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Protective Antigen Complexes with Increased Stability and Uses Thereof

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Protective Antigen Complexes with Increased Stability and Uses Thereof I 1111111111111111 1111111111 1111111111 1111111111 11111 11111 lll111111111111111 US010188716B2 c12) United States Patent (IO) Patent No.: US 10,188,716 B2 Bann et al. (45) Date of Patent: Jan.29,2019 (54) PROTECTIVE ANTIGEN COMPLEXES Williams et al (Protein Science. 2009. 18: 2277-2286).* WITH INCREASED STABILITY AND USES Chadegani, Fatemeh, et al., F Nuclear Magnetic Resonance and THEREOF Crystallographic Studies of 5-Fluorotryptophan-Labeled Anthrax Protective Antigen and Effects of the Receptor on Stability, Copyright (71) Applicants:Wichita State University, Wichita, KS 2014 American Chemical Society, Open Access on Jan. 3, 2015, (US); Case Western Reserve Biochemistry 2014, 53, 690-701 (12 pages). University, Cleveland, OH (US) Wimalasena, D. Shyamili et al, Evidence That Histidine Protonation of Receptor-Bound Anthrax Protective Antigen is a Trigger for Pore (72) Inventors: James G. Bann, Wichita, KS (US); Formation, Biochemistry, 2010, 49 (33), pp. 6973-6983, DOI: Masaru Miyagi, Cleveland, OH (US) 10.1021/bil00647z, Publication Date (Web): Jul. 22, 2010, Copyright © 2010 American Chemical Society (11 pages). (73) Assignees: Wichita State University, Wichita, KS Rajapaksha, Maheshinie et al., pH effects on binding between the (US); Case Western Reserve anthrax protective antigen and the host cellular receptor CMG2, University, Cleveland, OH (US) Protein Science: A Publication ofthe Protein Society.2012;21( 10): 1467- 1480. doi: 10.1002/pro.2136 (14 pages). ( *) Notice: Subject to any disclaimer, the term ofthis Williams, Alexander S et al., Domain 4 of the anthrax protective patent is extended or adjusted under 35 antigen maintains structure and binding to the host receptor CMG2 U.S.C. 154(b) by O days. at low pH, Protein Science 2009, 18: 2277-2286. doi:10.1002/pro. 238, Aug. 31, 2009 (10 pages). (21) Appl. No.: 15/886,112 Hu, Lei et al., Comparison of the Structural Stability and Dynamic Properties of Recombinant Anthrax Protective Antigen and Its (22) Filed: Feb. 1, 2018 2-Fluorohistidine-LabeledAnalogue, Journal of Pharmaceutical Sci­ ences, vol. 101, No. 11, Nov. 2012, doi: 10.1002/jps.23294. Epub (65) Prior Publication Data Aug. 21, 2012 (11 pages). US 2018/0169208 Al Jun. 21, 2018 Mullangi, Vennela et al, Long-Range Stabilization of Anthrax Protective Antigen upon Binding to CMG2, Biochemistry, 2014, 53 Related U.S. Application Data (38), pp. 6084-6091, DOI: 10.1021/bi500718g, Publication Date (Web): Sep. 3, 2014 Copyright© 2014 American Chemical Society (62) Division of application No. 14/987,505, filed on Jan. (8 pages). 4, 2016. Zhang, Jeney et al., Stabilization of vaccines and antibiotics in silk (60) Provisional application No. 62/099,356, filed on Jan. and eliminating the cold chain, Proc Natl Acad Sci U SA. Jul. 24, 2, 2015. 2012; 109(30): 11981-11986. Published online Jul. 9, 2012. doi: 10.1073/pnas.1206210109 PMCID: PMC3409735 (6 pages). (51) Int. Cl. Office Action in corresponding U.S. Appl. No. 14/987,505, dated A61K 39/002 (2006.01) Nov. 8, 2017. A61K 39107 (2006.01) A61K 39/40 (2006.01) * cited by examiner A61K 45106 (2006.01) A61K 39/00 (2006.01) Primary Examiner - Jennifer E Graser (52) U.S. Cl. (74) Attorney, Agent, or Firm - Hovey Williams LLP CPC A61K 39107 (2013.01); A61K 39/40 (2013.01); A61K 45106 (2013.01); A61K (57) ABSTRACT 2039/6031 (2013.01); A61K 2039/622 Immunogenic compositions against Bacillus anthracis com­ (2013.01) prising a stabilized protective antigen complex are dis­ (58) Field of Classification Search closed. The stabilized complex comprises protective antigen None protein and capillary morphogenesis protein-2, with the See application file for complete search history. capillary morphogenesis protein-2 being bound to the pro­ tective antigen protein along a binding interface. The stabi­ (56) References Cited lized protective antigen complex has increased thermal and structural stability, along with resistance to premature pro­ U.S. PATENT DOCUMENTS teolytic degradation. Methods of using the same to induce an immunogenic response in a subject against B. anthracis 7,731,979 B2 6/2010 Bann infection are also disclosed. OTHER PUBLICATIONS 19 Claims, 11 Drawing Sheets (3 of 11 Drawing Sheet(s) Filed in Color) Rajapaksha et al (Protein Science. 2012. 21:1467-1480).* Mullangi et al (Biochemistry. 2014. 53: 6084-6091 ). * Specification includes a Sequence Listing. U.S. Patent Jan.29,2019 Sheet 1 of 11 US 10,188,716 B2 A so B 8000 -+.t- 5Hr* PA-280nm 0000 ,.....:;.-5FTro PA-'.!05nr, 4(/ ~WTPA __..., WT PA-2f,Cnm ~ ----·SFTrpPA ........_WTPA-29!inm 'S... .woo I 1 .,"' zooo ·e 30 s<.> "'<!I Z' <> 0 "' ~ ;fl t -toOO Iu.. % -4000 !ii; -imoo-----..... ___..._ ______, lW 340 SllO 350 400 420 440 1$1) 190 200 210 220 ~I) 2>W 2~0 200 W;,vel2no1h {llm) W«1el~lh tnmJ C 1~0 D eo ,. "' ~~SHrpPll.,,, 1$ 00 "' ... j ;!! ~ S; ,. ¥.., 150 <:l .,,<( "'g ~ ....... W-fPA ? • ,. l 50 n ~ E -!:>- :5FTfpf>A ;!! " ,!~" ~- w l3!'.I 1 ~t 140 ti> o' ;t~· ......... ➔ \ ~ ~ 3 <( ,u .. rn s,::: ia· 20. A. "'.. 3 :g .. ,: "- ! PA,, ~ } ;: ,., e· ti 40 z ~- ~ .. 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(M) C) His336 D) His616 ,:: • 0.010 0.010 • 0000 O.®O ..,.,.,_,_:_,--,,--.,--,--,---,--.,..--..,---,--...,--..,...--, 0 2 3 4 5 0 2 3 4 5 Gdn-HCI {M} Gdn-HCl (M} Fig. 9 U.S. Patent Jan.29,2019 Sheet 10 of 11 US 10,188,716 B2 120 100 80 60 20 --------------------- 0 1 2 2.5 3 4 Gdn HCl (M) Fig.10 e• 00 • ~ ~ ~ ~ o.oo, (A) His86 .. (B) His263 (C) His304 /! C ~ • ... --.,.-•-,;:, = ,,...,-p-----c,·-·•0 0.03 / .d./~: ,,// 0.04 . ,,// 0.010 >" ..... 0.02 '7~ / l / /_,/ ~ :!::,. - '.E ~ .;,,; 'b ,/ ~ ? 0.02 ~ OJJ05 N 0.01 '"\,Ci .,,// N ~// ,;,/ .---,-··•-··'·····/''''.·· 0 o~ ___ o_ ... __ ......... ··" ~_,.. .... \,Ci 0.00 0.00 0.000-l I- 1----,---....--~--,-----,..---, 4 6 8 4 6 8 10 4 6 8 10 pH* pH* pH * rJJ ('D=­ 0.020 (E) His336 0.06 (F) His597 ('D..... _... 9 .... 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