Therapeutics and Vaccines

The following Therapeutics and Vaccines are currently available for licensing from OTAM:

• Hyperthermic Nanotechnologies for Cancer Therapy
• Compositions and Methods for Treating Cancer
• Novel Agents For Specific Targeting and D elivery to Cancer Cells   
• Platform for Targeted Delivery of Cancer Therapeutics and Diagnostics      
• Novel Cytotoxins that Selectively Target and Kill Cancer Cells In Vivo   
• Acellular animal vaccine for Bordetella bronchiseptica mediated respiratory infections  
• A Flagellin-Based Vaccine Technology has created an array of vaccine opportunities
• Carnosine Improves Cardiac Function: Treating Heart Failure
• Novel Cytotoxic Compounds
• Novel Insulin-Responsive Glucose Transporter
• Unique Platinum-based Chemotherapeutics to Treat Drug Resistant Tumors
• Preventing Cell Death

Hyperthermic Nanotechnologies for Cancer Therapy 

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INVENTORS:   Dr. Steven Akman, Dr. David Carroll, Dr. Frank Torti, Dr. Suzy Torti, Dr. Omkaram Nalamasu, Dr. Pulickel Ajayan

Wake Forest University researchers in Cancer Biology and the Center for Nanotechnology and Molecular Materials have collaborated with researchers at Rennselaer Polytechnic Institute to develop a highly-effective nanoparticle-based cancer therapy. This unique chemotherapeutic-free technology was highlighted in an International Journal of Nanomedicine manuscript that showed that 96% of kidney cancer cells can be killed after a single 4 minute treatment. The in vitro data presented in that manuscript has been followed up with extraordinary in vivo data published in PNAS that resulted in a 100% reduction of a tumor on the flank of a nude mouse in ten days after one 30-second treatment! Even more remarkable, the reduction in tumor size remained constant up to the end of the experiment (30 days later)!

Additional Information

• Patent Cooperation Treaty (PCT) Application no. 2007/139936
• “Thermal Ablation Therapeutics Based on CNx Multi-walled Nanotubes” International Journal of Nanomedicine (2007) Vol. 2, Issue 4 
• “Long-term Survival Following a Single Treatment of Kidney Tumors with Multiwalled Carbon Nanotubes and Near-Infrared Radiation” PNAS (2009) Vol. 106, No. 31

Licensing Contact Information 

Stephen J. Susalka, Ph.D.
Assistant Director
Email: ssusalka@wakehealth.edu
Phone: (336) 716-3729 

Compositions and Methods for Treating Cancer 

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INVENTORS: Dr. David L. Carroll, Dr. Nicole Levi-Polyachenko, Dr. John H. Stewart

Researchers at Wake Forest University and Wake Forest School of Medicine have developed novel nanoparticle-based compositions that can be used to maximize the effectiveness of IPHC while reducing the toxicity of the chemotherapeutic agent to healthy cells. Methods of using this composition has been shown experimentally in vitro to reduce the therapy time by over 200 fold (from 2 hours to a mere 30 seconds). In addition to IPHC, this technology can be used for a whole host of hyperthermic-based chemo-therapeutics. This technology was recently featured in a SciBx article.

Background   

Intraperitoneal hyperthermic chemotherapy (IPHC) is a promising therapy for peritoneal dissemination of colorectal and appendiceal cancers. IPHC involves a multi-hour circulation of heated anti-cancer drugs (such as oxaliplatin or mitomycin C) in the peritoneum. Hyperthermia increases cellular metabolism and membrane permeability resulting in enhanced drug uptake by cells. Although IPHC has significantly improved patient outcomes, the procedure is hampered by the time that the patient must be anesthetized (hours) and amount of drug perfusate necessary (liters). 

Additional Information

• Rapid Photothermal Intracellular Drug Delivery Using Multiwalled Carbon Nanotubes Molecular Pharmaceutics 2009 Jul 2.
• Nanotubes for rapid photothermal intracellular drug delivery SciBX Article 
• Compositions and Methods for Treating Cancer PCT Application WO/2008/112277

Licensing Contact Information

Stephen J. Susalka, Ph.D.
Assistant Director
Email: ssusalka@wakehealth.edu
Phone: (336) 716-3729 

Novel Agents For Specific Targeting and D elivery to Cancer Cells  

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INVENTORS:  Dr. Waldemar Debinski, Hetal Pandya, Denise Gibo

Researchers at Wake Forest School of Medicine have developed novel recombinant delivery proteins, derived from the interleukin-13 (IL-13) protein scaffold, which specifically target the IL-13Ra2 receptor over-expressed in various cancers, such as glioblastoma multiforme, head and neck, pancreatic, ovarian and prostate cancers. The recombinant proteins provide a novel platform for developing highly targeted cancer therapeutics.

Unique Mechanism of action
The recombinant proteins consist of three major domains: 

1. A ligand that specifically binds to the cancer-associated receptor IL-13Ra2 and provides specificity to cancer cells over-expressing this cancer biomarker.  
2. An endosomal translocation domain, which ensures intra-cytosolic delivery.   
3. An intra-cellular compartment localization signal sequence that ensures efficient transport to intracellular organelles such as mitochondria or the cell nucleus.   

Technology Highlights

• The recombinant proteins have been conjugated to a fluorescent label and were shown to specifically deliver the label to the nucleus of IL-13Ra2 over-expressing GBM cells. 
• The recombinant protein module can be attached to various chemotherapeutic agents such as cytotoxins, radiopharmaceuticals or photochemicals, enabling specific targeting of cancer therapeutics and improved efficacy of these agents as they are delivered to their site(s) of action.
• The delivery proteins are single-chain proteins giving ease of synthesis and cost-effective production.   

Additional information

Additional information is available upon request.

Status

Patent Pending

Licensing Contact

Camilla P. Hansen, Ph.D.
Licensing Analyst
Email: chansen@wakehealth.edu
Phone: 336-716-3729

Platform for Targeted Delivery of Cancer Therapeutics and Diagnostics 

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INVENTORS:  Dr. Waldemar Debinski, Hetal Pandya, Denise Gibo

Researchers at Wake Forest School of Medicine have discovered and synthesized novel heptapeptides  that target cancerous tissue over-expressing the IL-13R a 2 receptor, a proven clinical target for cancer therapeutics and diagnostics, while sparring healthy, normal tissue.  The heptapeptides selectively bind to  a novel site on the IL-13R a 2 receptor with low-micromolar affinity and are internalized upon binding, providing a unique platform  for developing highly targeted cancer therapeutics and/or diagnostics for indications such as glioblastoma multiforme, head and neck, pancreatic, ovarian and prostate cancer. Recently concluded in vivo  studies show promising results (non-disclosed data).

Commercial opportunities  

Additional information is available upon request.

Status

Patent Pending

Licensing Contact

Camilla P. Hansen, Ph.D.
Licensing Analyst
Email: chansen@wakehealth.edu
Phone: 336-716-3729

Novel Cytotoxins that Selectively Target and Kill Cancer Cells In Vivo 

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INVENTORS:  Dr. Waldemar Debinski, Jill Wykosky, Denise Gibo

Researchers at Wake Forest School of Medicine have developed novel potent cytotoxins  based on a platform of the tumor suppressor protein ephrinA1 as a targeting delivery protein. The cytotoxins have been tested in vivo against human Glioblastoma multiforme (GBM) cells and in vitro against GBM, breast and prostate cancer cells, all of which over-express the EphA2 receptors. The cytotoxic conjugates selectively kill these cancer cells while sparing normal cells and are excellent candidates for developing targeted therapeutics for various solid tumor cancers, such as GBM, head, neck, pancreatic, ovarian and prostate cancers.

Technology Highlights

• EphrinA1-derived cytotoxins result in 56% tumor reduction in mice harboring human GBM xenograft tumors with no observed toxicity.
• Cytotoxins potently bind to, internalize and kill GBM, prostate and breast cancer cells in vitro with IC₅₀ in the 10^-11 M range.
• Cytotoxins are specific for cancer cells over-expressing the EphA2 receptor and do not target normal cells.  

Unique Possibilities

• The cytotoxins selectively target cells over-expressing EphA2 in solid tumors, resulting in highly targeted drug delivery for various cancers.
• Both EphA2 and IL-13Ra2 targeted cytotoxins potently kill human GBM cells, and a combinatorial therapeutic scheme targeting the EphA2, IL-13Ra2 and Fra-1 proteins, which are over-expressed in at least 95% of GBM, may be effective in all GBM patients. 

Additional information

• Wykosky et al. Mol Cancer Ther 2007; 6(12), 3208-3218.
• Wykosky et al. Clin Cancer Res 2008; 14(1), 199-208.
• US Patent application 12/201,662.

Status

Patents pending

Licensing Contact

Camilla P. Hansen, Ph.D.
Licensing Analyst
Email: chansen@wakehealth.edu
Phone: 336-716-3729

Acellular animal vaccine for Bordetella bronchiseptica mediated respiratory infections 

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INVENTORS: Dr. Rajendar K. Deora, Meenu Mishra, and Neelima Sukumar

Background

The bacterium Bordetella bronchiseptica causes respiratory diseases in various animals, such as swine, dogs, cats, sheep, guinea pigs, rabbits, mice, and rats. In year 2000, respiratory disease due to B. bronchiseptica was the greatest cause of mortality in swine, and the annual economic impact of B. bronchiseptica mediated porcine respiratory disease in the U.S. alone is estimated to be at least $57M. B. bronchiseptica is also capable of infecting immunocompromised humans, e.g. AIDS and cystic fibrosis patients. 

Commercially available B. bronchiseptica vaccines include live, attenuated, heat-killed, or genetically modified bacteria, all of which are associated with problems such as persistence of vaccine strain in the host, retention of some of the virulence characteristics and poor induction of antibody response and protective immunity. In contrast, the acellular vaccine developed at Wake Forest School of Medicine can efficiently elicit protective immune responses without the risk of subsequent infection by the vaccine strain and disease. 

Invention

Researchers at Wake Forest School of Medicine have developed, manufactured and tested an acellular B. bronchiseptica vaccine comprised of the immunogenic BcfA (Bordetella colonization factor A) protein, which with remarkable efficacy establishes protective immunity in vivo against Bordetellae infections. Proof of concept has been established in an in vivo mouse model, and both passive and active immunization have been shown to induce complete protection from bordetellosis, greatly decreased bacterial burden, high antibody titers and markedly reduced pulmonary injury.

Highlights

• Vaccine does not contain whole-cell bacteria, which eliminates the risk of infection by vaccine strain in the host and subsequent disease or zoonosis.
• Vaccine is cost-effectively produced by using recombinant DNA techniques.
• Vaccine is highly potent and targets multiple animal species of B. bronchiseptica strains.
• BcfA protein can be incorporated into a multivalent vaccine, which gives prospects of obtaining greater efficacy and broader protection.

Additional Information

• Patent pending: PCT/US2008/012051
• Sukumar N. et al. Infection and Immunity, 2009, 77(2), p 885-895

Licensing Contact

Camilla P. Hansen, Ph.D.
Licensing Analyst
Email: chansen@wakehealth.edu
Phone: 336-716-3729

A Flagellin-Based Vaccine Technology has created an array of vaccine opportunities 

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Overview

Researchers at Wake Forest School of Medicine have developed, manufactured and tested a number of new vaccines based on a platform of flagellin as an adjuvant and carrier of a range of protein antigens.  Flagellin fusion protein vaccines for plague (federal government grant opportunity), for Pseudomonas aeruginosa (>$1.5B market), for cancer (>$500M market) and for pneumococcus (>$3B market) efficiently elicit significant protective immune responses in animal models and are simple to make using recombinant DNA techniques.  Recently, a program to develop vaccines against drugs of abuse using flagellin as a platform has also been initiated (>$1B market).

 Vaccine Companies can greatly benefit from licensing any of these available fusion protein vaccines. The new approach of using the proven adjuvant flagellin as an antigen carrier provides highly potent and cost-effective vaccines and is a versatile platform for developing multiple preventive and therapeutic. In addition, a long-term research collaboration may be established.

Plague vaccine (Patent pending)
INVENTORS: Dr. Steven Mizel and Anna N. Honko

Pneumonic plague is a rapidly progressing disease with a mortality rate approaching 100%. To date, there is no licensed vaccine for plague that is effective against the pneumonic form of the disease.  Our plague vaccine is a safe alternative using a fusion protein which comprises flagellin and the F1- and V-antigens of Yersinia pestis.
Highlights:

• Phase 1 clinical trial will commence in 2012.
• Vaccine is equally effective when given intranasally or intramuscularly and does not elicit any adverse reactions, providing multiple safe routes of administration.
• Vaccine elicits sterile immunity in mice challenged with Y. pestis, i.e. the vaccine promotes complete bacterial clearance.
• Vaccine is dramatically more potent than other plague vaccines, i.e. less vaccine is required to elicit a protective immune response, resulting in cost-effective treatment and production.
• GMP manufactured vaccine has a stability of over 10 months at 4°C, providing a shelf-stable vaccine.

Pseudomonas aeruginosa vaccine (Patent pending)
INVENTORS: Dr. Steven Mizel, Dr. Daniel J Wozniak and Dr. Eric T. Weimer

There is currently no approved vaccine for Pseudomonas aeruginosa, a major cause of morbidity and mortality in Cystic Fibrosis patients and ventilated patients. Our vaccine targets this unmet need by producing a robust immune response using a fusion protein of flagellin and the OprI and OprF antigens.
Highlights:

• Vaccine produces a protective immune response in young African green monkeys and a dramatically enhanced P. aeruginosa clearance in mice with no lung damage.
• Multivalency of the vaccine creates a synergistic effect, giving an improved immunogenic response and better vaccine coverage compared to other P. aeruginosa vaccines in development.
• Vaccine is highly potent, resulting in efficacious low-dose vaccine formulations that are cost-effective to produce.

Cancer vaccine (Patent pending)
INVENTOR: Dr. Steven Mizel

The cancer vaccine market is a growing market with great opportunities for entry. Approximately 1.5 million Americans are being diagnosed with cancer annually, and the annual overall cost of the disease is estimated to be $230B. Still, an efficient treatment strategy is non-existing for many types of cancers. Our flagellin-based vaccine technology is a potential platform technology that may provide a preventive or treatment option for many of these cancers.
Highlights:

• Breast cancer vaccine, consisting of a fusion protein of flagellin and the Fra-1 antigen, elicits reduced tumor growth in mice.
• Vaccine is selective for breast cancer cells and not invasive, as compared to standard therapy such as surgery, radiation therapy and chemotherapy, which may lead to safer cancer treatment strategies.
• Any cancer antigen can be incorporated into the flagellin fusion protein, giving prospects of developing various cancer vaccine treatments and having a substantial market share.
• On-going research at Wake Forest is examining the effect of incorporating other cancer antigens into the fusion protein vaccine.

Pneumococcal vaccine (Patent pending)
INVENTORS: Dr. Steven Mizel and Dr. Sean Reid

Current vaccines only cover 85-90 % of pneumococcal serotypes responsible for pneumococcal diseases, and diseases caused by serotypes not covered by the available vaccines are on the rise. In fact, each year there are an estimated 175,000 hospitalized cases of pneumococcal pneumonia in the US alone. Our pneumococcal vaccine consisting of a fusion protein of flagellin and various pspA antigens is likely to have greater breadth of protection than the existing vaccines, resulting in better prevention of disease. Currently, the vaccine has been observed to induce a robust immune response in mice.

Drugs of abuse vaccine (Patent pending)
INVENTOR: Steven Mizel

Drug abuse is a global health problem. In the US alone, abuse of illicit drugs affects 9 % of the population and nicotine addiction affects 20 % of the population. Vaccine therapy has emerged as a promising tool for combating drug abuse. However, current strategies need a large number of immunizations, large amounts of material and result in rapid decline in antibody titers. In contrast, a vaccine comprised of a drug-flagellin conjugate may promote long-lasting high levels of antibody production with small amounts of material, due to the powerful adjuvant activity of flagellin. Early preclinical work has been initiated at WFUHS to evaluate the effect of flagellin-based vaccines for drugs of abuse.

Additional information

• US20080220011A1: Use of Flagellin in Tumor Immunotherapy
• US20080124361A1: Use Of Flagellin In The Immunotherapy Of Yersinia Pestis
• Mizel SB et al. Flagellin-F1-V fusion protein is an effective plague vaccine in mice and two species of nonhuman primates. Clin Vaccine Immunol. 2009 Jan: 16(1):21-8.
• Weimer ET et al. Immunization of young African green monkeys with OprF epitope 8-OprI-type A- and B-flagellin fusion proteins promotes the production of protective antibodies against nonmucoid Pseudomonas aeruginosa. Vaccine. 2009 Sep 8 (Epub ahead of print).
• Weimer ET et al. A fusion protein vaccine containing OprF epitope 8, OprI, and type A and B flagellins promotes enhanced clearance of nonmucoid Pseudomonas aeruginosa. Infect Immun. 2009 Jun;77(6):2356-66.

Licensing contact

Camilla P. Hansen, Ph.D.
Licensing Analyst
Email: chansen@wakehealth.edu
Phone: 336-716-3729

Carnosine Improves Cardiac Function: Treating Heart Failure

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Novel Cytotoxic Compounds

Researchers at Wake Forest University (WFU), the National Cancer Institute (NCI) and the University of New Hampshire have developed a novel class of anti-tumor compounds that have been tested in vivo against human tumor cells.
Unpublished efficacy, pharmacokinetic and toxicity tests have been performed in vivo.  Hollow fiber animal studies with viable human tumor cells inserted into mice were performed by the NCI’s Rapid Access to Intervention Development (RAID) program.  Twelve different human tumor cell lines were implanted into living mice both intraperitoneally (IP) and subcutaneously and allowed to form viable cell masses.  The compound was administered IP at two dose levels.

• IP: Over ½ of the human tumor cell lines were reduced by 50% or more
• Three human tumor cell lines were completely killed in vivo: lung, colon and glioma

Pharmacokinetic data includes plasma absorption and clearance after subcutaneous, intraperitoneal and intravenous administration.  A toxicity range-finding protocol has been preformed resulting in an optimal animal model for further toxicity testing.
In vitro assays have also been performed.  Efficacy was demonstrated against human and mouse bladder cancer cell lines with an IC₅₀ of 4.6 micromol/liter.

Publications detailing the in vitro data are available upon request.  Complete in vivo data is available under an appropriate confidentiality agreement.

Covered by United States Patent 6,589,966, “Cytotoxic metal chelators and methods for making and using same”. 

Novel Insulin-Responsive Glucose Transporter

Executive Summary

Researchers at Wake Forest University have identified, cloned and expressed a novel, insulin-responsive glucose transporter that is located in a Type II Diabetes linked region of chromosome 20: Glut10.  Polymorphisms have been discovered which are significantly associated with incidence of Type II Diabetes.  In the United States and Europe, 47.3 million people have Type II Diabetes.  These individuals do not need insulin injections.  They are able to produce insulin, but their bodies do not use the insulin properly to remove glucose from the body. 
Glut10 and its polymorphisms represent an exciting new target for therapeutic compounds which will address Type II Diabetes.  Screening compounds against the polymorphisms as well as the wild-type should allow for the discovery of new compounds that increase the total glucose transport in people with Type II Diabetes.

Publications

Dawson, et al “Sequence & Functional Analysis of GLUT10: A glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1” (copy available upon request)

Intellectual Property

United States Patent 6,849,728 “GLUT10: a glucose transporter in the type 2 diabetes linked region of chromosome 20Q12-13.1”

Unique Platinum-based Chemotherapeutics to Treat Drug Resistant Tumors 

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INVENTOR: Ulrich Bierbach

Researchers in the Department of Chemistry at Wake Forest University have developed a new class of platinum-acridine chemotherapeutics. Because of their novel drug–DNA interaction, these compounds exhibit a potent cytotoxic response in a tumor cell line previously shown to be difficult to kill by standard therapies (including platinum-based drugs). In addition, these compounds significantly slowed the progression of this aggressive form of cancer in vivo.

Unique Mechanism of Action

• Novel platinum-based antineoplastics both bind to DNA at the platinum site as well as intercalate via the acridine moiety
• Exhibits a unique pharmaceutical activity by rapidly binding and disrupting DNA in regions not targeted by cisplatin 
• These compounds do not induce cross-links (as seen in other platinumbased chemotherapeutics) and do not require hydrolytic activation prior to binding to their pharmacological target

High Efficacy

• Novel platinum-based drugs were 10-fold more cytotoxic than cisplatin in H460 cell proliferation assays with IC50 values in the nanomolar range
• The new analogue significantly reduces H460 tumor growth in a xenograft model at doses an order of magnitude lower than those typically administered for cisplatin

Additional Information

• J Med Chem. 2008, 51, 7574–7580
• SciBX Cover Story “Expanding Platinum’s Potential”

Licensing Contact

Stephen J. Susalka, Ph.D.
Assistant Director
Email: ssusalka@wakehealth.edu
Phone: (336) 716-3729

Preventing Cell Death

Researchers at Wake Forest University (WFU) have demonstrated in vivo compounds and methods for preventing cellular death. The compounds and methods have been shown to be effective in lessening the amount of cell death when applied to damaged cells. Possible applications include topical forumulations for the treatment of damaged skin, stroke, spinal injury and retinal damage.

More specifically research has shown that heat shock proteins, especially Heat Shock Protein 70, can be effective in preventing cell damage or in preventing the death of previously damaged cells.

Intellectual Property
U.S. Patent 5,348,945

Key Publications
Yu Q. et al. Retinal uptake of intravitreally injected Hsc/Hsp70 and its effect on susceptibility to light damage. Mol Vis. 2001 Mar 7;7:48-56.

For information about licensing contact
Dean Stell (dstell@wakehealth.edu)
Phone: 336-716-3729