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(12) Patent Application Publication (10) Pub. No.: US 2010/0221242 A1 O'keefe Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0221242 A1 O'keefe Et Al US 2010O221242A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0221242 A1 O'Keefe et al. (43) Pub. Date: Sep. 2, 2010 (54) ANTI-VIRAL GRIFFITHSIN COMPOUNDS, Publication Classification COMPOSITIONS AND METHODS OF USE (51) Int. Cl (76) Inventors: Barry R. O'Keefe, Frederick, MD A 6LX 39/395 (2006.01) (US); Toshiyuki Mori, Osaka (JP); A638/16 (2006.01) James B. McMahon. Frederick A638/08 (2006.01) MD (US) s s A638/10 (2006.01) A6II 35/74 (2006.01) Correspondence Address: A6II 35/12 (2006.01) LEYDIG, VOIT & MAYER, LTD. A 6LX 3L/7052 (2006.01) TWO PRUDENTIAL PLAZA, SUITE 4900, 180 CI2N 7/00 (2006.01) NORTH STETSONAVENUE A6IP3L/2 (2006.01) CHICAGO, IL 60601-6731 (US) (52) U.S. Cl. ............ 424/130.1: 514/12: 514/16: 514/15; 514/14: 514/13; 424/93.2; 424/93.21: 514/44 R: (22)22) PCT Fled:1. Dec.ec. 1,1 2006 (57) ABSTRACT (86). PCT No.: PCT/USO6/4593O A method of inhibiting a viral infection of a host comprising 371 1 administering to the host an anti-viral griffithsin polypeptide S (c)( ), comprising SEQID NO: 3 or a fragment thereof comprising (2), (4) Date: Sep. 29, 2008 at least eight contiguous amino acids, a nucleic acid encoding O O the anti-viral polypeptide, or an antibody to the anti-viral Related U.S. Application Data polypeptide. A method of inhibiting a virus in a sample com (60) Provisional application No. 60/741,403, filed on Dec. prising contacting the sample with an anti-viral griffithsin 1, 2005. polypeptide or antibody thereto also is provided. Patent Application Publication Sep. 2, 2010 Sheet 1 of 7 US 2010/0221242 A1 Patent Application Publication Sep. 2, 2010 Sheet 2 of 7 US 2010/0221242 A1 Patent Application Publication Sep. 2, 2010 Sheet 3 of 7 US 2010/0221242 A1 FIG. 3 Purified PCR product Digestion of the PCR product with Nicoland Xho Ligation of the digested PCR product to pET-28a(+) Transformation of E. coli with the ligated DNA Isolation of recominant clones Expression of His-GRFT Prepare crude soluble cytosolic fraction Patent Application Publication Sep. 2, 2010 Sheet 4 of 7 US 2010/0221242 A1 120 FIG. 4a 100 80 60 40 20 0.001 0.01 0.1 1 10 FIG 4b 1 OO 80 60 40 20 0.001 0.01 0.1 1 10 Patent Application Publication Sep. 2, 2010 Sheet 5 of 7 US 2010/0221242 A1 FIG. 5a gp16 gp12 SCD4 gp41 IgG (bovine) a-acid glyco Aprotinin HuSA O.O O.2 0.4 0.6 O.8 1.0 1.2 1.4 Absorbance (405 nm) FIG. 5b O 1OO 200 3OO 400 500 GRFT (pmol) Patent Application Publication Sep. 2, 2010 Sheet 6 of 7 US 2010/0221242 A1 FIG. 6 Purified Griffithsin (GRFT) immunization of New Zealand White Rabbit (day 1) 100 micrograms GRFT in Freunds's Complete Adjuvant BOOster Injections on Days 7, 21, 42, 63, 78 and 112 50 micrograms GRFT in Freund's Incomplete Adjuvant Rabbit Sacrificed Blood Collected Rabbit Serum Separated from the Whole Blood Purification of lgG Fraction from Rabbit Serum Protein-A-Sepharose Column Purified Polyclonal Anti-Griffithsin-Antibodies Patent Application Publication Sep. 2, 2010 Sheet 7 of 7 US 2010/0221242 A1 ALT9W/W TONOO TO Z 9 0 O? TOLNOO SIW 96 US 2010/0221242 A1 Sep. 2, 2010 ANTI-VIRAL GRIFFITHSIN COMPOUNDS, 0005 Infection of people by influenza viruses is also a COMPOSITIONS AND METHODS OF USE major cause of pandemic illness, morbidity and mortality worldwide. The adverse economic consequences, as well as TECHNICAL FIELD OF THE INVENTION human Suffering, are enormous. Available treatments for established infection by this virus are either minimally effec 0001. The invention relates to an anti-viral Griffithsin tive or ineffective; these treatments employ amantatadine, polypeptide related conjugates, compositions, nucleic acids, rimantadine and neuraminidase inhibitors. Of these drugs, vectors, host cells, antibodies, and methods for their produc only the neuraminidase inhibitors are substantially active tion and use. against multiple strains of influenza virus that commonly infect humans, yet these drugs still have limited utility or BACKGROUND OF THE INVENTION efficacy against pandemic disease. 0006 Currently, the only effective preventative treatment 0002 Although the field of viral therapeutics has against influenza viral infection is vaccination. However, this, advanced in response to the need for treatments and prophy like the drug treatments, is severely limited by the propensity lactics effective against diverse classes of viruses, the threat of influenza viruses to mutate rapidly by genetic exchange, of viruses remain among several human populations across resulting in the emergence of highly resistant viral strains that the world. rapidly infect and spread throughout Susceptible populations. 0003 Retroviruses, such as HIV, continue to pose a threat In fact, a vaccination strategy is only effective from year-to to humans. There are many ways in which an agent can year if the potential pandemic strains can be identified or exhibit anti-retroviral activity (e.g., see DeClercq, Adv. Virus predicted, and corresponding vaccines prepared and admin Res., 42: 1-55 (1993); DeClercq, J. Acquir. Immun. Def. istered early enough that the year's potential pandemic can be Synd., 4: 207-218 (1991); and Mitsuya et al., Science, 249: aborted or attenuated. Thus, new preventative and therapeutic 1533-1544 (1990). Nucleoside derivatives, such as AZT, interventions and agents are urgently needed to combat influ which inhibit the viral reverse transcriptase, were among the enza viruses. first clinically active agents available commercially for anti 0007 New agents with broad anti-influenza virus activity HIV therapy. Although very useful in some patients, the util against diverse strains, clinical isolates and Subtypes of influ ity of AZT and related compounds is limited by toxicity and enza virus would be highly useful, since Such agents would insufficient therapeutic indices for fully adequate therapy. most likely remain active against the mutating virus. The two Also, given the subsequent revelations about the true dynam major types of influenza virus that infect humans are influ ics of HIV infection (Coffin, Science, 267: 483-489 (1995); enza A and B, both of which cause severe acute illness that and Cohen, Science, 267: 179 (1995)), it has become increas may include both respiratory and gastrointestinal distress, as ingly apparent that agents acting as early as possible in the well as other serious pathological sequellae. An agent that has viral replicative cycle are needed to inhibit infection of newly anti-influenza virus activity against diverse strains and iso produced, uninfected immune cells generated in the body in lates of both influenza A and B, including recent clinical response to the virus-induced killing of infected cells. Also, it isolates thereof, would be particularly advantageous for use is essential to neutralize or inhibit new infectious virus pro in prevention or treatment of hosts susceptible to influenza duced by infected cells. virus infection. 0004 Effective means for preventing HIV infection also 0008. The predominant mode of transmission of influenza are needed as a global priority. Heterosexual transmission viral infection is respiratory, i.e., transmission via inhalation accounts for the majority of new cases of HIV infection each of virus-ladenaerosolized particles generated through cough year. Current reports from the World Health Organization ing, Sneezing, breathing, etc., of an influenza-infected indi estimate that a total of more than 40 million people are now vidual. Transmission of infectious influenza virions may also infected with HIV. HIV prevention research has to date occur through contact (e.g., through inadvertent hand-to focused predominantly on vaccine development. However, mouth contact, kissing, touching, etc.) with saliva or other no effective preventative or therapeutic vaccine has been bodily secretions of an infected individual. Thus, the primary identified thus far. New approaches to vaccine development, first points of contact of infectious influenza virions within a as well as entirely different strategies and agents for prevent susceptible individual are the mucosal surfaces within the ing person-to-person transmission of HIV infection, are oropharyngeal mucosa, and the mucosal Surfaces within the needed. One approach showing great promise is the develop upper and lower respiratory tracts. Not only do these sites ment and use of topical microbicides. In this approach, a comprise first points of virus contact for initial infection of an Suitable antiviral agent is applied directly at the potential site individual, they are also the primary sites for production and of virus exposure, e.g., the genital mucosa in the case of HIV. exit (e.g., by coughing, Sneezing, salivary transmission, etc.) A suitable antiviral agent is one which inactivates or inhibits of bodily fluids containing infectious influenza viral particles. infectivity of a virus upon contact of the antiviral agent with Therefore, availability of a highly potent anti-influenza virus the virus. Suitable animal models are available for demon agent, having broad-spectrum activity against diverse strains strating in Vivo efficacy of Such approaches for preventing and isolates of influenza viruses A and B, which could be transmission of immunodeficiency viruses, such as HIV. For applied or delivered topically to the aforementioned mucosal instance, the HIV-inactivating protein, cyanovirin-N, has sites of contact and infection and transmission of infectious been shown to inhibit the sexual transmission of a chimeric influenza viruses, would be highly advantageous for thera simian/human immunodeficiency virus (SHIV) infection in a peutic and preventative inhibition of influenza viral infection, primate model employing macaques exposed to the virus either in susceptible uninfected or infected hosts. vaginally or rectally (C-C Tsai et al., AIDS Res. Hum. Retro 0009 Highly pathogenic avian H5N1 influenza A viruses viruses, 19, 535-541 (2003) and C-C Tsai et al., AIDS Res.
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