US2023265215A1PendingUtilityA1

Therapeutic antibodies that bind to the serine protease domain of masp-2 and uses thereof

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Assignee: OMEROS CORPPriority: Dec 10, 2021Filed: Dec 7, 2022Published: Aug 24, 2023
Est. expiryDec 10, 2041(~15.4 yrs left)· nominal 20-yr term from priority
Inventors:Thomas DudlerPeter Kurt Nollert Von SpechtMunehisa YabukiSadam Yaseen
A61K 2039/505C07K 2317/92C07K 2317/34C07K 2317/33C07K 2317/76C07K 2317/52C07K 2317/565C07K 2317/24A61P 3/00C07K 2317/55C07K 2317/90C07K 16/40
66
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Claims

Abstract

Isolated monoclonal antibodies and antigen-binding fragments thereof are provided that specifically bind to an epitope within the serine protease domain of human MASP-2. In some embodiments, the antibodies or antigen-binding fragments thereof inhibit lectin pathway complement activation. Also provided are polynucleotides encoding the disclosed monoclonal antibodies or antigen-binding fragments thereof, and cloning vectors or expression cassettes comprising such polynucleotides. Further provided are methods of inhibiting lectin pathway complement activation and methods of treating lectin pathway diseases and disorders.

Claims

exact text as granted — not AI-modified
1 . An isolated monoclonal antibody or antigen-binding fragment thereof that specifically binds to an epitope located within the serine protease domain of human MASP-2, wherein said epitope is located within amino acids  496 DIRMGTLKRLSPHYTQAW 513  (SEQ ID NO:6), wherein the antibody or antigen-binding fragment thereof inhibits lectin pathway complement activation. 
     
     
         2 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment competes with C4 binding to MASP-2. 
     
     
         3 . The isolated antibody, or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof forms a hydrogen bond with least one of human MASP-2 Lys 503 and/or His 508. 
     
     
         4 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof forms a hydrogen bond with human MASP-2 His 508. 
     
     
         5 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof forms a van-der-Waals contact with one or more of the following human MASP-2 amino acids: Asp 496, Lys 503, Ser 506, Pro 507, His 508 and Trp 513. 
     
     
         6 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region comprising a HC-CDR1 having the sequence NXXMH, wherein X at position 2 is H or Y and wherein X at position 3 is H or W; a HC-CDR2 set forth as SEQ ID NO:63 (DIDXSDSEXXYXXKFKD) wherein X at position 4 is P or A; and wherein X at position 9 is T or I, and wherein X at position 10 is H or Y, and wherein X at position 12 is I or N; and wherein X at position 13 is E or Q; and a HC-CDR3 set forth as SEQ ID NO:18 (GDITTTLRYFDV); and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:64 (SASSSVXYMY) wherein X at position 7 is R or S; a LC-CDR2 set forth as SEQ ID NO:34 (DTSNLAS) and a LC-CDR3 set forth as SEQ ID NO:36 (QQWSSYPLT); or   (b) a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:25 (SYWMH), a HC-CDR2 set forth as SEQ ID NO:27 (NINPSNGGTNCNEKFKN) and a HC-CDR3 set forth as SEQ ID NO:29 (WAYDAMDY) and a LC-CDR1 set forth as SEQ ID NO:41 (RASESVDSYGNSFMH), a LC-CDR2 set forth as SEQ ID NO:43 (FASNLES) and a LC-CDR3 set forth as SEQ ID NO:45 (QQSNEDPLT).   
     
     
         7 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWMH). 
     
     
         8 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:56 (NYHMH). 
     
     
         9 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO: 57 (NHHMH). 
     
     
         10 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD). 
     
     
         11 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR2 comprises SEQ ID NO:22 (DIDPSDSEIYYNQKFKD). 
     
     
         12 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR2 comprises SEQ ID NO:53 (DIDASDSETHYIEKFKD). 
     
     
         13 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY). 
     
     
         14 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the LC-CDR1 comprises SEQ ID NO:39 (SASSSVSYMY). 
     
     
         15 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWMH); SEQ ID NO:56 (NYHMH) or SEQ ID NO:57 (NHHIVIH), the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD), the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         16 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWMH); the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         17 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:56 (NYHMH); the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         18 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:57 (NEIHMH); the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         19 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWM); the HC-CDR2 comprises SEQ ID NO:16 (DIDPSDSETHYIEKFKD), and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         20 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWM); the HC-CDR2 comprises SEQ ID NO:53 (DIDASDSETHYIEKFKD), and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         21 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:56 (NYHMH); the HC-CDR2 comprises SEQ ID NO:53 (DIDASDSETHYIEKFKD), and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         22 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:57 (NHHMH); the HC-CDR2 comprises SEQ ID NO:53 ((DIDASDSETHYIEKFKD) and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         23 . The isolated antibody or antigen-binding fragment thereof of claim  6 (a), wherein the HC-CDR1 comprises SEQ ID NO:14 (NYWM); the HC-CDR2 comprises SEQ ID NO:22 (DIDPSDSEIYYNQKFKD) and the HC-CDR3 comprises SEQ ID NO:18 (GDITTTLRYFDV) and the LC-CDR1 comprises SEQ ID NO:39 (SASSSVSYMY) the LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS) and the LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT). 
     
     
         24 . The isolated antibody or antigen-binding fragment of claim  6 (a), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a heavy chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:7, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:49 or SEQ ID NO:50 and a light chain comprising a light chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:10 or SEQ ID NO:47. 
     
     
         25 . The isolated antibody or antigen-binding fragment of claim  6 (a), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a heavy chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:49 or SEQ ID NO:50 and a light chain comprising a light chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:47. 
     
     
         26 . The isolated antibody or antigen-binding fragment of claim  6 (a), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a heavy chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:8 and a light chain comprising a light chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:11. 
     
     
         27 . The isolated antibody or antigen-binding fragment of claim  6 (b), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a heavy chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:9 and a light chain comprising a light chain variable region at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:12. 
     
     
         28 . The isolated antibody or antigen binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, and an antigen-binding fragment of any of the foregoing. 
     
     
         29 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof is selected from the group consisting of a single chain antibody, an ScFv, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, a univalent antibody lacking a hinge region and a whole antibody. 
     
     
         30 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , further comprising an immunoglobulin constant region. 
     
     
         31 . The isolated antibody or antigen binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is humanized. 
     
     
         32 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgG immunoglobulin selected from the group consisting of IgG1, IgG2, and IgG4. 
     
     
         33 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises one or more mutations in the Fc region. 
     
     
         34 . The isolated antibody or antigen-binding fragment thereof of  claim 33 , wherein the Fc region comprises an S228P amino acid substitution. 
     
     
         35 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the serine protease domain of human MASP-2 with an affinity of less than 20 nM. 
     
     
         36 . The isolated antibody or antigen-binding fragment thereof of  claim 35 , wherein the antibody or antigen-binding fragment thereof binds to the serine protease domain of human MASP-2 with an affinity of less than 10 nM. 
     
     
         37 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof inhibits the lectin pathway in mammalian blood. 
     
     
         38 . The isolated antibody or antigen-binding fragment thereof of  claim 37 , wherein lectin pathway inhibition comprises a decrease in C3b deposition under lectin pathway-specific assay conditions. 
     
     
         39 . The isolated antibody or antigen-binding fragment thereof of  claim 37 , wherein lectin pathway inhibition comprises a decrease in C4 deposition under lectin pathway-specific assay conditions. 
     
     
         40 . The isolated antibody or antigen-binding fragment thereof of  claim 37 , wherein lectin pathway inhibition comprises a decrease in MAC deposition under lectin pathway-specific assay conditions. 
     
     
         41 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof does not inhibit the classical pathway in mammalian blood. 
     
     
         42 . A composition comprising the antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         43 . The composition of  claim 42 , wherein said composition is formulated for subcutaneous administration. 
     
     
         44 . An isolated polynucleotide encoding the heavy and light chain variable regions of an antibody or antigen-binding fragment thereof of  claim 1 , or a combination of an isolated polynucleotide encoding the heavy chain variable region of an antibody or antigen-binding fragment thereof of  claim 1  and an isolated polynucleotide encoding the light chain variable region of an antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         45 . (canceled) 
     
     
         46 . A cloning vector or expression vector comprising the polynucleotide or combination of polynucleotides of  claim 44 . 
     
     
         47 . A combination of a cloning vector or expression vector comprising an isolated polynucleotide encoding the heavy chain variable region of an antibody or antigen-binding fragment thereof of  claim 1  and a cloning vector or expression vector comprising an isolated polynucleotide encoding the light chain variable region of an antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         48 . A host cell comprising one or more cloning vectors or expression vectors of  claim 46  or  claim 47 . 
     
     
         49 . A process for producing an antibody or antigen-binding fragment thereof comprising culturing the host cell of  claim 48  and isolating the antibody or antigen-binding fragment thereof. 
     
     
         50 . A method of inhibiting lectin pathway complement activation in a mammal, the method comprising administering to a mammalian subject in need thereof an amount of a composition according to  claim 42  comprising a high affinity MASP-2 inhibitory antibody or antigen-binding fragment thereof sufficient to inhibit lectin pathway complement activation in the mammal. 
     
     
         51 . The method of  claim 50 , wherein the subject in need thereof is suffering from, or at risk for developing a lectin-pathway disease or disorder selected from the group consisting of: a thrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno-occlusive disease and diffuse alveolar hemorrhage.

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