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US 2015/0353911A1 Salas Et Al US 20150353911A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0353911A1 Salas et al. (43) Pub. Date: Dec. 10, 2015 (54) CHMERC CLOTTING FACTORS on Feb. 1, 2013, provisional application No. 61/801, 603, filed on Mar. 15, 2013, provisional application (71) Applicant: Biogen Idec MA Inc., Cambridge, MA No. 61/829,775, filed on May 31, 2013. (US) Publication Classification (72) Inventors: Joe Salas, Wayland, MA (US); Elena Kistanova, Brookline, MA (US); Vu (51) Int. Cl. Phong Hong, Cambridge, MA (US); CI2N 9/64 (2006.01) Adam R. Mezo, Carmel, IN (US); A638/48 (2006.01) Robert T. Peters, West Roxbury, MA A647/48 (2006.01) (US) (52) U.S. Cl. CPC ........ CI2N 9/6432 (2013.01); A61K 47/48238 (73) Assignee: Biogen Idec MA Inc., Cambridge, MA (2013.01); A61 K38/4846 (2013.01): CI2N (US) 9/6437 (2013.01); C12Y 304/21021 (2013.01); CI2Y 304/21006 (2013.01) Appl. No.: 14/406,160 (21) (57) ABSTRACT (22) PCT Fled: Jun. 7, 2013 The invention provides chimeric clotting factors comprising an activatable clotting factor and an enhancer moiety. The (86) PCT NO.: PCT/US13A44842 activatable clotting factor allows the chimeric clotting factor S371 (c)(1), to be activated at the site of coagulation. The enhancer moiety (2) Date: Dec. 5, 2014 can additionally improve procoagulation activities of the chi meric clotting factors. The chimeric clotting factors can fur ther be improved by fusion to a half-life extender, which Related U.S. Application Data improves a pharmacokinetics property of the chimeric clot (60) Provisional application No. 61/657,685, filed on Jun. ting factor. The invention also includes methods of making 8, 2012, provisional application No. 61/759,817, filed and methods of using these chimeric clotting factors. Patent Application Publication Dec. 10, 2015 Sheet 1 of 25 US 2015/0353911A1 *************&~~~~~~~~ epeoseouo?e|nôeoO N | Patent Application Publication Dec. 10, 2015 Sheet 2 of 25 US 2015/0353911A1 e S. s: s s gs & e seas *---- s * s s s&s S. s & s sos S. six s s s s se Patent Application Publication Dec. 10, 2015 Sheet 3 of 25 US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 4 of 25 US 2015/0353911A1 33$ ass s Patent Application Publication Dec. 10, 2015 Sheet 5 of 25 US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 6 of 25 US 2015/0353911A1 •091 OZI #:08 09 is:{38 . , is Patent Application Publication Dec. 10, 2015 Sheet 7 of 25 US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 8 of 25 US 2015/0353911A1 sissis Patent Application Publication US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 10 of 25 US 2015/0353911A1 it is 3.8 Patent Application Publication Dec. 10, 2015 Sheet 11 of 25 US 2015/0353911A1 »001 Patent Application Publication Dec. 10, 2015 Sheet 12 of 25 US 2015/0353911A1 0009 Patent Application Publication Dec. 10, 2015 Sheet 13 of 25 US 2015/0353911A1 Hoosi §§§ St.03S3 Patent Application Publication Dec. 10, 2015 Sheet 14 of 25 US 2015/0353911A1 EN cy is f s sess water s s ocee Patent Application Publication Dec. 10, 2015 Sheet 15 of 25 US 2015/0353911A1 s - t -S -8 s : (Nui) uo eu aduloo Patent Application Publication Dec. 10, 2015 Sheet 16 of 25 US 2015/0353911A1 Patent Application Publication US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 18 of 25 US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 19 of 25 US 2015/0353911A1 007 punoduuoo ??i ************************************** 00900Z00|| ?un?onu?s?punoduuoo 00}, 06 09 0/ 09 09 07 09 0Z i; 38 Patent Application Publication Dec. 10, 2015 Sheet 20 of 25 US 2015/0353911A1 $ s aosomeoawaeLae| s O &|001 sea Patent Application Publication Dec. 10, 2015 Sheet 21 of 25 US 2015/0353911A1 Patent Application Publication Dec. 10, 2015 Sheet 22 of 25 US 2015/0353911A1 |nvwoaouxvivo1-ºººo^xooaººº1 |NivwogouxiwayoHºoaxa-Huleuo?ubn Patent Application Publication Dec. 10, 2015 Sheet 23 of 25 US 2015/0353911A1 uo?ssaadx2984-HA! ***~~~~~~~~~~~~~~*~~~~*~*~~~~--~~~~~~~~~ 2x(RKR) - Cys CC Patent Application Publication Dec. 10, 2015 Sheet 24 of 25 US 2015/0353911A1 OWITS sesses Patent Application Publication Dec. 10, 2015 Sheet 25 of 25 US 2015/0353911A1 981-11A4-vu,gouo?ea?owuqquouqu.1334eÅessºapuaºouuod?Oe??A3 US 2015/03539 11 A1 Dec. 10, 2015 CHMERC CLOTTING FACTORS kinetic properties, have reduced clearance rates, have improved manufacturability, have reduced thrombogenicity, BACKGROUND OF THE INVENTION or have enhanced activity, or more than one of these charac 0001 Initiation of the extrinsic clotting pathway is medi teristics. ated by the formation of a complex between tissue factor, which is exposed as a result of injury to a vessel wall, and SUMMARY OF THE INVENTION Factor VIIa. This complex then converts Factors IX and X to 0006. The present invention provides a chimeric protein their active forms (Factor IXa and Xa). Factor Xa converts comprising (i) an activatable clotting factor (Ac), (ii) an limited amounts of prothrombin to thrombin on the tissue enhancer moiety (Em), and (iii) an optionally linker moiety factor-bearing cell. This resulting thrombin is then able to (L or L1) between the activatable clotting factor and the diffuse away from the tissue-factor bearing cell and activate enhancer moiety. The activatable clotting factor and the platelets, and Factors V and VIII, making Factors Va and enhancer moiety can be linked or associated with each other, VIIIa. Dung the propagation phase of coagulation, Factor Xa but may not be chemically crosslinked. The chimeric: protein is generated by Factor IXa (in complex with factor VIIIa) on can be represented by formula Ac-L-Em or Em-L-Ac, the surface of activated platelets. Factor Xa, in complex with wherein Ac comprises the activatable clotting factor; L com the cofactor Factor Va, activates prothrombin into thrombin, prises the optional linker moiety; and Em comprises the generating a thrombin burst. The cascade culminates in the enhancer moiety. conversion of fibrinogen to fibrin by thrombin, which results 0007. In one embodiment, the activatable clotting factor in the formation of a fibrin clot. Factor VII and tissue factor comprises a clotting factor Zymogen comprising a heavy are key players in the initiation of blood coagulation. chain (HC) and a light chain (LC) and a protease-cleavage site 0002 Factor VII is a plasma glycoprotein that circulates in inserted between the HC and the LC. The clotting factor blood as a single-chain Zymogen, which is catalytically inac Zymogen can be a FVII protein (e.g., FVII, functional frag tive. Although single-chain Factor VII may be converted to ments, derivatives, or variants thereof) or a FX protein (FX, two-chain Factor VIIa by a variety of factors in vitro, Factor functional fragments, derivatives, or variants thereof). Xa is an important physiological activator of Factor VII. The Embodiments of the present invention include a chimeric conversion of Zymogen Factor VII into the activated two protein further comprising a self-immolative moiety (e.g., chain molecule occurs by cleavage of the peptide bond link PABC) inserted between the protease-cleavage site and the ing the Arginine residue atamino acid position 152 and the Ile HC. The protease-cleavage site inserted between the HC and residue at amino acid position 153. In the presence of tissue the LC can be cleaved by a protease selected from thrombin factor, phospholipids and calcium ions, the two-chain Factor (factor IIa), factor XIa, factor XIIa, kallikrein, factor VIIa, VIIa activates Factor X or Factor IX. Factor VIIa is thought to factor IXa, factor Xa, or any combinations thereof, wherein be the physiologic initiator of the clotting cascade by acting at the protease-cleavage site is not naturally occurring in the the Surface of a TF-bearing cell and generating the initial clotting factor Zymogen. amount of thrombin that then diffuses to platelets to activate 0008. In another embodiment, the enhancer moiety com and prime them for the propagation phase of thrombingen prises a clotting cofactor, a procoagulant peptide, or an anti eration. Therapeutically, recombinant FVIIa acts by activat gen-binding moiety. Examples of the clotting cofactors ing Factor X on the Surface of activated platelets, bypassing include, but are not limited to, Tissue Factor, a fragment (e.g., the need for FIXa or FVIIIa to generate a thrombin burst soluble tissue factor), a variant, or a derivative thereofor FVa, during the propagation phase of coagulation. Since FVIIa has a fragment, a variant, or derivative thereof. Non-limiting relatively low affinity for platelets, recombinant FVIIa is examples of the antigen binding moiety include an antibody dosed at Supra-physiological levels. This process is thought to or an antigen-binding fragment thereof which is capable of be tissue factor-independent. binding to the FVII protein or the FX protein and enhances the 0003) Factor X is also synthesized as a single-chain activity of FVII or FX, respectively. polypeptide containing the light and heavy chains connected 0009. In some embodiments, the chimeric protein further by an Arg-Lys-Arg tripeptide. The single-chain molecule is comprises a heterologous moiety (Het) (e.g., a half-life then converted to the light and heavy chains by cleavage of extender) linked to the activatable clotting factor, the linker two (or more) internal peptide bonds. In plasma, these two moiety, or the enhancer moiety. Non-limiting examples of the chains are linked together by a disulfide bond, forming Factor half-life extender include an immunoglobulin constant region X. Activated Factor X, Factor Xa, participates in the final or a portion thereof (e.g., an Fc moiety or an FcRn binding common pathway whereby prothrombin is converted to partner), albumin, transferrin, an albumin binding moiety, a thrombin, which in turn converts fibrinogen to fibrin.
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