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JP-7857045-B2 - Therapeutic antibody that binds to the serine protease domain of MASP-2 and its use

JP7857045B2JP 7857045 B2JP7857045 B2JP 7857045B2JP-7857045-B2

Inventors

  • ダドラー トーマス
  • ノラート フォン スペヒト ペーター クルト
  • 矢吹 宗久
  • ヤシーン サダム

Assignees

  • オメロス コーポレーション

Dates

Publication Date
20260512
Application Date
20221207
Priority Date
20211210

Claims (20)

  1. An isolated monoclonal antibody or its antigen-binding fragment that specifically binds to an epitope located within the serine protease domain of human MASP-2, wherein the epitope is an amino acid 496 DIRMGTLKRLSPHYTQAW 513 (SEQ ID NO:6) Located within, the antibody or its antigen-binding fragment inhibits lectin pathway complement activation and comprises (a) a heavy chain variable region comprising HC-CDR1 containing SEQ ID NO:14 (NYWMH), SEQ ID NO:56 (NYHMH), or SEQ ID NO:57 (NHHMH), HC-CDR2 containing SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD), and HC-CDR3 containing SEQ ID NO:18 (GDITTTLRYFDV), as well as a light chain variable region comprising LC-CDR1 containing SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 containing SEQ ID NO:34 (DTSNLAS), and LC-CDR3 containing SEQ ID NO:36 (QQWSSYPLT); or (b) HC-CDR1, SEQ ID NO:25 (SYWMH) Heavy chain variable regions including HC-CDR2, indicated as NO:27 (NINPSNGGTNCNEKFKN), and HC-CDR3, indicated as SEQ ID NO:29 (WAYDAMDY), as well as LC-CDR1, indicated as SEQ ID NO:41 (RASESVDSYGNSFMH), LC-CDR2, indicated as SEQ ID NO:43 (FASNLES), and LC-CDR3, indicated as SEQ ID NO:45 (QQSNEDPLT). The isolated monoclonal antibody or its antigen-binding fragment, comprising the above.
  2. HC-CDR1 contains SEQ ID NO:14 (NYWMH), and HC-CDR2 contains SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  3. HC-CDR1 contains SEQ ID NO:56 (NYHMH), and HC-CDR2 contains SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  4. HC-CDR1 contains SEQ ID NO:57 (NHHMH), and HC-CDR2 contains SEQ ID NO:16 (DIDPSDSETHYIEKFKD) or SEQ ID NO:53 (DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  5. HC-CDR1 contains SEQ ID NO:14 (NYWM), and HC-CDR2 contains SEQ ID NO:16 (DIDPSDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  6. HC-CDR1 contains SEQ ID NO:14 (NYWM), and HC-CDR2 contains SEQ ID NO:53 (DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  7. HC-CDR1 contains SEQ ID NO:56 (NYHMH), and HC-CDR2 contains SEQ ID NO:53 (DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  8. HC-CDR1 contains SEQ ID NO:57 (NHHMH), and HC-CDR2 contains SEQ ID NO:53 ((DIDASDSETHYIEKFKD) Including HC-CDR3 SEQ ID NO:18 (GDITTTLRYFDV) An isolated antibody or antigen-binding fragment according to claim 1, comprising, wherein LC-CDR1 comprises SEQ ID NO:32 (SASSSVRYMY), LC-CDR2 comprises SEQ ID NO:34 (DTSNLAS), and LC-CDR3 comprises SEQ ID NO:36 (QQWSSYPLT).
  9. An isolated antibody or antigen-binding fragment according to claim 1, comprising a heavy chain containing 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 containing SEQ ID NO:10 or SEQ ID NO:47.
  10. An isolated antibody or antigen-binding fragment according to claim 1, comprising a heavy chain containing SEQ ID NO:9 and a light chain containing SEQ ID NO:12.
  11. An isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 10 , selected from the group consisting of a humanized antibody, a chimeric antibody, a mouse antibody, and any of the aforementioned antigen-binding fragments.
  12. An isolated antibody or its antigen-binding fragment according to any one of claims 1 to 10, selected from the group consisting of a single-chain antibody, ScFv, Fab fragment, Fab' fragment, F(ab')2 fragment, a monovalent antibody lacking a hinge region, and a complete antibody.
  13. An isolated antibody or its antigen-binding fragment according to any one of claims 1 to 10 , which binds to the serine protease domain of human MASP-2 with an affinity of less than 20 nM.
  14. An isolated antibody or its antigen-binding fragment according to any one of claims 1 to 10 , which inhibits the lectin pathway in the blood of a mammal.
  15. An isolated antibody or its antigen-binding fragment according to any one of claims 1 to 10 , which does not inhibit the classical pathway in the blood of a mammal.
  16. A composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.
  17. Isolated polynucleotides encoding the heavy chain variable region and the light chain variable region of an antibody or antigen-binding fragment according to any one of claims 1 to 10 .
  18. A cloning vector or expression vector comprising isolated polynucleotides encoding the heavy chain variable region and the light chain variable region of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 10 .
  19. A host cell comprising one or more cloning vectors or expression vectors according to claim 18 .
  20. A process for producing an antibody or antigen-binding fragment according to any one of claims 1 to 10 , comprising the steps of culturing the host cells according to claim 19 and isolating the antibody or its antigen-binding fragment.

Description

Field of Invention The present invention relates to an antibody that binds to the serine protease domain of MASP-2, as well as related compositions and methods. Statement Regarding Sequence Listing The sequence listing relating to this application is provided in XML format instead of hard copy and is incorporated herein by reference. The XML file containing the sequence listing is named MP10329PCT.XML. This XML file is 89KB in size, was created on November 21, 2022, and submitted via the Patent Center along with the filing of this specification. Background The complement system supports innate host defense against pathogens and other acute invaders (MK Liszewski and JPA Atkinson, 1993, in "Fundamental Immunology" (3rd edition, Raven Press, Ltd., New York) edited by W. Paul), and also plays a role in immune surveillance against cancer (P. Macor, et al., Front. Immunol., 9:2203, 2018). The complement system involves more than 30 liquid-phase and membrane-bound proteins (S. Meyer, et al., mAbs, 6:1133, 2014). The majority of these are regulatory proteins that coordinate a cascade of highly controlled activation events. The complement system responds rapidly to molecular stress signals via a cascade of sequential proteolytic reactions initiated by the binding of pattern recognition receptors (PRRs) to unique structures on damaged cells, biomaterial surfaces, or invading microorganisms (Reis et al., Nat. Rev. Immunol., 18:5, 2018). Activation of the complement cascade induces diverse immune effector functions, including cell lysis, phagocytosis, chemotaxis, and immune activation (S. Meyer, et al., 2014). Furthermore, the complement system also acts as a bridge between innate immune responses and subsequent adaptive immune activation. In addition to its anti-infective properties, the complement system is involved in the clearance of immune complexes and apoptotic cells, tissue regeneration, hematopoietic progenitor cell recruitment, and angiogenesis (TMPierpont et al., Front. Oncol., 8:163, 2018). The complement system can be activated by three distinct pathways: the classical pathway, the alternative pathway, and the lectin pathway. See Figure 1. The classical pathway (CP) is primarily initiated by antibody-antigen complexes. Antibodies of subclasses IgM and IgG bind to antigens on the surface of pathogens or target cells, recruiting the C1 complex. The C1 complex consists of a multimolecular recognition subcomponent C1q (composed of six heterotrimers: C1qA, B, and C chains) and C1q-associated serine proteases, namely C1r and C1s. When C1q binds to the Fc region of either an antigen-bound IgM or at least two IgG antibodies bound to their respective antigens, the serine protease C1r is self-activated into its enzymatically active form, and subsequently cleaves and activates its substrate C1s. Once activated, C1s cleaves C4 into its fragments C4a and C4b. C2 binds to C4b to form the C4bC2 complex. In the second cleavage stage, C1s cleave C2 within the C4bC2 complex, releasing C2b to form the complement C3-converting enzyme complex C4bC2a, also known as C3-converting enzyme. This complex then cleaves the abundant plasma complement component C3 into C3a and C3b. The lectin pathway is triggered by the binding of pattern recognition molecules, such as mannose-binding lectins (MBLs), ficolin, or collectin-11 and collectin-10, to pathogen-associated molecular patterns (PAMPs) or apoptotic or modified host cells. These recognition molecules form complexes with MBL-associated serine proteases MASP-1 and MASP-2, activating them upon binding to their respective cognitive ligands. Activated MASP-2 cleaves C2 bound to C4 and C4b to form C3 convertase (C4bC2a). The alternative pathway is initiated by the spontaneous hydrolysis of C3 to C3(H2O) ("tickover"), where C3(H2O) binds to factor B (fB). The resulting C3(H2O)fB complex requires the enzymatic activity of another highly specific serine protease called complement factor D to convert it to an enzymatically active C3 convertase. The availability of enzymatically active factor D is considered a limiting factor in the alternative pathway amplification loop; for factor D to become available, the action of another enzyme, MASP-3, is required for pro-Factor D (proCFD) to be converted to its active form, mature factor D (matCFD, or simply CFD) (Dobo et al., 2016). CFD activates the fB bound to C3(H2O) to Ba and Bb. Bb is also a serine protease and is involved in the formation of the alternative pathway C3 convertase C3(H2O)Bb, which cleaves C3 into C3a and C3b. Due to this mechanism, the alternative pathway is constitutively low in activity. Newly generated C3b, formed by C3(H2O)Bb or by the lectin and classical C3 convertases C4bC2a, binds to target surfaces such as bacterial cells and sequesters fB, forming the C3bfB complex. This complex is then cleaved by CFD to create the alternative pathway C3 convertase complex C3bBb, forming an AP amplification loop. This convertase can be