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###### Department of Health and Human Services

###### National Institutes of Health 

# AGENCY:

National Institutes of Health, Public Health Service, HHS. 

# ACTION:

Notice. 

# SUMMARY:

The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing. 

# ADDRESSES:

                        Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804;                         *telephone:*                         301/496-7057;                         *fax:*                         301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.                     

## Humanized Anti-Carcinoma CC49 Monoclonal Antibodies 

*Description of Technology:*                     The technology describes the humanization of a murine anti-carcinoma antibody CC49 which has been shown to react with Tumor Associated Glycoprotein 72 (TAG-72), an antigen which is expressed on human breast, ovarian, colorectal, and other carcinomas.                 

The invention includes a new method of humanization of a rodent antibody which is based on grafting all the Complementarity Determining Residues (CDRs) of a rodent antibody onto a human antibody framework. Additionally, the method identifies Specificity Determining Residues (SDRs), the amino acid residues in the hypervariable regions of an antibody that are most critical for antigen binding activity and of rendering any antibody minimally immunogenic in humans by transferring the SDRs of the antibody to a human antibody framework. The resulting humanized antibodies, including CDR variants thereof (including a CH2 deleted version), are also embodied in the invention, as are methods of using the antibodies for therapeutic and diagnostic purposes. 

                    Furthermore, these antibodies are suitable for radiolabeling for the application in radioimmunotherapy (RIT) based treatment of several cancers. Phase I results of radioimmunotherapy for ovarian cancer using90                    Yttrium-CC49 murine monoclonal antibodies have shown promising results and confirms feasibility of the use of these antibodies for RIT. Promising pharmacokinetic data for the radiolabeled humanized antibodies in colon carcinoma xenograft models were recently published.                 

### Applications and Modality 

1. A humanized anti-cancer CC49 monoclonal antibody has been developed. 

2. New methods of humanization of rodent antibodies have been identified. 

3. The antibody(s) has been shown to react with Tumor Associated Glycoprotein 72 (TAG-72), an antigen which is expressed on human breast, ovarian, colorectal, and other carcinomas. 

4. These antibodies are suitable for radiolabeling for the application in radioimmunotherapy (RIT) based treatment of several cancers. 

5. These antibodies can be useful in diagnosis and treatment of several cancers. 

*Development Status:*                     The technology is currently in the pre-clinical stage of development. Phase I results of                           ( print page 27819)                        radioimmunotherapy for ovarian cancer using90                    Yttrium-CC49 murine monoclonal antibodies have shown promising results and confirms feasibility of the use of these antibodies for radioimmunotherapy (RIT).                 

*Inventors:*                     Syed V. Kashmiri (NCI), Eduardo A. Padlan (NIDDK), Jeffrey Schlom (NCI).                 

### Publications 

                    1. RD Alvarez                     *et al.*                     A Phase I study of combined modality90                    Yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer. Clin Cancer Res. 2002 Sep; 8(9):2806-2811.                 

                    2. A Forero                     *et al.*                     A novel monoclonal antibody design for radioimmunotherapy. Cancer Biother Radiopharm. 2003 Oct;18(5):751-759.                 

                    3. PC Chinn                     *et al.*                     Pharmacokinetics and tumor localization of (111) in-labeled HuCC49DeltaC(H)2 in BALB/c mice and athymic murine colon carcinoma xenograft. Cancer Biother Radiopharm. 2006 Apr;21(2):106-116.                 

### Patent Status 

1. U.S. Patent No. 6,818,749 issued November 16, 2004 and U.S. Patent Application 10/927,433 filed August 25, 2004 as well as issued and pending foreign counterparts [HHS Ref. No. E-259-1998]; 

2. European Patent No. 00365997 issued September 14, 1994 and its counterpart in Japan [HHS Ref. Nos. D-003-1992/0-EP-07 and D-003-1992/0-JP-05]; 

3. U.S. Patent No. 5,472,693 issued December 5, 1995 [HHS Ref. No. D-003-1992/2-US-01]; 

4. U.S. Patent No. 6,051,225 issued April 18, 2000 [HHS Ref. No. D-003-1992/3-US-01]; 

5. U.S. Patent No. 5,993,813 issued November 30, 1999 [HHS Ref. No. D-003-1992/2-US-02]; 

6. U.S. Patent No. 6,641,999 issued November 4, 2003 [HHS Ref. No. D-003-1992/2-US-04]; 

7. European Patent No. 628078 issued December 8, 1999 and its counterparts in Japan, Canada and Australia [HHS Ref. Nos. D-004-1992/0-EP-06, D-004-1992/0-JP-03, D-004-1992/0-CA-04 and D-004-1992/0-AU-05]; 

8. U.S. Patent No. 5,877,291 issued March 2, 1999 [HHS Ref. No. D-004-1992/1-US-01]; 

9. U.S. Patent No. 5,892,020 issued April 6, 1999 [HHS Ref. No. D-004-1992/1-US-01] and its foreign counterparts; 

10. Taiwanese Patent No. 173667 issued July 10, 2003 [HHS Ref. No. D-001-1996/0-TW-03]; 

11. U.S. Patent No. 6,737,060 issued May 18, 2004 [HHS Ref. No. D-001-1996/1-US-03]; 

12. U.S. Patent No. 6,737,061 issued May 18, 2004 [HHS Ref. No. D-001-1996/1-US-04]; 

13. U.S. Patent No. 6,753,152 issued June 22, 2004 [HHS Ref. No. D-001-1996/1-US-05]; 

14. U.S. Patent No. 6,752,990 issued June 22, 2004 [HHS Ref. No. D-001-1996/1-US-06]; 

15. U.S. Patent No. 6,329,507 issued December 11, 2001 [HHS Ref. No. D-001-2006/0-US-01] and 

16. U.S. Patent No. 6,071,515 issued June 6, 2000 [HHS Ref. No. D-001-2006/0-US-03]. 

*Licensing Availability:*                     Available for exclusive and non-exclusive licensing.                 

*Licensing Contact:*                     Michelle Booden, PhD.; 301/451-7337;                     *boodenm@mail.nih.gov*

*Collaborative Research Opportunity:*                     The National Cancer Institute's Laboratory of Tumor Immunology and Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-carcinoma antibodies. Please contact John D. Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                 

## Enhanced T-cell Activation by Costimulation: an Effective Immunotherapy for Cancer and Infectious Diseases 

*Description of Technology:*                     Cancer immunotherapy is a recent approach where tumor associated antigens (TAAs), which are primarily expressed in human tumor cells and not expressed or minimally expressed in normal tissues, are employed to generate a tumor specific immune response. Specifically, these antigens serve as targets for the host immune system and elicit responses that result in tumor destruction. The initiation of an effective T-cell immune response to antigens requires two signals. The first one is antigen specific via the peptide/major histocompatibility complex and the second or “costimulatory” signal is required for cytokine production, proliferation, and other aspects of T-cell activation.                 

The present technology describes recombinant poxvirus vectors encoding at least three or more costimulatory molecules and TAAs. The use of three costimulatory molecules such as B7.1, ICAM-1 and LFA-3 (TRICOM®) has been shown to act in synergy with several tumor antigens and antigen epitopes to activate T cells. The effects with TRICOM® were significantly greater than with one or two costimulatory molecules. Laboratory results support the greater effect of TRICOM® to activate both CD4+ and CD8+ T cells. The invention also describes the use of at least one target antigen or immunological epitope as an immunogen or vaccine in conjunction with TRICOM®. The antigens include but are not limited to carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), and MUC-1. 

The combination of CEA, MUC-1, and TRICOM® is referred to as PANVAC® and the combination of PSA and TRICOM® is referred to as PROSTVAC®. 

*Licensing Availability:*                     The technology is available for exclusive and non-exclusive licensing in combinations and for different fields of use. Some potential licensing opportunities are as follows:                 

1. TRICOM® (alone or with a transgene for a tumor antigen and/or an immunostimulatory molecule); 

2. The antigens only, including but not limited to CEA, PSA, and MUC-1; 

3. PANVAC® and/or PROSTVAC®; and 

4. Recombinant fowlpox-GM-CSF. 

*Application(s) and Modality:*                     Vector-based TRICOM® (alone or with a transgene for a tumor antigen and/or an immunostimulatory molecule), PANVAC® and PROSTVAC® and combinations thereof can be a potential novel immunotherapeutic approach for the treatment of cancer and infectious diseases.                 

### Advantages 

1. The technology is beyond proof-of-concept, supported by laboratory results and publications. 

2. Phase I and Phase II clinical data available. 

3. Fewer validation studies are required compared to other immunotherapy related technologies. 

*Development Status:*                     Phase I and Phase II results available for poxvirus recombinants containing transgenes for TRICOM®, CEA-TRICOM®, PANVAC®, and PROSTVAC®. Further clinical studies are ongoing for other combinations.                 

*Inventors:*                     Jeffrey Schlom (NCI)                     *et al.*

### Publications 

                    1. Kaufman HL, Cohen S, Cheung K, DeRaffele, Mitcham J, Moroziewicz D, Schlom J, and Hesdorffer C. Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors.                     *Human Gene Ther.*                     17:239-244, 2006.                 

                    2. Kantoff PW GL, Tannenbaum SI, Bilhartz DL, Pittman WG, Schuetz TJ. Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with                           ( print page 27820)                        hormone-refractory prostate cancer (HRPC). 2006 ASCO Annual Meeting Proceedings, Part I, abstract 2501.                    *J Clin Oncol.*; 24.                 

                    3. Marshall J, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwa L, Park S, Panicali D, Schlom J. A phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM (B7-1/ICAM-1/LFA-3) alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without GM-CSF, in patients with CEA-expressing carcinomas.                     *J Clin Oncol.*                     23:720-731, 2005.                 

                    4. Palena C, Foon KA, Panicali D, Yafal AG, Chinsangaram J, Hodge JW, Schlom J, and Tsang KY. A potential approach to immunotherapy of chronic lymphocytic leukemia (CLL): enhanced immunogenicity of CLL cells via infection with vectors encoding for multiple costimulatory molecules.                     *Blood*                     106:3515-3523, 2005.                 

                    5. Gulley J, Todd N, Dahut W, Schlom J, Arlen P. A phase II study of PROSTVAC-VF vaccine, and the role of GM-CSF, in patients (pts) with metastatic androgen insensitive prostate cancer (AIPC) [abstract].                     *J Clin Oncol.*                     2005; 23 (16S Pt 1): 2504.                 

                    6. Yang S, Hodge JW, Grosenbach DW, and Schlom J. Vaccines with enhanced costimulation maintain high avidity memory CTL.                     *J. Immunol.*                     175:3715-3723, 2005.                 

                    7. Yang S, Tsang KY, and Schlom J. Induction of higher avidity human CTL by vector-mediated enhanced costimulation of antigen-presenting cells.                     *Clin Cancer Res.*                     11:5603-5615, 2005.                 

                    8. Hodge JW, Chakraborty M, Kudo-Saito C, Garnett CT, Schlom J. Multiple costimulatory modalities enhance CTL avidity.                     *J Immunol.*                     174:5994-6004, 2005.                 

                    9. Tsang K-Y, Palena C, Yokokawa J, Arlen PM, Gulley JL, Mazzara GP, Gritz L, Gómez Yafal A, Ogueta S, Greenhalgh P, Manson K, Panicali D, and Schlom J. Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules.                     *Clin Cancer Res.*                     11:1597-1607, 2005.                 

                    10. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing.                     *Cancer Res.*                     64:4328-4337, 2004.                 

                    11. Zeytin HE, Patel AC, Rogers CJ, et al. Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice.                     *Cancer Res.*                     64:3668-3678, 2004.                 

                    12. Palena C, Zhu M-Z, Schlom J, and Tsang K-Y. Human B cells that hyperexpress a triad of costimulatory molecules via avipoxvector infection: an alternative source of efficient antigen-presenting cells.                     *Blood*                     104:192-199, 2004.                 

                    13. Kudo-Saito C, Schlom J, and Hodge JW. Intratumoral vaccination and diversified subcutaneous/intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules.                     *Clin Cancer Res.*                     10:1090-1099, 2004.                 

                    14. Hodge JW, Poole DJ, Aarts WM, Gomez Yafal A, Gritz L, and Schlom J. Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses.                     *Cancer Res.*                     63:7942-7949, 2003.                 

                    15. Hodge JW, Grosenbach DW, Aarts Wm, Poole DJ, and Schlom J. Vaccine therapy of established tumors in the absence of autoimmunity.                     *Clin Cancer Res.*                     9:1837-1849, 2003.                 

                    16. Aarts WM, Schlom J, and Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and anti-tumor activity.                     *Cancer Res.*                     62:5770-5777, 2002.                 

                    17. Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation.                     *Cancer Res.*                     59: 5800-5807, 1999.                 

### Patent Status 

1. U.S. Patent No. 6,969,609 issued November 29, 2005 as well as issued and pending foreign counterparts [HHS Ref. No. E-256-1998/0]; 

2. U.S. Patent Application No. 11/321,868 filed December 30, 2005 [HHS Ref. No. E-256-1998/1]; and 

3. U.S. Patent No. 6,756,038 issued June 29, 2004 as well as issued and pending foreign counterparts [HHS Ref. No. E-099-1996/0]; 

4. U.S. Patent No. 6,001,349 issued December 14, 1999 as well as issued and pending foreign counterparts [HHS Ref. No E-200-1990/3-US-01]; 

5. U.S. Patent No. 6,165,460 issued December 26, 2000; as well as issued and pending foreign counterparts [HHS Ref. No E-200-1990/4-US-01]; 

6. U.S. Patent No. 7,118,738 issued October 10, 2006 as well as issued and pending foreign counterparts [HHS Ref. No E-154-1998/0-US-07]; 

7. PCT Application No. PCT/US97/12203 filed July 15, 1997 [HHS Ref. No E-259-1994/3-PCT-02]; 

8. U.S. Patent Application Nos. 10/197,127 and 08/686,280 filed July 17, 2002 and July 25, 1996 [HHS Ref. No E-259-1994/3-US-08 and /4-US-01]; 

9. U.S. Patent No. 6,946,133 issued September 20, 2005 as well as issued and pending foreign counterparts [HHS Ref. No E-062-1996/0-US-01]; 

10. U.S. Patent Application No. 11/606,929 filed December 1, 2006 [E-062-1996/0-US-11]; 

11. U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued May 17, 2005, April 15, 2003 and April 4, 2000 respectively, as well as issued and pending foreign counterparts [HHS Ref. Nos. E-260-1994/1-US-03, US-02, US-01]; and 

12. U.S. Patent. Application No. 11/090,686 filed March 8, 2005 [HHS Ref. No E-260-1994/1-US-04]. 

*Licensing Contact:*                     Michelle Booden, PhD, 301/451-7337;                     *boodenm@mail.nih.gov.*

*Cooperative Research and Development Agreement (CRADA) Opportunity:*                     A CRADA partner for the further co-development of this technology is currently being sought by the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI.                 

The CRADA partner will: 

1. Generate and characterize recombinant poxviruses expressing specific tumor-associated antigens, cytokines, and/or T-cell costimulatory factors, 

2. Analyze the recombinant poxviruses containing these genes with respect to appropriate expression of the encoded gene product(s), 

3. Supply adequate amounts of recombinant virus stocks for preclinical testing, 

4. Manufacture and test selected recombinant viruses for use in human clinical trials, 

5. Submit Drug Master Files detailing the development, manufacture, and testing of live recombinant vaccines to support the NCI-sponsored INDs, 

6. Supply adequate amounts of clinical grade recombinant poxvirus vaccines for clinical trials conducted at the NCI Center for Cancer Research (CCR), and 

7. Provide adequate amounts of vaccines for extramural clinical trials through a clinical agreement with the Division of Cancer Treatment and Diagnosis, NCI. 

NCI will: 

1. Provide genes of tumor-associated antigens, cytokines and other immunostimulatory molecules for incorporation into poxvirus vectors, 

                    2. Evaluate recombinant vectors in preclinical models alone and in combination therapies,                           ( print page 27821)    

3. Conduct clinical trials of recombinant vaccines alone and in combination therapies, and 

4. Provide Drug Master Files currently supporting the clinical use of the recombinant poxvirus vaccines. 

                    If interested in the above described CRADA, please submit a statement of interest and capability to Kevin Chang, PhD, in the NCI Technology Transfer Center at                     *changke@mail.nih.gov*                     or 301-496-0477.                 

Dated: May 11, 2007. 

Steven M. Ferguson, 

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.

[FR Doc. E7-9541 Filed 5-16-07; 8:45 am] 

BILLING CODE 4140-01-P