39 polypeptide and that is capable of inhibiting the ATPase activity of a soluble extracellular domain human CD39 polypeptide , wherein the antibody or antibody fragment comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 31 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NOS: 36 or 37.2. The antibody or antibody fragment of claim 1 , wherein the antibody or antibody fragment comprises a heavy chain comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 38 and a light chain comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS: 39 or 40.3. The antibody or antibody fragment of claim 2 , wherein the antibody or antibody fragment comprises heavy chain framework FR1 claim 2 , FR2 and FR3 amino acid sequences from the human IGHV1-3 gene; and light chain framework FR1 claim 2 , FR2 and FR3 amino acid sequences from the human IGKV4-1 gene.45-. (canceled)6. The antibody or antibody fragment of claim 1 , wherein the antibody or antibody fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36.7. An antibody or antibody fragment claim 1 , wherein the antibody or antibody fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid ...

CD73 BLOCKADE

This invention relates to antibodies that bind an epitope present on CD73 expressed at the surface of cells, including tumor cells, and that inhibit the enzymatic (ecto-5′ nucleotidase) activity of the CD73 enzyme. Such agents can be used for the treatment of diseases such as cancers. 142-. (canceled)43. An isolated antibody that specifically binds a human CD73 polypeptide at the surface of a cell and that is capable of neutralizing the 5′-ectonucleotidase activity thereof , wherein the antibody inhibits the activity of the human CD73 polypeptide without detectably reducing binding between the CD73 polypeptide and a substrate thereof , wherein the antibody is furthermore capable of neutralizing the 5′-ectonucleotidase activity of a soluble human CD73 polypeptide.44. The antibody of claim 43 , wherein the antibody binds an epitope present on CD73 in the “open” conformation when not bound to substrate and in the “closed” conformation when bound to a substrate.45. The antibody of claim 43 , wherein neutralization of the enzymatic activity of CD73 is determined by assessing neutralization of 5′ ectonucleotidase activity in MDA-MB-231 cells by quantifying hydrolysis of AMP to adenosine.46. The antibody of claim 43 , wherein the antibody binds an epitope comprising 1 claim 43 , 2 claim 43 , 3 or 4 of the residues selected from the group consisting of K97 claim 43 , E125 claim 43 , Q153 and K330 (with reference to SEQ ID NO: 1).47. The antibody of claim 43 , wherein said antibody binds an epitope comprising 1 claim 43 , 2 claim 43 , 3 claim 43 , 4 or 5 residues selected from the group consisting of A99 claim 43 , E129 claim 43 , K133 claim 43 , E134 claim 43 , and A135 (with reference to SEQ ID NO: 1).48. The antibody of claim 43 , wherein the antibody specifically hinds a human CD73 polypeptide without causing substantial intracellular internalization of the CD73 polypeptide.49. The isolated antibody of claim 43 , wherein the antibody substantially lacks binding claim 43 ...

ANTI-CD39 ANTIBODIES

The present invention relates to antigen-binding compounds that inhibit CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g. cancer. 1. An antibody that binds a human CD39 polypeptide expressed by a cell and that neutralizes the ATPase activity thereof , selected from the group consisting of:(a) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 26 and a light chain comprising an amino acid sequence of SEQ ID NO: 9;(b) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 27 and a light chain comprising an amino acid sequence of SEQ ID NO: 9;(c) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 28 and a light chain comprising an amino acid sequence of SEQ ID NO: 9; and(d) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 29 and a light chain comprising an amino acid sequence of SEQ ID NO: 9.2. An antibody that binds human CD39 and that neutralizes the ATPase activity thereof , selected from the group consisting of:(a) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7;(b) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9;(c) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 11;(d) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 12 and a light chain ...

ANTI-KIR3D ANTIBODIES

The present invention provides antigen-binding proteins capable of binding to KIR3D polypeptides. The antibodies have increased activity in the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sézary Syndrome. 1. An isolated antibody that specifically binds to an epitope within the KIR3DL2 domain 0 having the amino acid sequence of SEQ ID NO: 21 , wherein said antibody inhibits proliferation of KIR3DL-expressing human T lymphocytes and comprises a constant region of human IgG isotype.2. The antibody of claim 1 , wherein said epitope is a common determinant shared by KIR3DL1 and KIR3DL2 polypeptides.3. The antibody of claim 1 , wherein said antibody specifically activates KIR3DL signaling on a KIR3DL-expressing cell.4. The antibody of claim 1 , wherein the antibody comprises a hypofucosylated Fc region claim 1 , wherein the antibody induces ADCC of a KIR3DL2-expressing target cell.5. The antibody of claim 1 , wherein said antibody binds to substantially the same epitope as a monoclonal antibody chAZ158.6. The antibody of claim 1 , wherein said antibody is bivalent.7. The antibody of claim 1 , wherein said antibody comprises a modified Fc domain.8. The antibody of claim 7 , wherein said modified Fc domain is hypofucosylated.9. The antibody of claim 1 , wherein said antibody is a monoclonal antibody or an antigen-binding fragment or derivative of a monoclonal antibody.10. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising the three CDRs of SEQ ID NOs: 11 to 13.11. The antibody of claim 1 , wherein the antibody comprises a light chain comprising the three CDRs of SEQ ID NOs: 14 to 16.12. The antibody of claim 11 , wherein said monoclonal antibody is chAZ158 claim 11 , or an antigen-binding fragment or derivative thereof.13. The antibody of claim 1 , wherein said antibody is an antibody fragment selected from Fab claim 1 , Fab′ claim 1 , Fab′-SH ...

MULTISPECIFIC NK ENGAGER PROTEIN

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease. 178-. (canceled)80. The multispecific antigen binding protein of claim 79 , wherein the therapeutic antibody specifically binds to an antigen expressed by cancer cells.81. The multispecific antigen binding protein of claim 79 , wherein the therapeutic antibody specifically binds to an antigen expressed by an infectious agent.82. The multispecific antigen binding protein of claim 81 , wherein said infectious agent is a virus claim 81 , parasite claim 81 , bacterium or another microbe.83. The multispecific antigen binding protein of claim 79 , wherein the therapeutic antigen-binding ABD comprises a Fab or comprises a Vdomain and a Vdomain separated by a linker comprising a linear or cyclic peptide.84. The multispecific antigen binding protein of claim 79 , wherein the NKp46-binding ABD comprises a Fab.85. The multispecific antigen binding protein of claim 79 , wherein the NKp46-binding ABD comprises a Vdomain and a Vdomain separated by a linker comprising a linear or cyclic peptide.86. The multispecific antigen binding protein of claim 79 , wherein said dimeric Fc polypeptide of (3) comprises a modification that enhances CD16A binding relative to the corresponding wild-type Fc region.87. The multispecific antigen binding protein of claim 79 , wherein the administration of said multispecific antigen binding protein to a subject increases the expression of CD137 on the surface of NK cells in said subject.88. The multispecific antigen binding protein of claim 79 , wherein the NKp46-binding ABD is comprised of a Vdomain and a Vdomain claim 79 , wherein each of the Vand Vdomains are positioned within a tandem variable region comprising a Vdomain and a Vdomain separated by a polypeptide linker.89. ...

MULTISPECIFIC ANTIGEN BINDING PROTEINS

Multimeric multispecific proteins formed from dimerization between CH1 and CK domains and that bind two target antigens are provided. The proteins have advantages in production and in the treatment of disease, notably cancer or infectious disease. 150-. (canceled)51. A multispecific protein comprising a first and a second polypeptide chain each comprising a variable domain fused to a CH1 or Cκ domain (a V-(CH1/Cκ) unit) , in turn fused at its C-terminus to a human Fc domain , wherein the V-(CH1/Cκ) unit of the first chain is bound , by CH1-Cκ dimerization , to the V-(CH1/Cκ) unit of the second chain thereby foaming a first antigen binding domain and a dimeric Fc domain , wherein one of the polypeptide chains further comprises an antigen binding domain that forms a second antigen binding domain , and wherein the Fc domain comprises N-linked glycosylation at residue N297 (Kabat EU numbering) and binds to a human CD16 polypeptide.52. A multispecific protein comprising three polypeptide chains , each comprise a variable domain fused to a CH1 or Cκ domain (a V-(CH1/Cκ) unit) , wherein a first (central) chain comprises two V-(CH1/Cκ) units and a human Fc domain interposed between the units , the second chain comprises one V-(CH1/Cκ) unit and a human Fc domain , and the third chain comprises one V-(CH1/Cκ) unit , wherein one of the V-(CH1/Cκ) units of the central chain is bound , by CH1-Cκ dimerization , to the V-(CH1/Cκ) unit of the second chain thereby forming a first antigen binding domain and a dimeric Fc domain , and wherein the other of the V-(CH1/Cκ) units of the central chain is bound , by CH1-Cκ dimerization , to the V-(CH1/Cκ) unit of the third chain thereby forming a second antigen binding domain , and wherein the Fc domain comprises N-linked glycosylation at residue N297 (Kabat EU numbering) and binds to a human CD16 polypeptide.53. A multispecific protein that binds to three antigens of interest and to a human CD16 polypeptide , the protein comprising three ...

MULTISPECIFIC NK ENGAGER PROTEIN

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease. 1. A multispecific antigen binding protein comprising a first antigen binding domain (“ABD”) , a second ABD , and a CD16A binding polypeptide , polypeptide or portion thereof capable of binding human CD16A which Fc polypeptide wherein one of the first or second ABDs binds to a human NKp46 polypeptide and the other binds an antigen of interest and the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest , wherein said lysis of the target cell is mediated by NKp46-signaling.278-. (canceled)79. The multispecific antigen binding protein of claim 1 , wherein the antigen of interest is expressed by a cancer cell.80. The multispecific antigen binding protein of claim 79 , wherein the antigen of interest is expressed by a hematological cancer.81. The multispecific antigen binding protein of claim 79 , wherein the antigen of interest is expressed by a solid tumor.82. The multispecific antigen binding protein of claim 79 , wherein the antigen of interest is expressed by an infectious agent.83. The multispecific antigen binding protein of claim 1 , which:(i) comprises an Fc polypeptide or portion thereof capable of binding human CD16A;(ii) it comprises an Fc polypeptide or portion thereof capable of binding human CD16A which is modified to enhance CD16A binding relative to the corresponding wild-type Fc region;(iii) binds to a NKp46 polypeptide monovalently;(iv) mediates lysis target cells by a combination of Nkp46 signaling and CD16-mediated antibody-dependent cell-mediated cytotoxicity (“ADCC”);(v) mediates NKp46 signaling mediated lysis and CD16-mediated lysis resulting in a synergistic enhancement in the lysis of target ...

PROCESS FOR PREPARING ELECTROACTIVE INSERTION COMPOUNDS AND ELECTRODE MATERIALS OBTAINED THEREFROM

A process for preparing an at least partially lithiated transition metal oxyanion-based lithium-ion reversible electrode material, which includes providing a precursor of said lithium-ion reversible electrode material, heating said precursor, melting same at a temperature sufficient to produce a melt including an oxyanion containing liquid phase, cooling said melt under conditions to induce solidification thereof and obtain a solid electrode that is capable of reversible lithium ion deinsertion/insertion cycles for use in a lithium battery. Also, lithiated or partially lithiated oxyanion-based-lithium-ion reversible electrode materials obtained by the aforesaid process. 159-. (canceled)60. A lithium-ion reversible electrode material , comprising micron size particles and submicron size particles , said micron size particles and submicron size particles having the nominal formula AB(XO)H , said micron size particles having a first pyrolytic carbon deposit wt. % ratio relative to the total weight of the AB(XO)H micron size particles and said submicron size particles having a second pyrolytic carbon deposit wt. % ratio relative to the total weight of the AB(XO)H submicron size particles , wherein said first pyrolytic carbon deposit wt. % ratio is different from said second pyrolytic carbon deposit wt. % ratio , and wherein:A is lithium, which may be partially substituted with another alkali metal representing less than 20 atomic % of said A;B is a main redox metal at oxidation level of +2 selected from the group consisting of Fe, Mn, Ni and any mixture thereof, which may be partially substituted by one or more additional metal at oxidation level between +1 and +5 and representing less than 35 atomic % of said main +2 redox metal, including 0;{'sub': '4', 'XOis any oxyanion wherein X is selected from the group consisting of P, S, V, Si, Nb, Mo and any combination thereof; and'}{'sub': '4', 'H is a fluoride, hydroxide or chloride anion representing less that 35 atomic % ...

Enzymatic conjugation of polypeptides

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.

ANTI-CD39 ANTIBODIES

The present invention relates to antigen-binding compounds that inhibit CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g. cancer. 139-. (canceled)40. An antibody that binds a human CD39 polypeptide expressed by a cell and that neutralizes the ATPase activity thereof , selected from the group consisting of:(a) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 26 and a light chain comprising an amino acid sequence of SEQ ID NO: 9;(b) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 27 and a light chain comprising an amino acid sequence of SEQ ID NO: 9;(c) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 28 and a light chain comprising an amino acid sequence of SEQ ID NO: 9; and(d) an antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 29 and a light chain comprising an amino acid sequence of SEQ ID NO: 9.41. An antibody that binds human CD39 and that neutralizes the ATPase activity thereof , selected from the group consisting of:(a) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7;(b) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9;(c) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 11;(d) an antibody comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 12 ...

MULTISPECIFIC ANTIGEN BINDING PROTEINS

Multimeric multispecific proteins formed from dimerization between CH1 and CK domains and that bind two target antigens are provided. The proteins have advantages in production and in the treatment of disease, notably cancer or infectious disease.

COMPOSITIONS AND METHODS FOR REGULATING NK CELL ACTIVITY

The present invention relates to novel compositions and methods for regulating an immune response in a subject. More particularly, the invention relates to specific antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects. The invention also relates to fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly in therapy, to increase NK cell activity or cytotoxicity in subjects. 17-. (canceled)8. An isolated antibody or antibody fragment that (a) cross-reacts with at least two different human KIR2DL polypeptides that each recognizes a different group of HLA-C class I allotypes , and (b) neutralizes the inhibitory activity of such polypeptides.9. The isolated antibody or antibody fragment of claim 8 , wherein the antibody binds to substantially the same epitope as does DF-200 (deposited as CNCM I-3224).10. The isolated antibody or antibody fragment of claim 8 , wherein said antibody competes with DF-200 (deposited as CNCM I-3224) for binding to said KIR2DL polypeptides.11. The isolated antibody or antibody fragment of claim 8 , comprising (i) a light chain CDR1 having the amino acid sequence of SEQ ID NO:3 claim 8 , (ii) a light chain CDR2 having the amino acid sequence of SEQ ID NO:5 claim 8 , and (iii) a light chain CDR3 having the amino acid sequence of SEQ ID NO:7.12. The isolated antibody or antibody fragment of claim 8 , comprising a light chain variable region having the amino acid sequence of SEQ ID NO:1.13. The isolated antibody or antibody fragment of claim 8 , comprising (i) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:20 claim 8 , (ii) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:21 claim 8 , and (iii) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:22.14. The isolated antibody or antibody fragment of claim 8 , comprising a heavy chain variable region having the amino ...

TLR3 BINDING AGENTS

Disclosed herein are anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies. 1. A monoclonal antibody that inhibits TLR3-mediated signaling in a TLR3-expressing cell , wherein the antibody binds to the glycan-free lateral surface of the N-terminal portion of the TLR3 polypeptide , wherein said antibody has reduced binding to a mutant TLR3 polypeptide comprising a mutation at residue 64 , 65 , 86 , 89 , 112 , 113 , 115 , 117 , 120 , 137 and/or 139 of the TLR3 polypeptide of SEQ ID NO: 1 , relative to binding between the antibody and a wild-type TLR3 polypeptide of SEQ ID NO: 1.2. The antibody of claim 1 , wherein the antibody has reduced binding to a TLR3 polypeptide having a mutation at residue 117 and 120 of the TLR3 polypeptide of SEQ ID NO: 1 claim 1 , relative to binding between the antibody and a wild-type TLR3 polypeptide of SEQ ID NO: 1.3. The antibody of claim 2 , wherein the antibody binds said TLR3 polypeptide on the backbone of the TLR3 polypeptide.4. The antibody of claim 1 , wherein the antibody competes with dsRNA for binding to the N-terminal portion of a human TLR3 polypeptide.56-. (canceled)7. The antibody of claim 1 , wherein the antibody does not substantially bind the glycan-containing lateral surface of the N-terminal portion of the TLR3 polypeptide.813-. (canceled)14. The antibody of claim 1 , wherein the antibody substantially maintains binding to (does not have a significant reduction in binding to) a TLR3 polypeptide having a mutation at residues D116 and/or K145 of the TLR3 polypeptide of SEQ ID NO: 1 claim 1 , relative to binding between the antibody and a wild-type TLR3 polypeptide of SEQ ID NO: 1.1522-. (canceled)23. The monoclonal antibody of claim 1 , wherein the antibody comprises:(i) a heavy chain comprising CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences of a heavy chain variable region of ...

CALIBRATION ARRANGEMENT FOR FREQUENCY SYNTHESIZERS

An electronic device has a calibration arrangement for controlling a frequency characteristic of a PLL circuit having a phase comparator having an output for generating a phase difference signal, a voltage controlled oscillator and a divider. The divisor of the divider is programmable, and the oscillator is also directly modulated by an oscillator modulation signal. A modulation unit has a modulation input for receiving a modulation signal and generates the oscillator modulation signal and the divisor such that modulation generates a predefined change of the output frequency and a change of the divisor proportional to said predefined change. The calibration arrangement receives the phase difference signal, and has a ripple detector for providing a detector output signal by detecting a ripple on the phase difference signal correlated to edges in the modulation signal. A calibration control unit adjusts the oscillator modulation signal based on the detector output signal such that the ripple is reduced. 2. The device as claimed in claim 1 , wherein the ripple detector comprises at least one sample and hold unit coupled to the calibration input claim 1 , and a detector having a detector input coupled to a sample and hold output signal of the sample and hold unit claim 1 ,the sample and hold unit being arranged for generating the sample and hold output signal by sampling on edges in the modulation signal.3. The device as claimed in claim 2 , wherein the ripple detector comprises a second sample and hold unit coupled to the calibration input claim 2 ,said first sample and hold unit being arranged for generating the first sample and hold output signal by sampling on positive edges in the modulation signal, andthe second sample and hold unit being arranged for generating a second sample and hold output by sampling on negative edges in the modulation signal, andthe detector having a second detector input coupled to the second sample and hold output signal, and being ...

NKp46 BINDING PROTEINS

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease. 1. An isolated multispecific protein comprising a first antigen binding domain and a second antigen binding domain , wherein one of the first or second antigen binding domains binds to a human NKp46 polypeptide and the other binds an antigen of interest , wherein the multispecific protein binds the NKp46 polypeptide monovalently , and wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest.249-. (canceled) This application is a divisional application of U.S. application Ser. No. 15/321,650, filed Dec. 22, 2016, which is a U.S. National Phase Application of Int'l Appl. No. PCT/EP2015/064063, filed Jun. 23, 2015, which claims priority to U.S. Provisional Application No. 62/108,088, filed Jan. 27, 2015, and U.S. Provisional Application No. 62/017,886, filed Jun. 27, 2014, each of which is incorporated herein by reference.This application includes as part of its disclosure a biological sequence listing which is being concurrently submitted through EFS-Web. Said biological sequence listing is contained in a file named “11562150001202.txt” which was created on Nov. 7, 2019, and has a size of 310,458 bytes, and is hereby incorporated by reference in its entirety.Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease.Bispecific antibodies binding two different epitopes, offer opportunities for increasing specificity, broadening potency, and utilizing novel mechanisms of action that cannot be ...

Compositions and methods for detecting tlr3

The present invention relates to antibodies, antibody fragments, and derivatives thereof that specifically bind to TLR3 cell receptors present on the surface of cells. The invention also relates to hybridomas producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to detect TLR3 levels on the surface of cells, and the use of such antibodies and compositions for diagnostic or therapeutic purposes in subjects.

ENZYMATIC CONJUGATION OF POLYPEPTIDES

The present application relates to methods for the enzymatic functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions. 1. A method for conjugating a hydrophobic , high molecular weight and/or charged organic compound to an antibody , comprising:a) providing an antibody having at least one acceptor glutamine residue; andb) reacting said antibody with a linker comprising a primary amine and a reactive group (R), in the presence of a TGase, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to a reactive group (R) via said linker, wherein the reaction mixture is free of organic solvent or contains less than 10% (v/v) or contains less than 5%, 4%, 3% or 2% (v/v) organic solvent; and (i) an antibody of step (b) comprising an acceptor glutamine linked to a reactive group (R) via a linker comprising a primary amine, with', '(ii) a compound comprising a moiety of interest (Z), wherein (Z) is a hydrophobic compound, a charged organic compound and/or organic compound having a molecular weight of at least 500, 700 or 800 g/mol, and a reactive group (R′) capable of reacting with reactive group R, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to moiety of interest (Z) via a linker comprising a primary amine., '(c) reacting, in the presence of organic solvent, optionally in the presence of at least 2%, 3%, 4%, 5% or 10% (v/v) organic solvent2. The method of claim 1 , wherein Z is a pyrrolobenzodiazepine.3. The method of claim 1 , wherein Z is a pyrrolobenzodiazepine dimer.4. The method of claim 1 , wherein Z is a C8/C8′-linked pyrrolobenzodiazepine dimer.5. The method of claim 1 , wherein antibody comprises human heavy and light chain constant regions claim 1 , wherein the heavy chain constant regions comprise a N297Q substitution and a Q295X ...

CD39 VASCULAR ISOFORM TARGETING AGENTS

The present invention relates to antigen-binding compounds that inhibit CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g. cancer. 1. An antibody that specifically binds human CD39 (NTPDase1) at the surface of a cell without binding to CD39-L1 , -L2 , -L3 or -L4 polypeptides , and that is capable of neutralizing the ATPase activity of human CD39 (NTPDase1) without substantially inducing or increasing the internalization of cell surface CD39 , wherein the antibody substantially lacks binding to human CD16 , CD32a , CD32b and CD64 polypeptides wherein the Vcomprises:{'sub': 1', '2', '3', '1', '2', '3, '(a) a CDR1 capable of contacting the N-terminal domain of CD39, wherein the residues at Kabat position 31, 32 and 33 have the formula XXX, wherein Xrepresents a histidine or asparagine, Xrepresents an aromatic residue, and Xrepresents glycine or another amino acid that avoids steric hindrance;'}{'sub': 1', '2', '3', '4', '5', '6', '7', '8', '9', '10', '11', '12', '13', '1', '2', '3', '4', '5', '6', '7', '8', '9', 'H', '10', '11', 'H', '12', '13, '(b) a CDR2-FR3 segment capable of contacting the C-terminal domain of CD39, wherein the residues at Kabat position 59-71 have the formula XXXXXXXXXXXXX(SEQ ID NO: 12), wherein Xrepresents a tyrosine, each of X, X, X, Xand Xeach represent any amino acid, Xrepresents glycine or another residue which does not introduce steric hindrance that reduces antigen binding, Xrepresents any amino acid, Xrepresents phenylalanine or another hydrophobic residue capable of maintaining the beta-strand position and Vdomain structure integrity, Xrepresents alanine, valine, leucine, threonine, or a hydrophobic residue, Xrepresents phenylalanine or another hydrophobic residue capable of maintaining the beta-strand ...

HUMANIZED ANTIBODIES WITH INCREASED STABILITY

The present invention provides antibodies having improved stability. Included are antibodies that are capable of binding to KIR3DL2 polypeptides. The antibodies are suitable for the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome, and KIR3DL2-expressing autoimmune disorders. 127-. (canceled)28. An antibody or antibody fragment that binds a KIR3DL2 polypeptide , comprising(a) a heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) comprising a sequence of SEQ ID NO: 2 (HCDR1). SEQ ID NO: 3 (HCDR2) and SEQ ID NO: 4 (HCDR3), respectively, and a light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) comprising a sequence of SEQ ID NO: 5 (LCDR1), 6 (LCDR2) and 7 (LCDR3), respectively, or(b) a heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) comprising a sequence of SEQ ID NO: 18 (HCDR1), SEQ ID NO: 19 (HCDR2) and SEQ ID NO: 20 (HCDR3), respectively, and a light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) comprising a sequence of SEQ ID NO: 21 (LCDR1), 22 (LCDR2) or 23 (LCDR3), respectively,wherein said antibody or antibody fragment comprises human heavy and light chain variable region framework sequences, wherein the heavy chain framework comprises a glutamine at residue 39 and the light chain framework comprises a glutamine at residue 38 (Abnum numbering).29. The antibody or antibody fragment of claim 28 , wherein said antibody or antibody fragment detectably reduces or eliminates binding between the KIR3DL2 and a HLA natural ligand of KIR3DL2.30. The antibody or antibody fragment of claim 28 , wherein said antibody or antibody fragment is not internalized when bound to KIR3DL2-expressing cells.31. The antibody or antibody fragment of claim 28 , wherein said antibody or antibody fragment detectably reduces binding between the KIR3DL2 and HLA-B27.32. The antibody or antibody fragment of claim 28 , wherein said antibody or antibody fragment does not substantially bind to a ...

Mica binding agents

The present invention relates to methods for the treatment of disorders mediated by MICA-expressing cells using antibodies, antibody fragments, and derivatives thereof that specifically bind MICA. The invention also relates to antibodies; cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; and pharmaceutical compositions comprising the same.

HUMAN ANTI-KIR ANTIBODIES

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects. 150-. (canceled)51. A method of potentiating natural killer (NK) cell activity in a subject comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to a Killer Immunoglobulin-Like Receptor (KIR) , or an antigen-binding fragment thereof , said antibody comprising: (i) a heavy chain CDR1 having the amino acid sequence corresponding to residues 31-35 of SEQ ID NO:17; (ii) a heavy chain CDR2 having the amino acid sequence corresponding to residues 50-65 of SEQ ID NO:17; (iii) a heavy chain CDR3 having the amino acid sequence corresponding to residues 99-112 of SEQ ID NO:17; (iv) a light chain CDR1 having the amino acid sequence corresponding to residues 24-34 of SEQ ID NO:15; (v) a light chain CDR2 having the amino acid sequence corresponding to residues 50-56 of SEQ ID NO:15; and (vi) a light chain CDR3 having the amino acid sequence corresponding to residues 89-97 or SEQ ID NO:15.52. The method of claim 51 , wherein the antibody or antigen-binding fragment comprises a light chain variable (V) region having the amino acid sequence set forth in SEQ ID NO: 15 and a heavy chain variable (V) region having the amino acid sequence set forth in SEQ ID NO: 17.53. The method of claim 52 , wherein the isolated antibody or antigen-binding fragment binds to each one of human KIR2DL1 claim 52 , human KIR2DL2 claim 52 , and human KIR2DL3 claim 52 ...

ENZYMATIC CONJUGATION OF ANTIBODIES

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions. 1. A human or humanized antibody comprising one or more solvent-exposed glutamine residues in a variable region and at least one acceptor glutamine residue in its constant region or in a sequence fused to a variable or constant region , wherein said one or more solvent-exposed glutamine residues are present in a light chain variable domain (VL) CDR at a Kabat position selected from the group consisting of 27 , 55 , and a combination thereof ,{'sub': 'n', 'wherein said antibody is conjugated via said acceptor glutamine residue to one or more moieties-of-interest (Z) through a linker that comprises a NH—(C)— moiety,'}wherein{'sub': 'n', '(C)is a substituted or unsubstituted alkyl or heteroalkyl chain, optionally wherein any carbon of the chain is substituted with an alkoxy, hydroxyl, alkylcarbonyloxy, alkyl-S—, thiol, alkyl-C(O)S—, amine, alkylamine, amide, or alkylamide, and n is an integer selected from among the range of 2 to 20; and'}Z is a reactive moiety or a moiety that improves the pharmacokinetic properties, a therapeutic moiety or a diagnostic moiety.2. The antibody of claim 1 , wherein the antibody is a tetrameric antibody and said constant region is a heavy chain constant region.34-. (canceled)5. The antibody of claim 1 , wherein the antibody comprises:a heavy chain framework region 1 (FR-H1) comprising a glutamine residue at Kabat position 1, 3, 5, 6, 10, 11, 12, 13 and/or 16;a heavy chain framework region 2 (FR-H2) comprising a glutamine residue at Kabat position 38, 39, 43 and/or 45;a heavy chain framework region 3 (FR-H3) comprising a glutamine residue at Kabat position 66, 75, 77, 81 and/or 85;a heavy chain framework region 1 (CDR-H1) comprising a glutamine residue at Kabat position 26 and/ ...

MULTISPECIFIC NKp46 BINDING PROTEINS

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease. 149-. (canceled)50. An isolated multispecific protein comprising a first antigen binding domain and a second antigen binding domain , wherein one of the first or second antigen binding domains binds to a human NKp46 polypeptide and the other binds an antigen of interest , wherein the multispecific protein binds the NKp46 polypeptide monovalently , and wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest.51. The isolated multispecific protein of claim 50 , wherein said lysis of the target cell is mediated by NKp46-signaling.52. The isolated multispecific protein of claim 50 , wherein the multispecific protein does not exhibit activation of NKp46-expressing NK cells when incubated with such NK cells in the absence of cells expressing the antigen of interest.53. The isolated multispecific protein of claim 50 , wherein the multispecific protein does not exhibit activation of NKp46-negative claim 50 , CD16-positive lymphocytes when incubated with such NK cells in the presence of cells expressing the antigen of interest.54. The isolated multispecific protein of claim 50 , wherein the multispecific protein is a heterodimer or a heterotrimer.55. The isolated multispecific protein of claim 50 , wherein the protein comprises at least a portion of an Fc domain claim 50 , is capable of binding to human neonatal Fc receptor (FcRn) and has decreased binding to a human Fcγ receptor compared to a full length wild type human IgG1 antibody.56. The isolated multispecific protein of claim 55 , wherein the Fc domain is interposed between the two antigen binding domains.57. The isolated multispecific protein of claim 50 , ...

Multispecific antigen binding proteins

Multimeric multispecific proteins formed from dimerization between CH1 and CK domains and that bind two target antigens are provided. The proteins have advantages in production and in the treatment of disease, notably cancer or infectious disease.

KIR3DL2 BINDING AGENTS

The present invention relates to methods for the treatment of cancer and inflammatory disease using antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind KIR3DL2. The invention also relates to antibodies, cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same. 1. A method for the treatment or prevention of disease in a patient in need thereof , the method comprising administering to said patient an effective amount of a composition comprising an antibody having (i) heavy chain CDRs 1 , 2 and 3 (HCDR1 , HCDR2 , HCDR3) , according to the Kabat definition , of the heavy chain variable region sequence of SEQ ID NO: 13 , and (ii) light chain CDRs 1 , 2 and 3 (LCDR1 , LCDR2 , LCDR3) , according to the Kabat definition , of the light chain variable region sequence of SEQ ID NO: 14.2. The method of claim 1 , wherein said disease is a CD4+ T cell lymphoma.3. The method of claim 2 , wherein said lymphoma is selected from Mycosis fungoides and Sezary Syndrome.4. A method for the treatment or prevention of spondylarthritis in a patient in need thereof claim 2 , the method comprising administering to said patient an effective amount of a composition comprising an antibody having (i) heavy chain CDRs 1 claim 2 , 2 and 3 (HCDR1 claim 2 , HCDR2 claim 2 , HCDR3) claim 2 , according to the Kabat definition claim 2 , of the heavy chain variable region sequence of SEQ ID NO: 13 claim 2 , and (ii) light chain CDRs 1 claim 2 , 2 and 3 (LCDR1 claim 2 , LCDR2 claim 2 , LCDR3) claim 2 , according to the Kabat definition claim 2 , of the light chain variable region sequence of SEQ ID NO: 14.5. A method for identifying a KIR3DL2-expressing cell in a subject claim 2 , the method comprising obtaining a biological sample from a subject comprising cells claim 2 , bringing said cells into contact with an antibody and assessing ...

KIR3DL2 BINDING AGENTS

The present invention relates to methods for the treatment of cancer and inflammatory disease using antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind KIR3DL2. The invention also relates to antibodies, cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same. 1. A monoclonal antibody that binds a KIR3DL2 polypeptide comprising an amino acid sequence of SEQ ID NO: 1 , wherein said antibody does not substantially bind to a KIR3DL1 polypeptide comprising an amino acid sequence of SEQ ID NO: 169 , and wherein said antibody is not internalized into KIR3DL2-expressing cells.2. The antibody of claim 1 , wherein the antibody causes an increase of the amount of KIR3DL2 polypeptides detectable at the cell surface of a KIR3DL2-expressing cell.3. The antibody of claim 1 , wherein said KIR3DL2-expressing cell is a CD4+ T cell lymphoma.4. The antibody of claim 3 , wherein said lymphoma is selected from Mycosis fungoides and Sezary Syndrome.5. The antibody of claim 1 , wherein said antibody has reduced binding to a mutant KIR3DL2 polypeptide selected from the group consisting of:a mutant KIR3DL2 polypeptide having amino acid mutations 160N and G62S,a mutant KIR3DL2 polypeptide having amino acid mutations R13W, A25T and Q27R,a mutant KIR3DL2 polypeptide having amino acid mutations Q56A and E57A, anda mutant KIR3DL2 polypeptide having amino acid mutations P14S, S15A and H23S,in each case, relative to binding between the antibody and a wild-type KIR3DL2 polypeptide of SEQ ID NO: 1.6. The antibody of claim 1 , wherein said antibody detectably reduces binding between the KIR3DL2 and a HLA class I-ligand of KIR3DL2.7. The antibody of claim 6 , wherein said antibody detectably reduces binding between the KIR3DL2 and a first HLA natural ligand of KIR3DL2 but does not detectably reduce binding between the KIR3DL2 and a ...

Cd73 blocking agents

Provided are antibodies that bind and inhibit CD73, are capable of increasing the proliferation of T cells in the presence of CD39-expressing B cells and ATP. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent cancer.

CD73 BLOCKADE

This disclosure relates to antibodies that bind an epitope present on CD73 expressed at the surface of cells, including tumor cells, and that inhibit the enzymatic (ecto-5′ nucleotidase) activity of the CD73 enzyme. Such agents can be used for the treatment of diseases such as cancers. 149-. (canceled)50. An isolated antibody that specifically binds a human CD73 polypeptide at the surface of a cell and that is capable of neutralizing the 5′-ectonucleotidase activity thereof , wherein the antibody does not substantially induce the internalization of the antibody-CD73 complex.51. The isolated antibody of claim 50 , wherein the antibody binds a CD73 polypeptide dimer in bivalent manner.52. The isolated antibody of claim 50 , wherein the antibody substantially lacks binding claim 50 , via an Fc domain claim 50 , to the human CD16 polypeptide (FcγIII receptor).53. The isolated antibody of claim 50 , wherein the antibody substantially lacks binding claim 50 , via an Fc domain claim 50 , to the human CD16A claim 50 , CD16B claim 50 , CD32A claim 50 , CD32B and CD64 polypeptides.54. The isolated antibody of claim 50 , wherein the antibody acts as an allosteric inhibitor of a human CD73 polypeptide expressed by a cell.55. The isolated antibody of claim 50 , wherein the antibody is capable of causing a decrease in the 5′-ectonucletidase activity of CD73 expressed by a cell by at least 80%.56. The method of claim 55 , wherein neutralization of the enzymatic activity of CD73 is determined by assessing neutralization of 5′ ectonucleotidase activity in MDA-MB-231 cells by quantifying hydrolysis of AMP to adenosine.57. The isolated antibody of claim 50 , wherein the antibody is capable of neutralizing the 5′-ectonucleotidase activity of a soluble human CD73 polypeptide.58. The isolated antibody of claim 50 , wherein the antibody is characterized by an ECfor neutralization of 5′-ectonucleotidase activity of cellular CD73 of no more than 1 μg/ml claim 50 , wherein neutralization of ...

ENZYMATIC CONJUGATION OF ANTIBODIES

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions. 1. A human or humanized antibody comprising an acceptor glutamine residue in its constant region or in a sequence fused to a variable or constant region , wherein said antibody is conjugated via said acceptor glutamine residue to one or more moieties-of-interest (Z) through a linker that comprises a NH—(C)— moiety ,wherein{'sub': 'n', '(C)is a substituted or unsubstituted alkyl or heteroalkyl chain, optionally wherein any carbon of the chain is substituted with an alkoxy, hydroxyl, alkylcarbonyloxy, alkyl-S—, thiol, alkyl-C(O)S—, amine, alkylamine, amide, or alkylamide, and n is an integer selected from among the range of 2 to 20; and'}Z is a reactive moiety or a moiety that improves the pharmacokinetic properties, a therapeutic moiety or a diagnostic moiety; andwherein the antibody comprises:a heavy chain framework region 1 (FR-H1) comprising a glutamine residue at Kabat position 1, 3, 5, 6, 10, 11, 12, 13 and/or 16;a heavy chain framework region 2 (FR-H2) comprising a glutamine residue at Kabat position 38, 39, 43 and/or 45; and/ora heavy chain framework region 3 (FR-H3) comprising a glutamine residue at Kabat position 66, 75, 77, 81 and/or 85.2. The antibody of claim 1 , wherein the antibody is a tetrameric antibody and said constant region is a heavy chain constant region.3. (canceled)4. (canceled)5. (canceled)6. The antibody of claim 1 , wherein the antibody comprises:a light chain framework region 1 (FR-L1) comprising a glutamine residue at Kabat position 6, 11, 17 and/or 18;a light chain framework region 2 (FR-L2) comprising a glutamine residue at Kabat position 37, 38, 42, 45 and/or 49;a light chain framework region 3 (FR-L3) comprising a glutamine residue at Kabat position 79.7. The antibody of ...

ANTI-MICA ANTIBODIES

The present invention provides antigen-binding proteins capable of binding to human MICA polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by MICA-expressing cells, particularly cancer.

HUMANIZED ANTIBODIES WITH INCREASED STABILITY

The present invention provides antibodies having improved stability. Included are antibodies that are capable of binding to KIR3DL2 polypeptides. The antibodies are suitable for the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome, and KIR3DL2-expressing autoimmune disorders. 2. The recombinant nucleic acid of claim 1 , wherein said heavy chain framework comprises human genes IGHV7-4-1 and/or IGHV1-c claim 1 , together with IGHJ6 claim 1 , and wherein said light chain framework comprises human genes IGKV4-1 and/or IGKV1-39 claim 1 , together with IGKJ4.3. The recombinant nucleic acid of claim 2 , wherein said heavy chain framework includes back mutation at any one or more residue 2 claim 2 , 38 claim 2 , 39 claim 2 , 40 claim 2 , 43 claim 2 , 48 claim 2 , 68 claim 2 , 72 claim 2 , 91 claim 2 , 108 claim 2 , and wherein said light chain framework includes back mutation at any one or more residue 3 claim 2 , 8 claim 2 , 9 claim 2 , 21 claim 2 , 43 claim 2 , 71 claim 2 , 78 claim 2 , 104.4. The recombinant nucleic acid of claim 1 , wherein said human heavy chain framework further includes the human genes IGHJ6 and said human light chain further includes the human genes IGKJ4.5. The recombinant nucleic acid of claim 1 , wherein said antibody or antibody fragment is a depleting antibody.6. The recombinant nucleic acid of claim 1 , wherein said antibody comprises a human heavy chain constant region comprising amino acid substitution(s) that increase binding to a human FcγIIIA (CD16) receptor.7. An expression vector comprising a recombinant nucleic acid of .8. A host cell comprising a recombinant nucleic acid of or an expression vector comprising said recombinant nucleic acid.9. The host cell of claim 8 , wherein said host cell is a CHO cell.10. A method of producing an antibody or an antibody fragment that binds to a KIR3DL2 polypeptide claim 8 , the method ...

Kir3dl2 binding agents

The present invention relates to a method of predicting or monitoring the sensitivity of a subject having a tumor to a chemotherapy, to a method of selecting an appropriate chemotherapeutic treatment of cancer, to a method of screening or identifying a compound suitable for improving the treatment of a cancer, and to corresponding kits. The method of predicting or monitoring the sensitivity of a subject having a tumor to a chemotherapy typically comprises a step a) of determining, in a biological sample from said subject, the presence, absence or expression level of at least one of a soluble B7H6 (sB7H6 or sB7-H6) and a soluble MIC (sMIC) and when the expression level is determined a step b) of comparing said expression level to a reference expression level, thereby assessing or monitoring whether the subject having a tumor is responsive or resistant to the chemotherapy.

HUMANIZED ANTIBODIES WITH INCREASED STABILITY

The present invention provides antibodies having improved stability. Included are antibodies that are capable of binding to KIR3DL2 polypeptides. The antibodies are suitable for the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome, and KIR3DL2-expressing autoimmune disorders. 1. An antibody or antibody fragment that binds a KIR3DL2 polypeptide , comprising(a) a heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) comprising a sequence of SEQ ID NO: 2 (HCDR1), SEQ ID NO: 3 (HCDR2) and SEQ ID NO: 4 (HCDR3), respectively, and a light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) comprising a sequence of SEQ ID NO: 5 (LCDR1), 6 (LCDR2) and 7 (LCDR3), respectively, or(b) a heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) comprising a sequence of SEQ ID NO: 18 (HCDR1), SEQ ID NO: 19 (HCDR2) and SEQ ID NO: 20 (HCDR3), respectively, and a light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) comprising a sequence of SEQ ID NO: 21 (LCDR1), 22 (LCDR2) or 23 (LCDR3), respectively,wherein said antibody or antibody fragment comprises human heavy and light chain variable region framework sequences, wherein the heavy chain framework comprises a glutamine at residue 39 and the light chain framework comprises a glutamine at residue 38 (Abnum numbering).2. The antibody or antibody fragment of claim 1 , wherein said antibody or antibody fragment detectably reduces or eliminates binding between the KIR3DL2 and a HLA natural ligand of KIR3DL2.3. The antibody or antibody fragment of claim 1 , wherein said antibody or antibody fragment is not internalized when bound to KIR3DL2-expressing cells.4. The antibody or antibody fragment of claim 1 , wherein said antibody or antibody fragment detectably reduces binding between the KIR3DL2 and HLA-B27.5. The antibody or antibody fragment of claim 1 , wherein said antibody or antibody fragment does not substantially bind to a KIR3DL1 polypeptide.6. ...

MICA BINDING AGENTS

The present invention relates to methods for the treatment of disorders mediated by MICA-expressing cells using antibodies, antibody fragments, and derivatives thereof that specifically bind MICA. The invention also relates to antibodies; cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; and pharmaceutical compositions comprising the same. 147-. (canceled)48. A monoclonal antibody comprising (i) a heavy chain comprising the CDR 1 (SEQ ID NO: 92) , 2 (SEQ ID NO: 95) and 3 (SEQ ID NO: 97) of the heavy chain variable region of SEQ ID NO: 90 and (ii) a light chain comprising the CDR 1 (SEQ ID NO: 98) , 2 (SEQ ID NO: 99) and 3 (SEQ ID NO: 100) of the light chain variable region of SEQ ID NO: 91.49. The antibody of claim 48 , wherein said antibody binds to a cell surface bound MICA polypeptide comprising an amino acid sequence of SEQ ID NO: 1 claim 48 , a cell surface bound MICA polypeptide comprising an amino acid sequence of SEQ ID NO: 2 claim 48 , and a cell surface bound MICA polypeptide comprising an amino acid sequence of SEQ ID NO: 4.50. The antibody of claim 48 , wherein said antibody has reduced binding to a mutant MICA polypeptide comprising a mutation at 1 claim 48 , 2 claim 48 , 3 claim 48 , 4 or more residues selected from the group consisting of E100 claim 48 , D101 claim 48 , N102 claim 48 , S103 claim 48 , T104 claim 48 , R105 claim 48 , N121 claim 48 , E123 claim 48 , T124 and E126 claim 48 , relative to binding between the antibody and a wild-type MICA polypeptide of SEQ ID NO: 1.51. A pharmaceutical composition comprising an antibody of claim 48 , and a pharmaceutically acceptable carrier.52. The antibody of claim 48 , wherein said antibody is coupled to a cytotoxic agent.53. The antibody of claim 48 , wherein said antibody is conjugated or coupled to a detectable agent.54. A recombinant nucleic acid encoding a heavy and/or light chain of the antibody of .55. A hybridoma or ...

Human anti-kir antibodies

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.

HETERODIMERIC ANTIGEN BINDING PROTEINS

Provided are heterodimeric proteins formed from dimerization between CH1 and CK domains and that bind a target antigen on a cell to be depleted. The proteins have advantages in production and in the treatment of disease, notably solid tumors or infectious disease. 135-. (canceled)36. A heterodimeric antigen binding protein having a single VH-VL domain pair , the protein comprising:a first polypeptide chain comprising an immunoglobulin variable domain fused to a CK domain in turn fused at its C-terminus to a human Fc domain, anda second polypeptide chain comprising an immunoglobulin variable domain fused to a CH1 domain in turn fused at its C-terminus to a human Fc domain,wherein one of the variable domains is a heavy chain variable domain and the other is a light chain variable domain, wherein the V-Cκ unit of the first chain is bound, by CH1-Cκ dimerization, to the V-CH1 unit of the second chain such that the variable domain of the first chain and the second chain form an antigen binding domain, and a dimeric Fc domain capable of binding to a human CD16 polypeptide is formed.37. The protein of claim 36 , wherein the variable domain of the first polypeptide chain is a VH domain and the variable domain of the second polypeptide chain is a VL domain.38. The protein of claim 36 , wherein the variable domain of the first polypeptide chain is a VL domain and the variable domain of the second polypeptide chain is a VH domain.39. The protein of claim 36 , wherein the first and second polypeptide chain are free of further immunoglobulin variable domains.40. The protein of claim 36 , wherein the protein comprises a single VH domain and a single VL domain.41. The protein of claim 36 , wherein the first and second polypeptide chains are free of any protein domains fused to the C-terminus of the Fc domain.42. The protein of claim 36 , wherein said antigen binding domain binds to an antigen of interest expressed at the surface of a cell to be depleted.43. The protein of claim 36 ...

MULTISPECIFIC ANTIGEN BINDING PROTEINS

Multimeric multispecific proteins that bind multiple target antigens are provided. The proteins have particular advantages when configured to bind a NK or T cell activating receptor and one or two cancer associated antigens, and can be used in the treatment of disease, notably cancer. 145-. (canceled)48. The multispecific protein of claim 46 , wherein said multispecific protein comprises a first claim 46 , second and third polypeptide chain claim 46 , comprising:a first (central) chain comprising a first CH1 or Cκ domain fused to an Fc region, and a variable domain fused to a second CH1 or Cκ domain (forming a V-(CH1/Cκ) unit);a second chain comprising a variable domain fused to a CH1 or Cκ domain, wherein the variable domain and CH1 or Cκ domain are complementary to the respective variable domain and CH1 or Cκ domain of the first chain, such that the second chain binds to the first chain by CH1-Cκ dimerization and VH-VK association, wherein the VH and VK together form a first antigen binding domain that binds a first antigen of interest; anda third chain comprising a CH1 or Cκ domain fused to an Fc region, wherein said CH1 or Cκ domain is complementary to the first CH1 or Cκ domain of the first chain, such that the third chain binds to the first chain by CH-Cκ dimerization and CH3-CH3 dimerization.49. The protein of claim 48 , wherein the first antigen of interest is an activating receptor expressed at the surface of an effector cell.50. The protein of claim 49 , wherein the activating receptor is NKp46.51. The protein of claim 49 , wherein the second and/or third antigen of interest a cancer claim 49 , viral or bacterial antigen.52. The multispecific protein of claim 46 , wherein said multispecific protein is a multispecific antigen binding protein comprising:(a) a first ABD that binds to a human NK cell activating receptor NKp46, NKp30 or NKG2D,(b) a second ABD that binds to a first pre-determined antigen of interest,(c) a third ABD that binds to a second, ...

SIGLEC-10 ANTIBODIES

This disclosure relates to agents that bind and neutralize the inhibitory activity of Siglec-10 in lymphocytes, notably by inhibiting the binding of Siglec-10 to its sialic acid ligands on target cells, notably tumor cells. Such agents can be used for the treatment of cancers. 143-. (canceled)44. A monoclonal antibody or antibody fragment that specifically binds to a human Siglec-10 polypeptide , wherein the antibody is capable of inhibiting the interactions between a Siglec-10 polypeptide and a human MDA-MB-231 and/or A375 cancer cell , wherein the antibody competes for binding to a human Siglec-10 polypeptide with an antibody selected from the group consisting of:(a) a monoclonal antibody comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 12 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 13;(b) a monoclonal antibody comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 20 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 21; and(c) a monoclonal antibody comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 28 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 29.45. The antibody or antibody fragment of claim 44 , wherein the antibody or antibody fragment lacks an Fe domain or comprises a human Fc domain that is modified to reduce binding between the Fc domain and an Fcγ receptor.46. The antibody or antibody fragment of claim 44 , wherein the antibody or antibody fragment does not substantially bind to any of the human Siglec-5 claim 44 , -7 or -11 polypeptides.47. The antibody or antibody fragment of claim 44 , which inhibits activation of the Siglec-10 by a sialic acid ligand of the Siglec-10 present on the surface of a tumor cell.48. The antibody or antibody fragment ...

Multispecific nk engager proteins

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease.

VARIABLE REGIONS FOR NKp46 BINDING PROTEINS

NKp-46-binding immunoglobulin variable regions, and proteins such as antibodies and multispecific proteins that comprise the variable regions are provided. The proteins can bind and specifically redirect NK cells to lyse a target cell of interest. The proteins have utility in the treatment of disease, notably cancer or infectious disease. 140-. (canceled)41. A protein or polypeptide comprising an antigen binding domain that binds a human NKp46 polypeptide , wherein the domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) combination selected from the group consisting of:(a) a VH comprising an amino acid sequence of SEQ ID NOS: 199 or 200 (NKp46-1 H1 or H3 variable domain), and a VL comprising an amino acid sequence of the amino acid sequence of SEQ ID NO: 201 (NKp46-1 L1 variable domain);(b) a VH comprising an amino acid sequence of SEQ ID NOS: 202, 203 or 204 (NKp46-2 H1, H2 or H3 variable domain), and a VL comprising an amino acid sequence of SEQ ID NO: 205 (NKp46-2 L1 variable domain);(c) a VH comprising an amino acid sequence of SEQ ID NOS: 206, 207 or 208 (NKp46-3 H1, H3 or H4 variable domain), and a VL comprising an amino acid sequence of SEQ ID NO: 209 (NKp46-3 L1 variable domain);(d) a VH comprising an amino acid sequence of SEQ ID NOS: 210, 211 or 212 (NKp46-4 H1 variable domain), and a VL comprising an amino acid sequence of SEQ ID NO: 213 (NKp46-4 L2 variable domain);(e) a VH comprising an amino acid sequence of SEQ ID NO: 215 (NKp46-9 H2 variable domain), and a VL comprising an amino acid sequence of SEQ ID NOS: 217 or 218 (NKp46-9 L1 or L2 variable domain); or(f) a VH comprising an amino acid sequence of SEQ ID NO: 216 (NKp46-9 H3 variable domain), and a VL comprising an amino acid sequence of SEQ ID NOS: 217 or 218 (NKp46-9 L1 or L2 variable domain).42. The composition of claim 41 , wherein the protein is an antibody.43. The composition of claim 41 , wherein the protein is a multispecific antigen binding protein.44 ...

MONOMERIC FC DOMAINS

Monomeric Fc-domains are provided, as well as multimeric and single chain proteins comprising the monomeric Fc-domains. The proteins have utility in the treatment of disease. Included, inter glia, are multi specific polypeptides. 136-. (canceled)37. A polypeptide chain capable of binding to human neonatal Fc receptor (FeRn) , comprising a first antigen binding domain (ABD) and , optionally , a second ABD (ABD) and a first and a second CH3 domain separated by a flexible linker , wherein the polypeptide chain has a domain arrangement selected from:(ABD)-linker-CH2-CH3-linker-CH3;{'sub': 1', '2, '(ABD)-linker-CH2-CH3-linker-CH3-linker-(ABD); and'}{'sub': 1', '2, '(ABD)-linker-CH1-CH2-CH3-linker-CH3-linker-(ABD).'}38. The polypeptide chain of claim 37 , wherein the first and second CH3 domain are separated by a linker of sufficient length to permit the first and second CH3 domain to associate with one another via non-covalent interactions.39. The polypeptide chain of claim 37 , wherein the amino acid sequence separating the first and second CH3 domains is a peptide linker having between 10 and 30 residues.40. The polypeptide chain of claim 37 , wherein the amino acid sequence separating the first and second CH3 domains is a peptide linker having the formula (GS)wherein x is 2 claim 37 , 3 claim 37 , 4 claim 37 , 5 or 6.41. The polypeptide chain of claim 37 , wherein the polypeptide substantially lacks binding via its Fc domain to one or more human Fey receptors selected from the group consisting of: CD16 claim 37 , CD32A claim 37 , CD32B and CD64.42. The polypeptide chain of claim 37 , wherein the CH2 domain comprises an amino acid substitution to decrease binding to a human Fey receptor.43. The polypeptide chain of claim 37 , wherein each ABD comprises the hypervariable regions claim 37 , optionally the heavy and light chain CDRs claim 37 , of an antibody.44. The polypeptide chain of claim 37 , wherein each ABD comprises an immunoglobulin heavy chain variable domain ...

Absorber rod assembly and absorber rod for nuclear reactor

An absorber cluster for a nuclear reactor includes at least a first absorber assembly ( 22 ) and a second absorber assembly ( 24 ). Each absorber assembly respectively comprises neutron absorbing elements ( 20 ). Absorber elements ( 20 ) of each of the first absorber assembly ( 22 ) and the second absorber assembly ( 24 ) are made from the same material or the same combination of materials selected from the group of neutron absorbing materials consisting of a first europium hafnate, a second europium hafnate, a first samarium hafnate, a second samarium hafnate, hafnium carbide and samarium hexaboride. The absorber elements ( 20 ) of the first absorber assembly ( 22 ) have a cross-sectional structure different to that of the absorber elements ( 20 ) of the second absorber assembly ( 24 ).

SIGLEC-9-NEUTRALIZING ANTIBODIES

This invention relates to agents that bind human Siglecs having inhibitory activity in immune cells, and that neutralize the inhibitory activity of such Siglec. Such agents can be used for the treatment of cancers or infectious disease. 153-. (canceled)54. An agent that binds a human Siglec-9 polypeptide and is capable of neutralizing the inhibitory activity of a Siglec-9 polypeptide expressed by a human NK cell , wherein the agent comprises an antigen binding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL) combination selected from the group consisting of:a VH comprising a CDR1, 2 and 3 of the VH domain having the amino acid sequence shown in SEQ ID NO: 15 and a FR1, 2 and 3 of a human IGHV1-69 (or optionally IGHV1-46) gene segment, and a VL comprising a CDR1, 2 and 3 of the VL domain having the amino acid sequence shown in SEQ ID NO: 16 and a FR1, 2 and 3 of a human IGKV-33 gene segment;a VH comprising a CDR1, 2 and 3 of the VH domain having the amino acid sequence shown in SEQ ID NO: 17 and a FR, 2 and 3 of a human IGHV1-69 (or optionally IGHV1-46) gene segment, and a VL comprising a CDR1, 2 and 3 of the VL domain having the amino acid sequence shown in SEQ ID NO: 18 and a FR1, 2 and 3 of a human IGKV1-33 gene segment;a VH comprising a CDR1, 2 and 3 of the VH domain having the amino acid sequence shown in SEQ ID NO: 19 and a FR1, 2 and 3 of a human IGHV7-4-1 gene segment, and a VL comprising a CDR1, 2 and 3 of the VL domain having the amino acid sequence shown in SEQ ID NO: 20 and a FRI, 2 and 3 of a human IGKV7-3 gene segment; a VH comprising a CDR1, 2 and 3 of the VH domain having the amino acid sequence shown in SEQ ID NO: 21 and a FR1, 2 and 3 of a human IGHV7-4-1 gene segment (optionally in combination with a IGHJ6 gene segment), and a VL comprising a CDR1, 2 and 3 of the VL domain having the amino acid sequence shown in SEQ ID NO: 22 and a FR1, 2 and 3 of a human IGKV1-39 gene segment;a VH comprising an amino acid ...

NKp46 BINDING AGENTS

The present invention provides antigen-binding proteins capable of binding to NKp46 polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by NKp46-expressing cells, particularly tumor cells.

Cd73 blockade

This disclosure relates to antibodies that bind an epitope present on CD73 expressed at the surface of cells, including tumor cells, and that inhibit the enzymatic (ecto-5′ nucleotidase) activity of the CD73 enzyme. Such agents can be used for the treatment of diseases such as cancers.

Multispecific proteins comprising an nkp46-binding site, a cancer antgienge binding site fused to a cytokine for nk cell engaging

Multi-specific proteins that bind to NKp46 and a cytokine receptor on NK cells, and optionally that further bind CD16A on NK cells, and that also bind to an antigen of interest (e.g. a cancer antigen) on a target cell (e.g. a cancer cell). The multi-specific proteins are capable of increasing NK cell cytotoxicity toward a target cell that expresses the antigen of interest (e.g., a cell that contributes to disease, a cancer cell).

Tlr3-retention agents

TLR3 BINDERS

Antibodies that bind human CD39 and inhibit ATPase activity of a soluble extracellular domain human CD39 polypeptide

The present invention relates to antigen-binding compounds that inhibit the enzymatic activity of soluble human CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer.

Tlr3 binding agents

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

Tlr3 binding agents

The invention provides anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies.

Tlr3 binding agents

The invention provides anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies.

TLR3 binding agents

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

TLR3 binding agents

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

Tlr3 binding agents

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

TLR3 binding agents

The invention provides anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies.

TLR3 binding agents

Disclosed herein are anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies.

Anti-kir3d antibodies

Humanized antibodies with increased stability.

La presente invención proporciona anticuerpos que tienen estabilidad mejorada. Se incluyen anticuerpos que son capaces de ligarse a polipéptidos KIR3DL2. Los anticuerpos son adecuados para el tratamiento de trastornos caracterizados por células que expresan KIR3DL2, particularmente células TCD4+, incluyendo afecciones malignas tales como Micosis Fungoide y Síndrome de Sezary, y trastornos autoinmunitarios que expresan KIR3DL2.

Anti-mica antibodies

The present invention provides antigen-binding proteins capable of binding to human MICA polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by MICA-expressing cells, particularly cancer.

Heterodimeric antigen binding proteins

Provided are heterodimeric proteins formed from dimerization between CH1 and CK domains and that bind a target antigens on a cell to be depleted. The proteins have advantages in production and in the treatment of disease, notably solid tumors or infectious disease.

Multispecific antigen binding proteins

Multimeric multispecific proteins that bind multiple target antigens are provided. The proteins have particular advantages when configured to bind a NK or T cell activating receptor and one or two cancer associated antigens, and can be used in the treatment of disease, notably cancer.

Pan-kir2dl nk-receptor antibodies and their use in diagnostik and therapy

Compositions and methods for detecting TLR3

The present invention relates to antibodies, antibody fragments, and derivatives thereof that specifically bind to TLR3 cell receptors present on the surface of cells. The invention also relates to hybridomas producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to detect TLR3 levels on the surface of cells, and the use of such antibodies and compositions for diagnostic or therapeutic purposes in subjects.

TLR3 binding agents

The invention provides anti-TLR3 antibodies as well as methods of making and using them. The antibodies are particularly adapted to the treatment of autoimmune or inflammatory diseases using anti-TLR3 antibodies.

Enzymatic conjugation of polypeptides

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.

Enzymatic conjugation of polypeptides

The present application relates to methods for the enzymatic functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.

Cd73 blockade

This disclosure relates to antibodies that bind an epitope present on CD73 expressed at the surface of cells, including tumor cells, and that inhibit the enzymatic (ecto-5' nucleotidase) activity of the CD73 enzyme. Such agents can be used for the treatment of diseases such as cancers.

Cd73 blocking agents

Provided are antibodies that bind and inhibit CD73, are capable of increasing the proliferation of T cells in the presence of CD39- expressing B cells and ATP. The disclosure also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent cancer.

Anti-cd39 antibodies

The present invention relates to antibodies that inhibit CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer.

NKp46 BINDING AGENTS

The present invention provides antigen-binding proteins capable of binding to NKp46 polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by NKp46-expressing cells, particularly tumor cells.

antibodies, agents, pharmaceutical composition, kit, nucleic acid, host cell, disease treatment or prevention methods, cell modulation, lymphocyte identification and patient selection and in vitro modulation and determination methods

Siglec-9 possui atividade inibidora em células imunes. A presente invenção refere-se a agentes que ligam Siglec-9 humano e neutralizam a sua atividade inibidora. Esses agentes podem ser utilizados para o tratamento de cânceres ou doenças infecciosas. Siglec-9 has inhibitory activity in immune cells. The present invention relates to agents that bind human Siglec-9 and neutralize its inhibitory activity. These agents can be used to treat cancers or infectious diseases.

Antibodies binding to receptors kir2dl1, -2, 3 but not kir2ds4 and their therapeutic use

Compositions and methods for regulating an immune response in a subject are de­scribed. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1­4F1. Described also are also fragments and derivatives of such antibodies, as well as phar­maceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.

Pan-KIR2DL NK-receptor antibodies and their use in diagnostik and therapy

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 14F1. Described also are fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.

Anti-kir3d antibodies

The present invention provides antigen-binding proteins capable of binding to KIR3D polypeptides. The antibodies have increased activity in the treatment of disorders characterized by KIR3DL2- expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome.

Anti-mica antibodies

The present invention provides antigen-binding proteins capable of binding to human MICA polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by MICA-expressing cells, particularly cancer.

Humanized antibodies with stability

The present invention provides stable antibodies. Included are antibodies that are capable of binding to KIR3DL2 polypeptides. The antibodies are suitable for the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome, and KIR3DL2-expressing autoimmune disorders.

NKp46 binding proteins

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease.

Mica binding agents

The present invention relates to methods for the treatment of disorders mediated by MICA-expressing cells using antibodies, antibody fragments, and derivatives thereof that specifically bind MICA. The invention also relates to antibodies; cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; and pharmaceutical compositions comprising the same.

Multispecific antigen binding proteins

Multimeric multispecific proteins formed from dimerization between CH1 and CK domains and that bind two target antigens are provided. The proteins have advantages in production and in the treatment of disease, notably cancer or infectious disease.

Multispecific NK engager protein

Multispecific proteins that bind and specifically redirect NK cells to lyse a target cell of interest are provided without non-specific activation of NK cells in absence of target cells. The proteins have utility in the treatment of disease, notably cancer or infectious disease.

Compositions and methods for regulating NK cell activity

The present invention relates to novel compositions and methods for regulating an immune response in a subject. More particularly, the invention relates to specific antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects. The invention also relates to fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly in therapy, to increase NK cell activity or cytotoxicity in subjects.

Methods and compositions for treating glioma

The present invention relates to a method for treating glioma in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of Junction-mediating and regulatory protein (JMY) inhibitor. Inventors have demonstrated that sublethal doses of irradiation promote the migration and invasiveness of human GSC lines using in vitro and in vivo assays. They have shown that radiation-induced migration occurs through the stabilization and nuclear accumulation of the transcription factor hypoxia-inducible factor 1 alpha (HIT la), which drives the transcription of Junction-mediating and regulatory protein (JMY). Interestingly, sub-lethal irradiation did not trigger the HIF1 a/JMY pathway or consistently enhance motility in differentiated glioma cells, suggesting that the pathway is specifically linked to cancer cells with stem-like properties. These data could thus open the way to the development of new therapeutic strategies targeting JMY to improve the efficacy of radiotherapy and prevent glioma recurrence associated with GSC migration.

Enzymatic conjugation of polypeptides

The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.