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Mucosal Cytotoxic T Lymphocyte Responses

Posted Aug 30 2010 5:00pm

Description of Invention:
The invention offered for licensing provides methods and compositions for induction of an antigen-specific, mucosal cytotoxic T lymphocyte (CTL) response useful in preventing and treating infections with pathogens that gain entry via a mucosal surface. The methods of the invention involve administering either a soluble antigen itself, or a polynucleotide encoding the soluble antigen, to a mucosal surface. The soluble antigens can be full length, naturally occurring polypeptides or fragments (i.e. peptides) derived from them. The soluble antigen is administered with an adjuvant at the mucosal site or without an adjuvant. Adjuvants can be, for example, Cholera toxin (CT), mutant CT (MCT), E. coli heat labile enterotoxin (LT) and others. Cytokines like IL-12 or IFNgamma can also be administered to enhance the immunoreactivity. Mucosal routes of administration include intrarectal (IR), intranasal (IN), intragastric (IG), intravaginal (IVG) or intratratracheal (IT). Soluble antigens can be derived from pathogenic viruses (e.g. HIV, influenza, or hepatitis virus), bacteria (e.g. Listeria monocytogenes), or prozoans. Furthermore, the soluble antigen can be tumor-associated antigen for cancer applications.

The utility of the technology has been extensively demonstrated when applied to HIV. Details about the HIV studies are provided in the eight (8) publications cited below.

  • Immunization to treat infectious diseases
  • Possible applications in cancer therapy

Development Status:
Proof of concept has been demonstrated, in particular as related to HIV.

Jay A Berzofsky (NCI)

Patent Status:
HHS, Reference No. E-268-1997/2
US, , Patent No. 6,749,856, Issued 15 Jun 2004
PCT, Application No. PCT/US98/19028 filed 11 Sep 1998

Foreign patents issued in Australia (Application Number 93862/98 and Patent Number 757310) and in European countries (Application Number 98946965.5 and Patent Number 1011720): Germany, France, Ireland, United Kingdom, Italy, Portugal and Spain

Relevant Publication:
  1. Belyakov IM, Derby MA, Ahlers JD, Kelsall BL, Earl P, Moss B, Strober W, Berzofsky JA. Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic cytotoxic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc Natl Acad Sci USA. 1998 Feb 17;95(4):1709-1714. [ PubMed: 9465081 ]
  2. Belyakov IM, Ahlers, JD, Brandwein BY, Earl P, Kelsall B, Moss B, Strober W, Berzofsky JA. The importance of local mucosal HIV-specific CD8+ cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12. J Clin Invest. 1998 Dec 15;102(12):2072-2081. [ PubMed: 9854042 ]
  3. Belyakov IM, Ahlers JD, Clements JD, Strober W, Berzofsky JA. Interplay of cytokines and adjuvants in the regulation of mucosal and systemic HIV-specific CTL. J Immunol. 2000 Dec 1;165(11):6454-6462. [ PubMed: 11086085 ]
  4. Belyakov IM, Hel Z, Kelsall B, Kuznetsov VA, Ahlers JD, Nacsa J, Watkins DI, Allen TM, Sette A, Altman J, Woodward R, Markham PD, Clements JD, Franchini G, Strober W, Berzofsky JA. Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat Med. 2001 Dec;7(12):1320-1326. [ PubMed: 11726972 ]
  5. Belyakov IM, Kuznetsov VA, Kelsall B, Klinman D, Moniuszko M, Lemon M, Markham PD, Pal R, Clements JD, Lewis MG, Strober W, Franchini G, Berzofsky JA. Impact of vaccine-induced mucosal high avidity CD8+ CTLs in delay of AIDS-viral dissemination from mucosa. Blood 2006 Apr 15;107(8):3258-3264. [ PubMed: 16373659 ]
  6. Belyakov IM, Isakov DV, Zhu Q, Dzutsev A, Berzofsky JA. A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J Immunol. 2007 Jun 1;178(11):7211-7221. [ PubMed: 17513770 ]
  7. Belyakov IM, Ahlers JD, Nabel GJ, Moss B, Berzofsky JA. Generation of functionally active HIV-1 specific CD8+ CTL in intestinal mucosa following mucosal, systemic, or mixed prime-boost immunization. Virology 2008 Nov 10;381(1):106-115. [ PubMed: 18793787 ]
  8. Sui Y, Zhu Q, Gagnon S, Dzutsev A, Terabe M, Vaccari M, Venzon D, Klinman D, Strober W, Kelsall B, Franchini G, Belyakov IM, Berzofsky JA. Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques. Proc Natl Acad Sci USA. 2010 May 25;107(21):9843-9848. [ PubMed: 20457926 ]

Licensing Status:
Available for licensing and commercial development.

Collaborative Research Opportunity:
The Center for Cancer Research, Vaccine Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Mucosal Cytotoxic T Lymphocyte Responses. Please contact John D. Hewes, Ph.D. at 301-435-3121 or for more information. Click here to view the NCI collaborative opportunity announcement.

Infectious Diseases
Infectious Diseases - Vaccines

For Licensing Information Please Contact:
John Stansberry Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-5236
Fax: 301-402-0220

Ref No: 424

Updated: 08/2010

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