Using mouse monoclonal antibodies (mAbs) raised against the mediators of quorum sensing (QS), the Auto-Inducing Peptides (AIPs), researchers at The Scripps Research Institute (TSRI) have demonstrated that S. aureus infections can be prevented in animal challenge models. This approach, known as quorum quenching (QQ) is unique in at least two significant ways: first, rather than eliminating bacteria associated with infection, the QQ approach modulates the global virulence of the invading pathogens, thus allowing the bacteria to be cleared by the host's immune system;second, the AIPs are not essential for the growth of the bacteria per se, so the selective pressure for the generation of resistance should be greatly reduced. Sorrento Therapeutics, Inc. (STI) has licensed QQ technology from TSRI. STI will humanize anti-AIP mouse mAbs and isolate a fully human anti-AIP2 antibody from its proprietary antibody library then combine them into the product candidate STI-001, a single tetraspecific antibody-like molecule, to prevent S. aureus infections through QQ. We here outline experiments for the development and validation of STI-001, an IgG-like molecule that would virtually eliminate morbidity and mortality when used in prophylactic settings. In Phase I, the murine anti-AIP mAbs 15B4 and 24H11 will be humanized, and characterized in vitro as well as in animal models. In addition, a human mAb against the remaining AIP not covered by the TSRI mAbs, namely AIP-2, will be identified from STI's antibody library and also generated. The anti-AIP mAbs will be combined into a single IgG-like molecule, namely product candidate STI-001, evaluated in vitro as well as in vivo and taken into STTR Phase II. In Phase II, STI-001 will be produced in large scale for testing in additional animal models and preclinical development, e.g. pharmacokinetic (PK), -dynamic (PD) and toxicological analyses as well as dosing studies. We will also generate a master cell bank and prepare/initiate IND filling. This immunotherapeutic approach of sequestering the mediators of bacterial virulence in order to prevent infection will provide a much needed alternative to traditional antibiotic-based treatments to ameliorate S. aureus infections, including those resistant to antibiotics.

Public Health Relevance

Despite the approval of numerous antibiotics over the past 60 years, bacterial disease remains a serious public health problem. Many of the most harmful bacteria, including Staphylococcus aureus, develop resistance to approved antibiotics (so-called superbugs) causing people with drug-resistant infections to become seriously ill or die. Sorrento Therapeutics Inc. is working on the development of a new way to prevent and even treat bacterial disease in a manner that we believe will be much more effective than using current antibiotic therapy and that will be unaffected by existing resistances.

Agency
National Institute of Health (NIH)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
4R42AI098182-03
Application #
8851014
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xu, Zuoyu
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sorrento Therapeutics, Inc.
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
Zhu, Jie; Kaufmann, Gunnar F (2013) Quo vadis quorum quenching? Curr Opin Pharmacol 13:688-98