“DGRs offer a competitive advantage to many bacteria and bacteriophages in nature, as they allow them to quickly adapt and survive under challenging conditions,” said Dr. Miller. “The typical DGR can theoretically generate more than 10 trillion diverse genetic sequences at select sites in target genes. Thus, DGRs can potentially be used to generate molecular diversity for protein engineering applications that are not practical with currently available technologies.

“Our new publication not only describes new mechanistic information about DGRs, but it also offers a blueprint for the use of DGRs in protein engineering,” Dr. Miller concluded.

AvidBiotics, which has worldwide rights to the DGR technology, is working  to apply this technology to both its product development platforms, as well as leverage its value through collaborations and licensing arrangements.

The Diversity Generating Retro-element (DGR) System is well suited for a variety of protein engineering applications, offering such advantages as:

• No need for repeated cycles of cloning and transformation as in phage display
• Mutagenesis “homes in” on specific amino acid positions of interest, not random ones, in the target protein
• A host bacterium does all the diversification “naturally”
• Diversification can be serially and cumulatively repeated without degeneration of the genetic mechanism or the protein scaffold

In addition to providing a tool for use with AvidBiotics’ targeted antibacterial and antiviral/anti-cancer product platforms, the DGR system could be applied to

• Protein engineering by optimizing or modifying particular sites of interest, applicable to any scaffold
• Generation of highly specific protein diagnostics to detect most any “analyte”
• Generation of reagents for product recovery processes
• Creation of kits and reagents for research laboratory use in protein engineering

About AvidBiotics

AvidBiotics is a developer of novel, non-antibody proteins as targeted therapeutics against bacteria, viral infections and cancers. The scaffolds of AvidBiotics’ proteins exhibit functional potency, e.g. killing, exceeding that of antibodies.  AvidBiotics has two proprietary product platforms. The first is a  new class of tailorable, targeted bactericidal agents for use in the treatment or prevention of specific bacterial infections. The second specifically flags virus-infected or cancerous cells for enhanced destruction by the Natural Killer and T cells of the potent innate immunity system.  AvidBiotics focuses on human therapeutic applications of its technologies, both on its own and in partnership with governmental agencies and research institutions, while taking advantage of further near-term collaborative opportunities offered by specific applications of its products and technology platforms in areas such as food safety, biodefense and animal husbandry.

South San Francisco, CA: A novel antibacterial protein targeted against E. coli O157:H7 may offer a way to prevent or treat serious food-borne bacterial infections, as demonstrated in a study published in the December issue of Antimicrobial Agents and Chemotherapy. Results in an animal model of E. coli infection showed that the orally administered protein, developed by AvidBiotics, Inc., could prevent or treat E. coli O157:H7-induced diarrhea and intestinal inflammation when administered either on a preventative basis or after the onset of diarrhea. Moreover, animals treated with the protein also carried and shed fewer of the E. coli O157:H7 bacteria in their feces.

“E. coli O157:H7 contamination of foods like ground meats or produce is a well-publicized public health problem, with life-threatening infection outbreaks reported around the world in recent years,” said Dean Scholl, Ph.D., lead author of the publication.  “Antibiotics are contraindicated for patients infected with enterohemorrhagic E. coli (EHEC) strains like O157:H7, because many of those drugs induce the bacteria to produce and release harmful toxins. Anti-diarrheal medications also do not benefit infected patients, as they cause the bacteria to be retained in the intestines, leading to greater toxin exposure. Thus the successful development of treatments that can prevent infection or limit symptoms and disease duration and the possible further spread of harmful bacteria without increasing toxin release could benefit both individual patients and affected communities.”

The study published by Dr. Scholl and his collaborators at AvidBiotics and Brigham and Women’s Hospital/Harvard Medical School assessed AvidBiotics’ anti-E. coli O157  protein, termed an Avidocin™ protein, in a rabbit model of infection and reported that:

• The Avidocin protein remained active within the treated animals’ intestinal tract for at least 24 hours post administration.
• When given shortly after the animals were infected with E. coli O157:H7 but before they developed active disease, the Avidocin protein inhibited bacterial colonization and/or the symptoms of infection. Animals that received the highest dose of protein studied did not develop diarrhea at any time during the experiment. In contrast, animals given buffer alone developed typical diarrhea within 1-2 days after infection, which worsened by the 3rd day of the study.
• Analyses of colon tissue showed less severe intestinal inflammation in Avidocin protein-treated animals compared to controls. Avidocin protein administration also greatly reduced the number of E. coli O157:H7 recovered from the intestine and the stool of treated animals.
• When the anti-E. coli O157:H7 Avidocin protein was administered to infected animals already exhibiting disease symptoms, the existing diarrhea began to resolve in treated animals compared to animals treated with placebo. This reduction in diarrhea persisted until the experiment was terminated, 9 days post infection, at which time the feces of the treated animals appeared closer to feces from uninfected animals than the still largely liquid stool of the control animals. Thus, even after the onset of diarrhea in E. coli O157:H7-infected animals, administration of the anti-E. coli O157:H7 Avidocin protein could still mitigate the effects of infection.

“These findings suggest that an Avidocin protein targeted against E. coli O157:H7 offers promise for both the prevention and treatment of infection by this important enteric pathogen,” concluded Dr. Scholl. “Moreover, this agent provides several significant advantages over conventional antibiotics, including a lack of drug-induced shiga toxin production and unintended collateral damage to normal intestinal bacterial populations. Additionally those rare variants of E. coli O157:H7 that  emerge resistant to the anti-E. coli O157:H7 Avidocin protein are likely to have compromised virulence, or disease-causing properties.”

About the Avidocin™ Protein Platform

AvidBiotics genetically engineers Avidocin proteins from R-type pyocins, antibacterial proteins produced by some Pseudomonas aeruginosa strains. These proteins specifically kill bacteria by binding to the bacterial cell and punching a hole in the cell envelope, causing membrane depolarization and ultimately cell death. AvidBiotics has previously demonstrated that Avidocin™ proteins can be engineered to recognize and kill in a highly targeted and specific manner a variety of bacteria, including E. coli, Salmonella, Shigella, Clostridium difficile, and Yersinia pestis (the bacterium that causes plague), thus serving as a platform for the production of numerous highly specific antibacterial agents.

AvidBiotics is also currently developing Avidocin™ proteins against Acinetobacter, a bacterium associated with serious, often broadly antibiotic-resistant infections in Intensive Care Units and those incurred by U.S. military deployed in Iraq and Afghanistan. In addition to the human health care uses of the Avidocin™ technology, AvidBiotics is collaborating with food safety and hygiene company EcoLab to develop antibacterial proteins for use against E. coli O157:H7 in meat processing.

About AvidBiotics

AvidBiotics is a developer of novel, non-antibody proteins as targeted therapeutics against bacteria, viral infections and cancers. The scaffolds of AvidBiotics’ proteins exhibit functional potency, e.g. killing, exceeding that of antibodies.  AvidBiotics has two proprietary product platforms. The first is this new class of tailorable, targeted bactericidal agents for use in the treatment or prevention of specific bacterial infections. The second specifically flags virus-infected or cancerous cells for enhanced destruction by the Natural Killer and T cells of the potent innate immunity system. AvidBiotics focuses on human therapeutic applications of its technologies, both on its own and in partnership with governmental agencies and research institutions, while taking advantage of further near-term collaborative opportunities offered by specific applications of its products and technology platforms in areas such as food safety, biodefense and animal husbandry.

Just in time for the holidays, researchers at Harvard Medical School’s Brigham and Women’s Hospital and AvidBiotics said Monday that the South San Francisco-based company’s Avidocin proteins could prevent and treat E. coli-related diarrhea and intestinal inflammation in animals.

If the Thanksgiving table conversation turns staid, you can find the results of the study in the December issue of the journal Antimicrobial Agents and Chemotherapy.

I spoke with Jim Knighton, co-founder and president of the “nine-people-and-a-dog” company, about the company’s food safety program, a key partnership and the new study.

“Recent discoveries regarding the importance of the human microbiota in human health and disease emphasize the need for narrow-spectrum antibacterial agents that avoid the collateral damage of broad-spectrum antibiotics,” said David Martin, M.D., AvidBiotics’ chief executive officer. “Avidocin™ proteins represent a new class of highly targeted bactericidal agents that avoid the problems associated with antibiotic overuse and abuse and offer opportunities for both the prevention and treatment of bacterial diseases.”

The new grants include:

• An R21 grant to fund the generation of a portfolio of Avidocin™ proteins , targeting foodborne bacteria causing gastrointestinal disease.
• An SBIR Phase 1 grant to fund the creation, evaluation and preclinical development of an engineered Avidocin™ protein targeting specifically Acinetobacter, a bacterium associated with serious, often broadly antibiotic-resistant infections in Intensive Care Units and incurred by U.S. military deployed in Iraq and Afghanistan.

This new funding adds to three other active grants received previously by AvidBiotics:

• A SBIR Phase 2 grant for the non-clinical development of Avidocin™ proteins against plague; this grant follows a previously completed Phase 1 grant for plague.
• A SBIR Phase 1 grant for development of Avidocin™ proteins against E. coli 0157:H7, an important cause of food borne bloody diarrhea that in some children results in kidney failure.
• A SBIR Phase 1 grant to develop targeted, soluble MICA molecules to recruit innate immunity cells to kill LCM and Yellow Fever Virus infected cells; this grant explores applications of AvidBiotics Micacide™ technology for the targeted killing of virus infected cells.

“This continued support from NIH validates the innovative nature and broad applicability of our technology and approach to the treatment of serious, often antibiotic-resistant infectious diseases,” said James L. Knighton, AvidBiotics’ president. “In the four years since AvidBiotics’ founding, we have received approximately $4 million in NIH funding covering aspects of each of the company’s three technologies: Avidocin™ proteins, Micacide™ proteins, and our technology for protein diversity generation, which can be applied to both product platforms.”

About AvidBiotics’ Technology

AvidBiotics is developing two proprietary platforms for the generation of non-antibody proteins against infectious diseases and cancers: Avidocin™ proteins and Micacide™ proteins.

Avidocin™ proteins are highly targeted, non-toxic, non-antibody proteins that specifically bind to a targeted bacterium and kill it by punching a hole. Such narrow-spectrum antibacterial killing avoids the collateral damage to beneficial bacteria such as that caused by broad-spectrum antibiotic use. Avidocin™ proteins kill antibiotic-resistant pathogens and do not promote the spread of multi-drug resistance, nor do they cause the release of exotoxins upon killing bacteria. Avidocin™ proteins have both prophylactic and therapeutic potential, and possible applications exist both within and outside of human health, including applications in human conditions like obesity, as well as in food safety, animal husbandry, biodefense and environmental management. AvidBiotics is currently developing an Avidocin™ protein approach against E. coli 0157:H7 for use in meat processing in collaboration with EcoLab, Inc.

Micacide™ proteins mimic natural immune targeting mechanisms to enhance the killing of virus-infected or cancerous cells by the innate immune system. Micacide proteins bind to specific targeted markers on the surface of infected or cancerous cells where they flag the cells for destruction by the innate immune system.

About AvidBiotics

AvidBiotics is a privately held developer of novel, non-antibody proteins as targeted therapeutics against infectious organisms and cancers. The company is focusing its own development efforts on human therapeutics, including Avidocin™ proteins against C. difficile GI tract infections and recurrent E. coli urinary tract infections, while taking advantage of near-term collaborative opportunities offered by other applications of its products and technology platforms including non-core applications in such areas as food safety, cleantech and biodefense. For more information on AvidBiotics, please visit our website at http://www.avidbiotics.com.